Antiaging Strategies and Remedies: A Landscape of Research Progress and Promise.

Introduction

The growing social and economic concern of an aging world population has catapulted aging-related research into the spotlight. Over the past decades, progress in medicine has powered a significant increase in life expectancy worldwide. More than 2 billion individuals are expected to be older than the age of 60 by 2050. 1 This demographic milepost will come with a major increase in age-related diseases, such as Alzheimer’s disease, cardiovascular disorders, and cancer, which effectively double in incidence every 5 years passing the age of 60. 2 The relationship between aging and these diseases has triggered fundamental research into the aging mechanisms and approaches to attenuate its effect.

The efforts to understand and prevent the effects of aging date back centuries, so antiaging research has a long history ( Figure 1 ). In ancient times many cultures developed traditional remedies and practices aimed at promoting longevity and slowing the aging process. For example, ancient Chinese medicine includes herbal remedies and acupuncture techniques designed to promote health and longevity. In the 16th century Italian physician and philosopher Girolamo Cardano wrote a treatise on aging and longevity, in which he discussed the physical and mental changes that occur with age and proposed strategies for promoting health and extending lifespan. 3 In the 19th century, French physiologist Claude Bernard proposed that aging is caused by changes in the internal ambiance of the body, including changes in metabolism and the accumulation of toxins. 4 In the early 20th century, scientists began to study the effects of diet and lifestyle on aging, with researchers like Elie Metchnikoff proposing that the gut microbiome plays a role in aging. 5 Also, Denham Harman proposed the free radical theory of aging, suggesting aging is caused by damage to cells and tissues by unstable molecules called free radicals. 6

An early step in the field of aging exploration has been the observation that restriction of caloric intake increases lifespan, first demonstrated in mice and rats 9 and later in other species as well, including primates. 58 , 59 Moreover, it was detected that dietary restrictions enhanced not only the lifetime but also the healthspan, suppressing the development of age-related diseases. 60 A concept emerged that correlation exists between lifespan and healthspan, described as the portion of lifespan free from disease. 61 A mutation accumulation theory that aging is a result of decline in the power of natural selection after reproduction was proposed in 1952. 11 Over 30 years later, landmark research in the nematode Caenorhabditis elegans demonstrated that the mutant nematode strain exhibits a 40–60% extended lifespan, showing that a single gene, the AGE-1 gene, can control the lifespan of an organism. 22

The close link between telomeres and aging originates in the discovery of a unique structure at the last portions of the Zea mays and Drosophila melanogaster chromosomes, hypothesized to play a significant role in preventing chromosome end fusion. 8 , 62 In the early 1960s, Hayflick noted that human cells in tissue culture cease dividing after a certain number of cell divisions by a process termed replicative senescence. 13 , 14 It was shown later that human fetal cells exhibited finite replication potential of 50–60 doublings, labeled as replicative senescence or the “Hayflick limit”. 13 , 14 The link between the ending of cell division and replication of telomeres was revealed in the early 1970s. 15 , 16 It was established that telomere attrition takes place in parallel with the replication lifespan of human primary cells, demonstrating that shortened telomeres cause the Hayflick limit. 63 It took nearly two decades for the suggested causative relationship between replication senescence and telomere shortening to be established. 64 , 65 The aging of cells could be associated with alterations in telomere length on genomic DNA. 66 , 67 Further on, via animal models, the function of telomeres in aging was authenticated and identified as an essential signaling pathway guiding the aging process. 68 Telomere dysfunction was shown to accelerate signs and symptoms of aging. 69 , 70 Later, transcriptomic studies revealed the p53 aging pathway promoting apoptosis, thus integrating three previously distinct theories of aging: genotoxicity (telomere dysfunction), oxidative damage, and mitochondrial decay. 41 , 71 , 72 Reactivation of endogenous telomerase, an enzyme that could extend telomere sequence, was demonstrated to reverse advanced premature aging in mice. 42 Of note, adenoviral delivery of telomerase in aged mice was demonstrated to enhance cardiac function after acute myocardial infarction, improve muscle coordination and kidney and liver performance, reduce insulin resistance and subcutaneous fat reduction, increase bone mineral density, and extend life expectancy without triggering a growth in cancer frequency. 51 , 68

In the early 1990s, the potential of human growth hormone (hGH) as an antiaging agent acting to increase lean body mass, decrease adipose tissue mass, and increase bone mineral density was reported. 23 hGH supplements became available, sparking controversy questioning their safety and effectiveness. Later on, aging research focused on the genetic pathways of aging, revealing a complex system of intracellular signaling pathways and higher-order processes. 61 , 73

Throughout the 1990s, researchers identified genes linked to aging, including the SIRT1 gene. Substantial attention was given to sirtuins after it was reported that overexpression of the SIR2 gene can prolong yeast lifespan by as much as 70%. 74 In the 2000s, advances in biotechnology and genetics led to the development of new antiaging therapies, including stem cell therapy, gene therapy, and telomerase activation. 32 , 33 , 35 , 37 , 38 In the 2010s and 2020s, the focus of antiaging research shifted toward advanced understanding of the mechanisms of aging and developing interventions that can slow or reverse the aging process, with ongoing studies exploring a range of potential interventions, including senolytics (drugs that clear out senescent cells), metformin (a diabetes drug that may have antiaging properties), and various forms of gene therapy. 41 , 42 , 46 − 57 Advances in gene editing technology, such as CRISPR/Cas9, allow for more precise manipulation of genes involved in the aging process. 75 It is important to note that while antiaging research has made significant strides over the years, most of this research is still conducted in non-human systems and there is still much that is not yet understood about the aging process and how to effectively prevent or reverse its effects.

The antiaging research area is still moderate in size, by an order of magnitude less for the number of related publications relative to more advanced areas, including those focused specifically on major age-associated diseases such as cancer, cardiovascular, and Alzheimer’s disease. However, understanding that advanced age is the major risk factor for all of these disorders has brought the rapidly growing field of aging research to the forefront.

The research focused on aging mechanisms and attributes, and the antiaging strategies and medical interventions, has undergone a steady growth, especially intense in the past decade ( Figure 2 ). The desire for enjoying a lifespan in a healthy, youthful condition is a universal human appeal. A characteristic feature of many recent antiaging strategies is that they are focused on prevention, trying to avoid disease via health preservation rather than cure disease after it occurs. Its basic approach is replacement therapy. 76 Since appropriate knowledge and expertise allowing to slow or halt the homeostatic decline in basic informational, regulatory, and protective molecules upon aging has not yet been established, replacement of those products such as hormones, cofactors, antioxidants, and others is routinely employed. Such a proactive approach meant to slow down or escape the development of age-associated disease is more rational than a reactive, symptomatic approach. 76

In this paper, we review the advances in the research on antiaging strategies and perspectives. We examine data from the CAS Content Collection, 77 the largest human-compiled collection of published scientific information, and analyze the publication landscape of recent research in this area in an effort to provide insights into the research advances and developments. We review the current concepts related to the major antiaging approaches to combat aging on the molecular, cellular, and organismic level. We further assess the state-of-the-art antiaging strategies and explore their correlations with age-related diseases, based on the data from the CAS Content Collection. Well-known and currently examined antiaging agents have been specified. Finally, we inspect clinical applications of antiaging products with their development pipelines.

The objective of this review is to provide a broad overview of the evolving landscape of current knowledge on preventive strategies and treatments in the field of aging, to outline challenges and evaluate growth opportunities, in order to further efforts to solve the problems that remain. The novelty and merit of the article stem from the extensive, wide-ranging coverage of the most up-to-date scientific information accumulated in the CAS Content Collection allowing unique, unmatched breadth of landscape analysis and in-depth insights.

Antiaging Strategies

Aging is typified by a gradual loss of physiological fitness, leading to deteriorated functions and enhanced vulnerability. Numerous age-related factors and attributes have been identified as hallmarks of aging, and the potential mechanisms of aging are extensively examined. At the molecular level, aging attributes include DNA damage, epigenetic modifications, telomere shortening, protein aggregation, and accumulation of aberrant mitochondria and lysosomes. 78 − 80 At the cellular and organismic level, aging hallmarks comprise cellular senescence, stem cell exhaustion, impaired nutrient sensing, and chronic low-level inflammation. 78 − 80

The modern concept of antiaging strategies is focused on promoting healthy aging and extending healthy lifespan. Rather than trying to reverse the aging process, antiaging strategies aim to reduce the risk of age-related diseases and disabilities, maintain physical and cognitive function, and enhance overall well-being later in life. 81 , 82 Key features of the modern concept of antiaging strategies include the following:

A focus on prevention: Antiaging strategies are centered on prevention, with an emphasis on reducing the risk of age-related diseases and disabilities before they occur. This may involve lifestyle changes such as healthy eating, exercise, and stress management, as well as preventive medical interventions such as vaccines and screening tests.

An integrated approach: Antiaging strategies recognize that aging is a multidimensional process that affects many aspects of our lives. This may involve interventions that target multiple aspects of aging, such as physical activity to maintain muscle mass and cognitive training to maintain mental function.

A personalized approach: Antiaging strategies are based on the understanding that there is no “one size fits all” approach to promoting healthy aging and that interventions may need to be tailored to individual needs and circumstances. This may involve the use of personalized medicine, genomics, and other technologies to identify individuals at higher risk of age-related diseases and tailor interventions accordingly.

An emphasis on quality of life: Antiaging strategies are focused on promoting not just longevity but also quality of life in later years. This may involve interventions that promote physical and cognitive function, as well as social and emotional well-being.

A multidisciplinary approach: Antiaging strategies involve a wide range of disciplines, including medicine, biology, psychology, sociology, and public health. Researchers and practitioners from these different fields work together to identify effective interventions and promote healthy aging at the individual, community, and societal levels.

A variety of antiaging strategies targeting the hallmarks of aging have been explored largely, including parabiosis (blood exchange), metabolic manipulation, senescent cell elimination, and cellular reprogramming. Most of them are targeted to multiple aging hallmarks ( Figure 3 ).

Parabiosis (Blood Exchange)

Blood transfusion/exchange has been believed to exhibit rejuvenation effect since ancient times. Parabiosis is a procedure of placing young blood into an old animal (heterochronic parabiosis) by joining the circulatory systems of the two animals so that they share their blood circulations. 83 , 84 The procedure has been reported to bring about an antiaging effect by specifically activating molecular signaling pathways in liver, muscle, or neural stem cells of the old parabiont resulting in increased tissue regeneration. 85 , 86 In the search for the physiological background of such rejuvenating effects, certain soluble blood factors have been identified as in part responsible, including the chemokine CCL11, the growth differentiation factor 11 (GDF11), a member of the TGF-β superfamily, and oxytocin. 86 − 89 It has been implied that parabiosis reverses age-related decline by targeting several aging hallmarks including stem cell exhaustion, cellular senescence, altered intercellular communication, and inflammaging ( Figure 3 ). 84 Still, the mechanisms of action of the factors identified as responsible for the rejuvenating effects in parabiosis animal studies remain largely unclear, with many unresolved issues. Further, a study of the lifespans of old and young rat pairs demonstrated that older partners lived for 4–5 months longer than controls, indicating that circulation of young blood might affect longevity. 90 A start-up company, Alkahest (San Carlos, CA, USA), initiated a clinical trial assessing the safety, tolerability, and feasibility of infusion of plasma from young donors to treat patients with mild-to-moderate Alzheimer’s disease. 91 The trials implied that the treatment with young fresh frozen plasma has been safe, well tolerated, and feasible. 92 Certain limitations of the study were the small sample size, short duration, and variation in study design, but the conclusion was that the results demand further examination in larger, double-blinded placebo-controlled clinical trials.

Metabolic Manipulation (mTOR Inhibitors)

The mammalian target of rapamycin (mTOR) signaling pathway has been identified as significant participant of cellular metabolism relating nutrient sensing to critical cellular processes that energize cell growth and proliferation. 93 mTOR belongs to a family of phosphatidylinositol kinase-related kinases, which are known to mediate cellular responses to stress factors such as DNA impairment and nutrient deficiency. In model studies on organisms such as Saccharomyces cerevisiae , Caenorhabditis elegans , and Drosophila melanogaster , mTOR has been identified as a negative regulator of life span. 93 The mTOR is involved in various distinctive aging pathways, such as nutrient sensing deregulation, proteostasis loss, autophagy impairment, mitochondrial dysfunction, cellular senescence, and stem cell function decline. 94 , 95 It has been reported to also manipulate gut microbiota and its metabolites. 96

One of the foremost pharmacological actions prolonging life span in certain model organisms is rapamycin. 93 Rapamycin is a natural product isolated from Streptomyces hygroscopicus , which exhibits antifungal, immunosuppressant, and antitumor proprieties, mediated by the inhibition of its target, mTOR. 97 , 98

Consistent with its central role in cellular metabolism, in synchronizing protein synthesis, energy metabolism, and autophagy, mTOR has been identified as an attractive target to ameliorate age-related pathologies. Inhibition of the mTOR pathway has profound effects on longevity and age-associated phenotypes across a wide variety of organisms. 93 However, the inherent mechanisms are still largely unclear and extensive research is still needed to fill many deficiencies in the available knowledge related to the mTOR function in the context of aging.

Senotherapy

Senotherapy involves development of potential therapeutic agents and approaches to explicitly target cellular senescence, a cell condition associated with aging and age-associated pathologies. 99 There are multiple senotherapeutic strategies including geroprotection which refers to strategies preventing or reversing cell senescence by preventing DNA damage, oxidative stress, proteotoxicity, telomere shortening, and other senescence promoters. 100 Senescence-associated secretory phenotype (SASP) inhibition is another strategy that is achieved with using agents restricting proinflammatory SASP production 101 , 102 such as glucocorticoids, 103 statins (simvastatin), 104 JAK1/2 inhibitors (ruxolitinib), 105 , 106 NF-κB and p38 inhibitors, and IL-1α blockers. Senescent cell elimination is another strategy that utilizes small molecule senolytic agents to transiently disable their survival pathways and antiapoptotic systems. 48 , 107 , 108 Unlike SASP inhibitors, senolytics can be successful following intermittent rather than continuous administration. 109 On the other hand, senescent cell modulation uses a wide range of agents called senomorphics suppressing senescent phenotypes without killing cells. 110 Gene therapy is another approach that edits cells’ genes to enhance their resistance to aging and senile diseases and prolong the lifespan of an organism. 111 , 112 Lastly, the Klotho gene has been identified as a gene involved with aging, 113 so senotherapeutic strategies have been developed to modulate Klotho expression, including administration of exogenous Klotho, Klotho agonists as well as indirect approaches, via regulation of the foodome and gut microbiota. 114

Cellular Reprogramming

Cellular reprogramming includes the conversion of terminally differentiated mature cells into induced pluripotent stem cells (IPSCs). This process involves complete dedifferentiation; i.e., the somatic cell identity has been erased as cells are converted to a pluripotent state. Reprogramming-induced rejuvenation strategy termed epigenetic rejuvenation implicates using a cocktail of four factors known as Yamanaka factors, a finding for which a Nobel prize was awarded in 2012. 43 It was shown that overexpression of four transcription factors (Oct3/4, Sox2, Klf4, and c-Myc, referred to as “OSKM” factors or the “Yamanaka factors”) reorganizes the epigenetic landscape and converts somatic cells to a IPSCs. 115 , 116 The process of rejuvenation by cellular reprogramming results in the amelioration of certain aging hallmarks such as mitochondrial dysfunction, telomere attrition, changes in epigenetic alterations, genomic instability, and senescence. 84

Furthermore, it has been recognized that cellular identity is determined by epigenetic changes rather than by genomic DNA alterations. 117 The process of generating iPSCs has been improved with time and has also been accomplished via chemical induction rather than gene expression. 118 − 120 IPSCs have effectively unlimited regenerative ability and offer the potential for tissue replacement to counteract age-induced decline. Therefore, iPSCs induction offers the potential of directed, personalized regenerative therapy for currently incurable diseases, such as certain neurodegenerative diseases, heart infarction, diabetes, and others. 121 Partial cellular reprogramming in mice has demonstrated promising results in alleviating age-associated symptoms without increasing the risk of cancer. 122

Telomere Reactivation

Telomere shortening takes place during aging and is related to certain age-associated diseases, including osteoarthritis, atherosclerosis, coronary heart disease, and atrial fibrillation. 123 − 125 It has been reported that aging can be impeded by telomerase overexpression; however, that can stimulate tumorigenesis. 126 − 128 Recently, that adverse effect has been eliminated by developing antiaging strategies based on a telomerase activation, telomerase expression activation, and telomerase gene therapy. It has been found that an extract of the plant Astragalus membranaceus , TA-65, is a telomerase activator, which can restore telomere length without provoking cancer and enhance age-related markers, including glucose tolerance, bone health, and skin quality. 129 Further, TERT transcription activator and sex hormones have been reported to be directly engaged in telomerase activation, which avoided telomere shortening and enhanced lifespan. 130 , 131 Reactivation of telomerase expression by using a gene therapy strategy has been reported as a successful approach for aging delay and lifespan extension of mice without cancer incidence. 132

Hormesis

Hormesis is defined as a dose-responsive phenomenon typified by low-dose stimulation and high-dose inhibition. 133 It has been identified as an overcompensation response for mild environmental stress related to the body’s intrinsic ability of self-maintenance and repair. In fact, the beneficial effects of mild stress on aging and longevity have been examined for a long time. 134 The term “hormetins” has been introduced to denote conditions and compounds that can induce health-beneficial physiological hormesis. 135

Beneficial hormetic effects of repeated mild heat stress on aging human cell cultures in terms of their structural and functional integrity have been demonstrated. 136 Other mild stresses have also been reported to defer aging and stimulate longevity in experimental animals. These include mild hyperthermia, irradiation, hypergravity, exercise, and caloric restriction, as well as chemical agents such as heavy metals, pro-oxidants, acetaldehyde, alcohols, and resveratrol. 137 − 140 In experimental animals, mild dietary stress without malnutrition postpones the majority of age-related physiological changes, prevents aging disease, and extends lifespan. 133

An area of interest regarding the dose–response model of hormesis in the brain is newly developing. 141 , 142 Cellular models of neurodegenerative diseases have implied that neurohormesis impacts cognitive performance as well as oxidative stress-modulated neurodegenerative responses. 141 , 142 The brain cells exhibit survival response networks that are regulated by genes involved in preserving cellular homeostasis during stressful conditions (vitagenes). 143 These genes recognize stressful incidents and work toward cell survival under stress conditions. 144

Hormonal Replacement

Hormone levels decline with age, as a result of the reduced gland secretion. 145 Diminished hormone levels are related to decline in bone mineral density, muscle mass, sexual appeal, erectile activity, and intellectual potential. 146 − 149 Therefore, hormone supplementation has been widely applied to help improve the quality of life in the elderly. 150

Perimenopause women suffer from discomforting symptoms such as hot flashes or vaginal dryness, so hormone replacement has been applied to lessen or eliminate them. Estrogens and progesterone have been beneficial in osteoporosis treatment. 151 During the recent decades, compounded bioidentical hormone therapy (cBHT) has become popular. 152 The term bioidentical refers to the chemical structure of menopausal hormone therapy being identical to that of endogenous hormones. Therapies include estriol alone and in combination with estradiol (biest) and estrone (triest), estradiol or estrone alone, progesterone, and androgens. 153 However, evidence of safety issues has progressively accumulated, such as irregularity of cBHT content, potential increase in endometrial cancer risk, lack of bioavailability data, and incomplete adverse event reporting. 153 − 157

Elderly men typically exhibit low testosterone levels which have been associated with certain age-related pathologies. 158 Sarcopenia and osteoporosis are more common in older men. Low plasma testosterone levels have been associated with sarcopenia and osteoporosis, as well as mild cognitive impairment and Alzheimer’s disease. 159 , 160 Therefore, testosterone replacement therapy has been found advantageous as it can augment muscle mass, physical strength, and body-mass index in elderly men. 157 , 161 However, adverse effects of the testosterone therapy such as polycythemia and risk of aggravating prostate cancer have been reported as well. 150 , 162 Selective androgen receptor modulators (SARMs) are nonsteroidal compounds with favorable oral bioavailability that were developed in the early 2000s in an attempt to overcome the pharmacological limitations of steroidal androgen receptor agonists (i.e., testosterone and DHT), which have known associations with liver and heart disease. 163 Recent systematic review on their safety indicates that their use may be associated with drug-induced liver injury, rhabdomyolysis, tendon rupture, and adverse cardiovascular outcomes. 164

Dehydroepiandrosterone (DHEA) is a precursor for sex hormones and is transformed into androgen or estrogen, respectively. The decrease of plasma DHEA levels in the elderly has been associated with certain age-related pathologies. In some reports, DHEA supplementation has been reported beneficial for alleviating vasomotor symptoms, preserving the integrity of the immune system, reducing bone loss, and increasing muscle mass and strength, enhancing physical performance, improving body mass index, as well as for mood and sexual function, however there is generally little evidence to support antiaging claims. 165 − 171 The adverse effects of DHEA are minimal. 172 , 173

Prebiotic/Probiotics and Fecal Transplantation

Microbiota plays such an essential role in human physiology and pathology that it is considered as an essential organ. 174 − 176 Recent reports on the involvement of microbiota in regulating health status and lifespan 177 , 178 have triggered significant growth in the field of life sciences research and industry. 179 Numerous studies have provided proof that microbiota-targeted interventions can have a therapeutic power not only for age-related diseases but also for delaying aging and promoting longevity. Longevity has been correlated to Firmicutes bacteria rearrangement and Proteobacteria enrichment and also a substantial decrease in Faecalibacterium prausnitzii and elevation of Eubacterium limosum levels within the gut microbiota. 180

Microbiota composition can be strongly modulated by certain factors including diet, probiotics/prebiotics/synbiotics, physical activity, drugs, and psychological stress. An imbalance in the microbiota called dysbiosis is a state characterized by distinct alterations in the microbiome resulting in modifications in their functional composition and metabolic performance. One microbiota-aimed intervention for dysbiosis is probiotic supplementation containing mainly Bifidobacterium and Lactobacillus species. 181 , 182 Another microbiota-aimed intervention is fecal microbiota transplantation which is a procedure used to restore the intestinal ecosystem through transferring of feces filtrate from a healthy donor into the gastrointestinal tract of the recipient. 183 Recently, its potential benefit and safety in pathologies commonly associated with aging, type 2 diabetes mellitus, metabolic syndrome, atherosclerosis, and neurodegenerative diseases have been demonstrated. 184 , 185

Caloric Restriction/Intermittent Fasting

One of the first antiaging approaches was developed from the observation that caloric intake control can increase lifespan, first demonstrated in mice and rats. 9 The reduction of caloric intake by some 10–30% as compared to ad libitum food intake has been demonstrated to extend the longevity of various species. Furthermore, among all antiaging interventions, dietary interventions have demonstrated the greatest promise. Recently, two related dietary interventions, caloric restriction and intermittent fasting, have been reported to effectively prolong the healthy lifetime of the nervous system by affecting basic metabolic and cellular signaling pathways that regulate longevity. 186 Multiple interactive pathways and molecular mechanisms exist by which caloric restriction and intermittent fasting benefit neurons. Indications exist that the advantages of caloric restriction are associated with modification of the metabolic rate. The key physiological routes that have been inferred as potential mechanisms by which caloric restriction stimulates longevity include (i) activation of AMP protein kinase, 187 (ii) sirtuins activation, 188 , 189 (iii) insulin-like growth factor-1 signaling inhibition, 190 and (iv) mammalian target of rapamycin inhibition. 191 , 192 These pathways promote the protein chaperones, neurotrophic factors, and antioxidant enzymes production, which facilitate cells managing stress and fight disease.

Although calorie restriction has exhibited the greatest efficiency of all antiaging interventions, it is a difficult strategy to successfully apply in humans, since it requires a high level of determination and self-control. As an alternate route, compounds that emulate the outcome of caloric restriction on health and longevity without an actual restriction named “calorie restriction mimetics” have been discovered (reviewed further in the paper). 193

Physical Exercise

Physical exercise has been well validated as an effective antiaging intervention. Regular physical activity of the elderly plays a vital role at a multisystem level, avoiding muscle atrophy, mending or sustaining cardiorespiratory health and cognitive performance, and enhancing metabolic activity. 194 − 196 Recommendations predicated on the most recent American College of Sports Medicine Guidelines advise that physical exercises for elderly need to involve aerobic exercise, muscle strengthening, and endurance training, as well as flexibility and neuromotor exercises. 197 The prospective benefits of the recommended physical activities include the following:

enhancing neurogenesis and reducing neurodegeneration and cognitive decline;

reducing blood pressure and augmenting various cardiovascular activities, e.g., maximum cardiac output, blood flow, endothelial performance, vagal tone and heart rate adaptability, and heart preconditioning;

advancing respiratory activity by enhancing ventilation and gas exchange;

augmenting metabolic activity in enhancing the resting metabolic rate, protein synthesis in muscles, and lipid oxidation;

boosting muscle performance and body composition by enhancing muscle strength and stamina, maintaining or restoring balance, motor control, and joint flexibility and mobility, as well as decreasing weight and local adiposity, and enhancing muscle mass and bone density. 195 , 196

Furthermore, physical exercise exhibits a significant antiaging impact at a cellular level, related to each and every aging hallmark. 194 Exercise plays a role in maintaining genomic stability. Data analysis comprising hundreds of genetic elements from a large number of exercising elderly individuals found a reduction in DNA methylation percentage in a dominating number of genes, specifically in genes associated with a cancer-defeating miRNA gene network. 198 Exercise exhibits a beneficial impact on telomere length as well, antagonizing the regular age-provoked telomere attrition. Possible mechanisms have been debated correlating exercise and telomere length declines to alterations in telomerase activity, inflammation, oxidative stress, and reduced skeletal muscle satellite cell content. 199 It has been documented that acute exercise protocols are correlated with increased heat-shock proteins transcription, which indicates potential positive impact of physical activity on proteostasis. 200

Stem Cell Therapy

Stem cell therapies are widely used in the regenerative medicine due to their intrinsic biological characteristics, including plasticity, self-renewal, and multiway differentiation ability. Stem cell treatment includes human autograft or allograft cultured stem cells locally injected into specific parts of the body or administered by intravenous infusion. 201 , 202 Bringing active stem cells into the body can rejuvenate existing cells and allow the body to age more gently and even reverse some impacts of aging. Currently, neural stem cells, bone marrow mesenchymal stem cells, umbilical cord mesenchymal stem cells, adipose stem cells, embryonic stem cells, and human induced pluripotent stem cells are the most closely related antiaging agents and exhibit direct (cellular replacement) and indirect (paracrine) effects. 202

Pluripotent stem cells naturally differentiate when culture conditions no longer support their pluripotency. 203 Hence, pluripotent stem cells can be directed toward preferred cell identities when specific stimuli are supplemented, such as those available during embryonic differentiation. There are many examples of pluripotent stem cells differentiation. The differentiation of pluripotent stem cells into renal podocytes, hematopoietic progenitor cells, neurons, endothelial cells, cardiac muscle cells, retinal progenitor cells, pancreatic β islet cells, or ciliated epithelial cells infers no limits to human tissue modeling in vitro . 204 − 211 The reported progress in organoids development also demonstrates the advanced knowledge in cell manipulations. Three-dimensional cultures of pluripotent cells let them organize and differentiate into spheroid structures, with several cohabitant cell types. The most sophisticated current organoid models relate to the brain, intestine, kidney, heart, or retina. 212 − 221 With the emergence of cell 3D-printing technologies using pluripotent stem cells or differentiated cells as inks, impressive progress has been successful in the formation of heterogeneous tissues. One such development, ear cartilage regeneration, utilizes this technology. 222 − 224

Stem cells may be capable of deferring aging in several ways:

Tissue regeneration: Stem cells can differentiate into various cell types and can thus replace damaged tissue, potentially reversing the impacts of aging.

Augmenting body’s repair mechanisms: Stem cells stimulate production of growth factors and other signaling molecules, thus enhancing the repair mechanisms of the body, allowing it to maintain healthy tissue and postpone age-related alterations.

Immune modulation: Stem cells may act as immunomodulators, affording a way to maintain a healthful immune system and avoid age-related immune dysfunction.

Lowering inflammation: Stem cells may have anti-inflammatory properties, thus reducing the chronic aging-related inflammation.

Oxidation protection: Stem cells may safeguard against oxidative stress, a process that can result in cell damage throughout aging.

Mitochondrial support: Stem cells can preserve mitochondrial health by intercellular communication via tunneling nanotubes physically transferring mitochondria from stem cells to unhealthy aging cells.

Dietary Supplementation

Dietary supplements, such as vitamins, minerals, amino acids, essential fatty acids, flavonoids, plants and herbs, and accessory food ingredients, are considered valuable and safe materials for prevention and treatment of chronic and acute diseases. 225

Interest in the therapeutic capacity of vitamin supplements, specifically vitamin D, for stimulating human longevity and reducing risk of aging-related pathologies is currently a hot topic in clinical studies. 226 It has been reported that vitamin D and its metabolites can delay age-associated diseases by lowering oxidative stress, strengthening innate immunity, preventing DNA damage and supporting DNA repair pathways, controlling mitochondrial and glucose metabolism, defeating cellular senescence, and enhancing telomerase activity. 225 , 227 − 229 These research findings imply that vitamin D consumption exhibits antiaging properties. A recent systematic review has also reported that vitamin D intake notably lowers the risk of acute respiratory infections. 230 Other vitamins such as B vitamins, K vitamins, and others have been examined as dietary supplements that assist healthy aging. 225 Vitamin B12 in combinations with bacopa, lycopene, and astaxanthin successfully alleviated cognitive delay associated with brain aging. 231 Improving vitamin interventions by combining them with other health-supporting supplements might result in successful clinical utilization.

Minerals are vital for health and well-being and are typically obtained from diet. Deficiencies in some minerals have been associated with age-related diseases such as dysregulated calcium levels being correlated to accelerated cellular aging. Calcium-related changes upon aging are also regarded as a contributing factor for neurological degenerative disorders such as Parkinson’s disease. There is evidence that aging individuals are at risk of calcium deficit, so appropriate calcium dietary intake can lower the risk of osteoporosis and bone fractures. 232 , 233 Zinc is another mineral that promotes healthy aging and supports the healthspan. Zinc has numerous biological roles, such as antioxidant, anti-inflammatory, immune modulation, DNA damage prevention, and others. Zinc insufficiency is often reported upon aging and contributes to age-associated disorders. Zinc supplementation is considered an efficient choice for controlling age-related health pathologies, including neurological disorders, infectious diseases, age-related macular degeneration. 234 , 235

Long-chain polyunsaturated fatty acid supplementation is believed to protect human health by affecting biological activities, notably aging processes. 236 , 237 Recent reports suggest that higher levels of ω3 fatty acids in circulation correlate with lower risk of premature death from age-associated diseases such as cardiovascular disease and cancer. 238 Dietary ω3 fatty acid consumption has been related to cognitive improvements in aging populations. 239 The ω3 fatty acids have been shown to exhibit anti-inflammatory, antiapoptotic, antioxidant, and endothelial vasodilator effects. 240

Autophagy Enhancement

Autophagy is a natural degradation process for removing unnecessary or dysfunctional cellular components via a lysosome-dependent mechanism. 81 , 241 , 242 Dysfunctional autophagy is known to contribute to neurodegeneration, 243 while improvement of autophagy has been believed to be useful for treating a variety of disorders, including metabolic disorders, neurodegenerative and infectious diseases, and cancers. 241 An unharmed autophagy performance in neurons exhibits a neuroprotective effect since autophagy expedites the elimination of pathogenic kinds of proteins such as α-synuclein involved in Parkinson’s disease 244 or tau-protein in Alzheimer’s disease. 245 , 246 Therapies involving autophagy enhancers such as rapamycin and lithium have been reported to engender favorable effects in animal models of Parkinson’s disease, such as reduced α-synuclein aggregation, oxidative stress, mitochondrial dysfunction, and neurodegeneration. 244 Delaying aging and stimulating longevity achieved through food deprivation and caloric restriction are facilitated through upregulation of autophagy because reducing autophagy diminishes the antiaging outcomes of caloric restriction. 241 , 247 , 248 Furthermore, studies have indicated that enhancing autophagy could reinstate the regenerative capacity of aging stem cells. 249 , 250 Therefore, autophagy enhancing interventions would likely facilitate successful aging and increased longevity.

Brain Antiaging Strategies

The brain is extremely sensitive to the effects of aging, manifested mainly as changes in cognitive capacity, as well as enhanced risk for developing certain neurological disorders. 251 , 252 Taking care of brain health requires the maintenance of brain functions in several aspects including cognitive ability, motor function, emotional health, as well as tactile function. 253

It has been evidenced recently that one of the best strategies for healthy brain aging is regular aerobic exercise. 254 It is suggested that exercise likely remains the most effective intervention for healthy brain aging because it stimulates strategic energy-sensing pathways that modulate multiple hallmarks of aging:

Dysregulated energy metabolism is a major hallmark of brain aging. Upon aging, fasting glucose levels increase, which is correlated with accelerated brain aging and inferior cognitive function. 255 , 256 Exercise is a kind of hormesis, an energetic stress (reduced cellular energy levels) to which the brain reacts with multiple metabolic, mitochondrial, and cellular responses. Essential examples include upregulation of glucose transporters (GLUT) and enhanced signaling through the low-energy sensors AMP protein kinase, sirtuin 1, and the mammalian target of rapamycin (mTOR) pathway. 195 , 256

Mitochondrial dysfunction is another universal hallmark of aging, 79 and it is specifically enhanced with brain aging. 256 It has been reported however that hippocampal gene expression patterns in older adults who are physically active exhibit enhanced mitochondrial energy production. 257

Curiously, exercise has been related to oxidative stress since enhanced metabolism upon exercise increases ROS generation. However, this effect is likely hormetic because exercise-associated oxidative stress results in greater long-term antioxidant ability. 195

Animal studies have demonstrated that exercise induces neurogenesis in the hippocampal dentate gyrus and is associated with increased neurogenesis, superior neuronal structure, and improved memory. 258 , 259

Telomere maintenance, which promotes the neuronal stem cells production, may protect against neurodegenerative diseases. It has been reported that regular exercise is associated with longer telomeres and reduced cellular senescence in both mice and humans. 79 , 195 , 256

Landscape View of the Antiaging Strategies Research: Insights the from CAS Content Collection

The CAS Content Collection 77 is the largest human-compiled collection of published scientific information, which represents a valuable resource to access and keep up to date on the scientific literature all over the world across disciplines including chemistry, biomedical sciences, engineering, materials science, agricultural science, and many more, allowing quantitative analysis of global research publications against various parameters including time, geography, scientific area, medical application, disease, and chemical composition. Currently, there are over 500 000 scientific publications (mainly journal articles and patents) in the CAS Content Collection related to aging physiology and antiaging strategies. There is a steady growth of these documents over time, especially intense in the past decade ( Figure 2 ).

Authors from China, the United States, Japan, and South Korea have published the highest number of journal articles and patents related to antiaging strategies ( Figure 4 ).

Patent protection is territorial, and therefore the same invention can be filed for patent protection in several jurisdictions. We thus searched for all related filings on aging mechanisms and antiaging strategies. Certain patent families might be counted multiple times when they filed in multiple patent offices. Figure 5 presents the flow of patent filings from various applicant locations to a variety of patent offices. There are various patent filing strategies: some patent assignees, such as those from China, for example, file exclusively in their home country patent office (CN), with only a small portion filing through the World International Patent Office WIPO (WO) or other jurisdictions. Others, for instance, the United States and France-based applicants, have a comparable numbers of their home country and WO filings and a sizable number of filings at other patent offices such as the European Patent Office (EP).

Figure 6 presents the most popular antiaging related concepts in the overall patent landscape of the CAS Content Collection. The concepts, antiaging cosmetics, and antioxidants are the distinct leaders.

We examined also the distribution and trends in the published documents dealing with prominent antiaging strategies ( Figure 7 ). Physical exercise comes up as the most studied approach, along with the metabolic manipulation ( Figure 7 A). This can be well anticipated considering the fact that these strategies are the ones related with the highest number of aging attributes ( Figure 3 ). Physical exercise has been well justified as one of the particularly effective and highly recommended antiaging practice. Regular physical activity of the elderly has a proven vital role at a multisystem level, avoiding muscle atrophy, mending or maintaining cardiorespiratory health and cognitive performance, and boosting metabolic activity. Next, the inhibition of the mTOR pathway has been shown to exhibit profound effects on longevity and age-related phenotypes across a wide variety of organisms. 93

With respect to the annual trends in the antiaging strategies related publications, parabiosis (blood exchange) attracts substantial recent attention ( Figure 7 B). It has been suggested that blood exchange reverses the age-associated decline by targeting multiple attributes of aging including stem cell exhaustion, cellular senescence, altered intercellular communication, and chronic inflammation ( Figure 3 ). A steady growth in the number of recent publications has been documented with respect to the prebiotic/probiotics and fecal transplantation as well ( Figure 7 B). Multiple studies have conveyed evidence that microbiota-targeted interventions can have a strong therapeutic power not only for age-associated diseases but also for delaying aging and stimulating longevity. Longevity has been correlated to certain bacteria phyla alterations: Firmicutes rearrangement and Proteobacteria enrichment, decrease in Faecalibacterium prausnitzii , and elevation of Eubacterium limosum . 180 Furthermore, microbiota composition can be intensely modulated by activities and interventions including diet, probiotics/prebiotics/synbiotics, physical activity, drugs, and psychological stress. 181 , 182 Fecal transplantation is another recently emerging intervention being looked at for a wide range of conditions including pathologies commonly associated with aging such as diabetes, metabolic syndrome, atherosclerosis, and neurodegenerative diseases. 184 , 185 Remarkably, recent animal studies showed that, similar to blood exchange, transfer of young donor microbiota into older animals can reverse age-related central nervous system and retinal inflammations and cytokine signaling, effects which are coincident with increased intestinal barrier permeability. 260 Microbial modulation emerges as therapeutically beneficial in preventing inflammation-associated tissue degradation in later life. 260

Next, we explored the correlations between the hallmarks of aging and the antiaging strategies as reflected by the number of documents in the CAS Content Collection ( Figure 8 ). Along with some foreseeable strong correlations such as stem cell exhaustion–stem cell therapies, lipid metabolic disorders–metabolic manipulations, impaired autophagy–autophagy enhancement, cellular senescence–senotherapy, and dysbiosis–prebiotic/probiotic/fecal transplantation, there are some that are less anticipated and instructive:

Metabolic manipulations appear closely aligned with the mitochondrial dysfunction and dysbiosis.

Metabolic manipulation have been recognized as a noteworthy strategy in mitochondrial medicine. 261 Cellular alterations triggered by mitochondrial dysfunction include enhanced reactive oxygen species production, enhanced lipid peroxidation, and modified cellular calcium homeostasis. Therefore, metabolic manipulation is aimed to prevent oxidative damage by ROS, adjustment of lipid peroxidation, amendment of altered membrane potential, and restoration of calcium homeostasis. 261

Autophagy enhancement associates with cellular senescence.

Autophagy has been initially reported to inhibit mesenchymal stem cells senescence by eliminating damaged cytoplasmic organelles and macromolecules, yet recent studies found that autophagy can in fact promote mesenchymal stem cells senescence by triggering the production of senescence-associated secretory proteins (SASP). 262

Epigenetic alterations and mitochondrial dysfunction are well linked to dietary supplementation.

Nutritional epigenetics is a novel subfield of epigenetics dealing with the specific effects of bioactive food constituents on epigenetics and their relations to phenotypes. Elucidating the epigenetic features prompted by bioactive food components might set the stage for personalized nutritional therapeutics and enhance the understanding of how organisms respond to specific diets or nutrients. 263 A recent study reported that fruit and juice epigenetic effects as assessed by DNA methylation are related to independent immunoregulatory routes, indicating the distinct health benefits of fruits and juices. The discovery of such differences among foods is the first step toward personalized nutrition. 264 Further, adequate nutrient levels are important for mitochondrial function as certain particular micronutrients play essential roles in energy metabolism and ATP production. 265

Stem cell therapies strongly affect cellular senescence.

One of the advantages of mesenchymal stem cell-based therapies is that they have demonstrated effectiveness by targeting multiple pathological pathways. 266 Recently, a study has indicated that mesenchymal stem cells could alleviate renal cellular senescence. 267

Lipid metabolism disorders appear impacted by dietary supplementation.

Recently, there is remarkable interest in the health benefits of food constituents against chronic diseases in which elevated lipids are a major issue. 268 The nutritional regulation of lipid metabolism has become an essential tool to prevent or reverse the development of lipid metabolism disorders.

Dietary supplementation emerges as well correlated with virtually all aging attributes and especially with dysbiosis.

We explored the correlations between the age-related diseases and the antiaging strategies as reflected in the number of documents in the CAS Content Collection ( Figure 9 ). Generally, metabolic manipulations, physical exercise, hormonal replacement, dietary supplementation, and stem cell therapies appear as well researched approaches against multiple pathologies.

Some particular correlations are noteworthy:

Stem cell therapies exhibit strong correlation with cancer.

Stem cell transplants are procedures that restore the hematopoietic stem cells in patients receiving high doses of chemotherapy or radiotherapy used to treat certain cancers. 269 − 271 Stem cell transplants do not typically work against cancer directly but rather help recover the body’s ability to produce stem cells after such high-dose interventions. Still, in multiple myeloma and some leukemias, a stem cell transplant may work against cancer directly, due to the graft-versus-tumor effect taking place after allogeneic transplants, when leukocytes from the donor attack the remaining cancer cells after high-dose treatments. This effect enhances the success of the treatments. 269 Growing evidence is also indicating that cancer stem cells can differentiate into various cell types, including noncancerous cells. Scientists are taking advantage of this observation through a treatment called differentiation therapy. 272

Metabolic manipulation approach is well correlated with virtually all age-associated diseases but specifically with diabetes and obesity.

Indeed, mTOR dysregulation is known to result in a number of metabolic pathologies, including obesity and type 2 diabetes. 273

Physical exercise seems like another potent approach against multitude of age-related diseases but especially against diabetes, cardiovascular disease, and obesity.

There is undeniable evidence of the efficacy of regular physical activity in the prevention of multiple chronic diseases, including age-associated disorders, e.g., cardiovascular disease, diabetes, cancer, hypertension, obesity, depression, and osteoporosis. 274 Physical exercise can enhance the cognitive power, prevent cognitive impairment, and attenuate the development and progression of Alzheimer’s disease. 275 , 276 Physical activity interventions successfully reduce the incidence of type 2 diabetes. 277

Dietary supplementation is also a prominent approach against multiple age-related diseases, especially diabetes, inflammation, cancer, cardiovascular disease, obesity, hypertension, and cognitive disorders.

Hormonal replacement exhibits strong correlation with osteoporosis

Estrogen deficiency is known as the major factor in the pathogenesis of postmenopausal osteoporosis. 278 Hormone replacement therapy, either estrogen alone or a combination of estrogen and progestin, has been approved for the prophylactics and therapy of osteoporosis in women and has been reported to rapidly normalize turnover, preserving bone mineral density at all skeletal sites. 279 , 280

Antiaging Drugs

The search for remedies that can prevent, slow, or reverse aging has a long history ( Figure 1 ) and is currently attracting a lot of attention. There is a steady growth of the number of journal articles related to the antiaging strategies and treatments over time, rather explosive in the past three years ( Figure 2 ). The number of patents rapidly grew until 2016–2017, possibly correlating with the initial accumulation of knowledge and its transfer into patentable applications. Later on, the patent number is at a steady level, after a peak in 2017, perhaps awaiting the forthcoming breakthroughs in the antiaging drug awareness.

A new domain of geriatric medicine termed geroscience has recently emerged aiming to develop new tools to enhance healthspan. 281 The key claim of geroscience is that aging can be controlled to delay or prevent the beginning of aging-related disorders by targeting the global aging process rather than treating aging disorders once they occur. Applying geroscience-based strategies in healthcare and clinical practice could open an opportunity to increase the proportion of healthy individuals and reduce morbidity to a restricted period near the end of life, which would bring significant economic and social benefits.

The extreme complexity of interactions among factors and pathways is implicated in the process of aging, and looking for pharmacological strategies targeting aging is certainly a very difficult task. Still, substantial progress has been made in this research field, recently. Significant antiaging capacity has been revealed in some natural compounds as well as in certain classes of chemically synthesized substances. These include calorie restriction mimetics such as metformin, rapamycin, and resveratrol. 282 Using several model organisms, such as yeast, worms, flies, and rodents, these potential drugs have been reported to extend life expectancy by up to 25–30%. 283 Great expectations are currently related to the development of senolytics, drugs that can selectively eliminate senescent cells. 284 Another hopeful class of pharmacological agents involve substances targeting the epigenetic control of gene expression such as histone deacetylase inhibitors, including sodium butyrate, suberoylanilide hydroxamic acid, and trichostatin A. 285

Another strategy of searching for antiaging agents involves assessing the healthspan-promoting ability of drugs that have been already approved by the regulatory authorities to treat certain chronic pathological conditions. These include common medications such as aspirin, metformin, melatonin, certain statins, vitamins, and antioxidants. 286 A benefit of repurposing such drugs is that their long-term safety has been repeatedly examined and approved, and their possible side effects have been well-known through various clinical trials and examinations. Evidence has been accumulated that such common drugs may indeed enhance health and well-being in elderly individuals suffering from a variety of age-related chronic pathologies. 281 , 286

The collection of currently explored antiaging agents is dominated by natural compounds, either pure substances or extracts. Vital nutrients such as certain vitamins, minerals (as micronutrients), amino acids, polyunsaturated fatty acids, probiotics, and plant metabolites, such as polyphenols and terpenoids, are recognized for their ability to prevent aging and promote healthy aging. Natural antiaging sources are present in a wide variety of foods including meat, fish, poultry, fruits, vegetables, herbs, cereals, nuts, grains, legumes, dairy products, cocoa/chocolate, as well as in beverages such as juice, tea, coffee, and wine. Natural extracts from plants and herbs such as green tea, turmeric, yerba mate, thyme, licorice, mulberry, and grape are also known for their antiaging, mainly antioxidant potencies. 287 − 291

Calorie Restriction Mimetics

Drug candidates and dietary supplements categorized as caloric restriction mimetics delay aging and extend healthspan and lifespan by modifying aging-associated pathways similarly to caloric restriction and intermittent fasting strategies. The term has been coined in a pivotal 1998 paper. 292 Because caloric restriction requires continuous effort and firm discipline, identifying active agents that produce similar but effortless effects have attracted significant attention. Such compounds would open the possibility of enhancing physiological functions, expanding longevity, and lowering risk of chronic diseases. 282 Various organic compounds have been shown to modulate antiaging pathways in a manner similar to caloric restriction and intermittent fasting. Examples of the most widely examined caloric restriction mimetics include rapamycin, metformin, resveratrol, acarbose, aspirin, glucosamine, nicotinamide riboside, and spermidine. 193 , 282 , 293

Rapamycin (CAS RN 53123-88-9) represents one of the best-known caloric restriction mimetics. 282 It is a macrolide compound isolated from Streptomyces bacteria. Rapamycin is an mTOR inhibitor and historically used to avoid immunosuppressive organ transplant rejection. 294 Inhibition of mTOR is known to activate autophagy, a cellular process recognized as a powerful antiaging approach, believed to also mediate the rapamycin effect. 295 Rapamycin treatment has been reported to extend lifespan and to enhance health markers in model organisms. 294 Certain reported adverse side effects such as cataract risks, infections, as well as insulin resistance restrain the use of rapamycin to delay aging and stimulate active searches for analogous mTOR inhibitors, so-called rapalogs, in an effort to find potential drugs with a better safety profile. 296 One of the first-generation rapalogs, everolimus (CAS RN 159351-69-6), found within the 95% similarity limit of rapamycin by CAS SciFinder n 297 has been approved to prevent organ rejection and for cancer treatment. Other compounds found within the 95% similarity limit of rapamycin by CAS SciFinder n 297 are listed in Table 1 . Later generation rapalog compounds are currently being examined in preclinical and clinical studies. 296

Metformin (dimethylbiguanide hydrochloride, CAS RN 657-24-9), an antidiabetic drug widely used for treatment of type 2 diabetes, is also considered a caloric restriction mimetic providing antiaging benefits, believed to be mediated by the activation of AMPK in C. elegans and rats. 293 , 298 It has been demonstrated that metformin administration prolongs the lifespan in animal models, including mammals. 44 In humans, metformin is shown to be beneficial against certain age-associated diseases, such as cancer, metabolic syndrome, as well as cognitive deficits and cardiovascular disorders. 299 − 301 However, metformin may cause adverse side effects, such as vitamin B deficiency and cognitive decline in older adults, as well as lowered testosterone levels, possibly resulting into erectile dysfunction. 302 , 303

Resveratrol (3,5,40-trihydroxystilbene, CAS RN 501-36-0), a SIRT activator, which is a natural polyphenolic phytoalexin mostly abundant in red wine and grape skins but also in berries and peanuts, has been widely investigated. 304 Resveratrol has been reported to prolong lifespan and delay the onset of aging-related markers in model organisms. 305 , 306 It also demonstrates ability to protect against an assortment of age-related disorders including type 2 diabetes, Alzheimer’s disease, and cancer. 307 A widespread opinion is that antiaging and longevity effects of resveratrol are mediated by sirtuins activation. 308 Resveratrol has been shown to target certain stress-related cellular mechanisms, such as AMPK and SIRT1, with both targets, AMPK and SIRT1, required for resveratrol-induced health promotion. Stimulation of SIRT1 brings about protein deacetylation and autophagy induction. 309 − 313 Other similar small-molecule SIRT1 activators have been examined including SRT-1720 (CAS RN 925434-55-5) and SRT2104 (CAS RN 1093403-33-8) and have been demonstrated to prolong lifespan, reducing inflammation and protecting from neurodegeneration in model organisms. 36

Spermidine (CAS RN 124-20-9) is a polyamine known to induce autophagy in various model organisms, which is considered causal for some of the reported beneficial effects such as cardioprotection. 314 The autophagy induction is believed to be result of the inhibition of certain acetyltransferase activity by spermidine. 315 Furthermore, spermidine is able to promote mitophagy. 316

Aspirin (acetylsalicylic acid, CAS RN 50-78-2), a nonsteroidal anti-inflammatory drug, has been in widespread medical use for a long time. It is known to quickly metabolize into salicylate in vivo , which inhibits EP300 by competing with acetyl-CoA, thus activating autophagy and exhibiting lifespan-prolonging effect in model organisms. 317

Acarbose (CAS RN 56180-94-0) is a widely used antidiabetic drug known for its ability to decrease plasma glucose and cholesterol levels by inhibiting intestinal α-glucosidase and pancreatic α-amylase. 318 It was recently reported to exhibit promise as an antiaging drug by increasing lifespan in mice 319 , 320 and relieve certain age-related pathologies. 321 Acarbose has been hypothesized to extend life span by controlling gut microbiota, thus reducing inflammatory reactions and therefore diminishing the risk of mitochondrial disorders and telomere attrition. 322

Senolytic Drugs

The small-molecule drugs known as senolytics selectively eliminate senescent cells. Senescent cells accumulate upon aging and cause multiple age-associated disorders. Furthermore, senescent cells are known to develop a senescence-associated secretory phenotype (SASP) to provoke immune clearance, which boosts chronic inflammation and plays a key role in aging and age-related diseases. 284 , 323 It is believed that chronic inflammation activated by senescent cells is among the main grounds of aging-associated pathologies. 283 Senolytic drugs are intended to delay, prevent, relieve, or treat such age-related diseases. As expected for therapeutics targeting one of the very fundamental aging mechanisms, the prospective uses of senolytics are variable, hopefully alleviating multiple conditions, opening a new route for curing age-related dysfunction and diseases.

The initially identified potential senolytic drugs have been discovered using a hypothesis-driven approach, 284 based on the observation that senescent cells resist apoptosis. 324 The basic drug discovery hypotheses suggested that (i) senescent cells resist apoptotic stimuli and (ii) senescent cells are in certain aspects similar to cancer cells that do not divide. 284 Further senolytic drug identification was bioinformatics-based 325 and initially included the natural flavonoid quercetin (CAS RN 117-39-5) targeting senescent umbilical vein endothelial cells (HUVECs) and the tyrosine kinase inhibitor dasatinib (CAS RN 302962-49-8) targeting senescent primary adipocyte progenitor cells. 284 Other members of this first generation senolytics class included fisetin, luteolin, curcumin, navitoclax , and others. 283 , 284 , 323 , 326 Figure 10 illustrates the use of the ChemScape tool within SciFinder n 297 to search for compounds of similar chemical structure to quercetin as potential antiaging drugs. The collection included kaempferol, luteolin, myricetin, fisetin, morin, isorhamnetin, galangin, tricetin, gossypetin, and others ( Figure 10 ). Currently examined senolytics include certain BCL-2 family inhibitors (e.g., ABT-737, navitoclax), HSP90 inhibitors (e.g., 17-DMAG (alvespimycin)), geldanamycin, 17-AAG (tanespimycin), STA-9090 (ganetespib), and p53-targeting compounds (e.g., FOXO4-DRI, UBX0101). 327

Recently, a specific bioactive fraction of Rhodiola complexed with a marine lipoprotein extract from Trachurus sp. has been shown to markedly stimulate cell proliferation rate in cells under oxidative stress, imitating what has been observed in the aging process. 328 This phytomarine complex with notable senolytic activity also considerably upregulates the vitagenes SIRT-1 and MMP2 328 and might offer an innovative approach to avoid oxidative stress damage and prevent cell aging. 329

The efficacy of the suggested senolytic drugs has been demonstrated in model organisms for age- and cellular senescence-associated physical disabilities, insulin resistance, cognitive decline, osteoporosis, osteoarthritis, and cancers. 284 Senolytic agents have the potential to delay, prevent, or treat senescence- and age-related disorders, based on successful forthcoming human clinical trials. Other promising senolytic drugs include acarbose , 17-α-estradiol , and nordihydroguaiaretic acid (NGDA). 319 Recently, new structurally diverse compounds with promising senolytic activity have been identified using deep learning neural networks simulations. 330 Lately, focus has been placed on natural senolytic compounds, which even though less potent than targeted senolytics, have the advantage of low toxicity. 331 The natural polyphenolic compounds oleuropein and its metabolite hydroxytyrosol, epigallocatechin-gallate (EGCG), fisetin, piperlongumine, and wogonin are just a few of the known natural senolytics. 331 , 332

Telomerase Activators

Therapeutic targeting of telomerase activity is another prospective antiaging approach. Since age-associated telomere shortening is known to play a key role in senescence, proper maintenance of telomeres is decisive for genome stability. 333 , 334 Telomerase is the reverse transcriptase enzyme, which is able to sustain telomere length via telomeric repeat addition onto the chromosomes ends. 335 Telomerase activation has been proposed to be an antiaging moderator, which can play a role in the aging-associated diseases therapy.

Several telomerase activator formulations have been examined as antiaging agents. Preliminary experimental data suggested that TA-65 (cycloastragenol, CAS RN 78574-94-4), an extract of Astragalus membranaceus roots, can perform as a telomerase activator, 129 but so far no sound clinical data have been reported. Another telomerase activator, metadichol (CAS RN 1627854-29-8), has been used to defeat organ failure by enriching cells with telomerase. 336 Another study reported that natural formulations including Centella asiatica extract (08AGTLF) comprising >95% triterpenes, Astragalus extract, TA-65, oleanolic acid (CAS RN 508-02-1), maslinic acid (CAS RN 4373-41-5), and certain multinutrient formulations trigger significant increase in telomerase activity. 337

Epigenetic Drugs

Epigenetic dysregulations associated with aging implicate intense health concerns for numerous pathologies including metabolic and cardiovascular diseases, psychiatric and neurodegenerative disorders, and cancer. Epigenetic drugs-based therapy has emerged as a potential strategy for treating certain aging-associated diseases. 338 Epigenetic modifications are known to be reversible, which makes them suitable targets for pharmacological intervention.

An assortment of therapeutics have been developed recently targeting epigenetic regulation, including DNA methyltransferase modulators, histone deacetylase modulators, histone acetyltransferase (HAT) modulators, and noncoding miRNAs, exhibiting possible effects against age-related disorders. 339 , 340 Among DNA methyltransferase modulators, 5-azacytidine (azacytidine, CAS RN 320-67-2) and 5-aza-2′-deoxycytidine (decitabine, CAS RN 2353-33-5) are the most thoroughly examined and demonstrate therapeutic potential against certain leukemias. 341 , 342 Histone deacetylase inhibitors include several chemical groups: cyclic peptides, hydroxamic acids, short chain fatty acids, and benzamides. 343 Experimental evidence shows significant life-extending potential of the histone deacetylase inhibitors such as 4-phenylbutyrate (PBA), trichostatin A, sodium butyrate, and suberoylanilide hydroxamic acid (SAHA). 344 , 345 A wide range of histone deacetylase inhibitors are emerging as potential anticancer medications, including belinostat, panobinostat, SAHA and FK228, 346 trichostatin A, sodium butyrate, vorinostat, valproic acid, and romidepsinor 347 demonstrating considerable activity in hematological and solid tumors.

Antioxidants

According to the oxidative damage theory of aging, 6 free radicals and other reactive oxygen species (ROS), developed throughout mitochondrial metabolism, may end up producing impaired molecules including carbonylated proteins, lipid peroxides, and oxidized DNA, 348 − 353 the accumulation of which is supposedly the primary cause of cellular senescence, age-related telomere attrition and diseases. 351 , 354 Accumulated ROS excess can be allegedly destroyed by the endogenous physiological antioxidative systems including the enzymes superoxide dismutase (SOD), glutathione reductase, catalase, and glutathione peroxidase, which help to keep the balance between oxidative and antioxidative processes. In terms of chronic oxidative stress, however, the endogenous antioxidant systems happen to be insufficiently effective, and it has been believed that administration of certain exogenous antioxidants such as vitamins E and C, curcumin, melatonin, β-carotene, lipoic acid, coenzyme Q10, glutathione, polyphenols, phytoestrogens, as well as certain minerals including zinc, manganese and selenium, can be a factor in maintaining homeostasis. 283

Vitamin E (CAS RN 1406-18-4) comprises a group of several fat-soluble compounds including tocopherols and tocotrienols, of which α-tocopherol is the most potent antioxidant form of vitamin E. Due to their lipophilic features, they can be found in lipoproteins, cellular membranes, and fat deposits. Vitamin E is the key defender against free radical effects. It is stored in the liver and fat cells and protects cellular components and especially cellular membranes from damage. 355 , 356 Vegetable oils such as sunflower, soybean, and safflower oils are some of the best sources of vitamin E.

Vitamin C ( l -ascorbic acid, CAS RN 50-81-7), a water-soluble vitamin naturally present in citrus and other fruits and vegetables, is an electron donor and a versatile free radical scavenger. It has been found to regenerate other antioxidants, including α-tocopherol (vitamin E) from the tocopheryl radical. 357 It is a particularly efficient antioxidant because of its high electron-donation power and ready conversion back to the active reduced form. Vitamin C is necessary for the biosynthesis of collagen, l -carnitine, and some neurotransmitters. It is also a participant in protein metabolism 358 , 359 and plays an significant role in immune function. 357

Curcumin (CAS RN 458-37-7) is the key active component of turmeric ( Curcuma longa ) root. It has been shown to exhibit antioxidant, anti-inflammatory, antineurodegenerative, and antitumor activities. 360 , 361 Recently it has been implied that curcumin upregulates SIRT3 expression in skeletal muscle tissues, 362 as well as in the brain after stroke. 363 Numerous other dietary polyphenols such as resveratrol and (−)-epigallocatechin-3-gallate (EGCG) have been shown able to mitigate age-produced cellular damage via metabolic formation of ROS, via specific cell-signaling actions that may stimulate SIRT1 activity. Furthermore, polyphenolic compounds have proven inhibitory activity against chronic vascular inflammation related to atherosclerosis. 364

Melatonin ( N -acetyl-5-methoxy tryptamine, CAS RN 73-31-4) is a hormone secreted by the pineal gland and regulates sleep/wake cycles. It is a well-recognized antioxidant able to support healthy aging. The endogenous melatonin levels have been found to decrease upon aging and even stronger in certain neurodegenerative disorders, especially Alzheimer’s disease, as well as in type 2 diabetes. 365 It has been reported relevant to the attenuation of inflammaging in the brain. 365 Studies have documented the ability of melatonin to increase SIRT levels against brain aging. 366 , 367

β-Carotene (CAS RN 7235-40-7) is a carotenoid, a micronutrient with numerous physiological functions. It is an antioxidant, which has been shown to inhibit the incidence and development of cancer. It also has an anti-inflammatory effect in various animal and cell models. 368 Its antiaging efficacy has been documented in vitro , using mesenchymal stem cells, as well as in vivo , in model animals. 369 It was implied to inhibit aging by regulating the KAT7-P15 signaling axis. 369 Other carotenoids, including α- and γ-carotenes, lycopene, lutein, β-cryptoxanthin, and zeaxanthin, are also known as effective natural antioxidants. Synergistic action of vitamins C and E, and carotenoids, has been reported to successfully prevent lipid peroxidation. 370

α-Lipoic acid (6,8-thioctic acid, CAS RN 1200-22-2) is a dithiol that acts as a coenzyme factor for certain redox reactions. It is synthesized in animals naturally and is essential for aerobic metabolism. Its efficiency in diseases associated with aging-provoked oxidative stress has been documented, so its dietary supplementation has been found beneficial. 371 − 373 Lipoic acid has been also shown to activate SIRT1 and SIRT3 in peripheral tissues, thus improving mitochondrial function and protecting against cardiac hypertrophy. 374 , 375

Coenzyme Q10 (CoQ10, CAS RN 303-98-0), a powerful antioxidant known to offer a variety of benefits to support healthy aging, is naturally produced in the body and is participating in energy production. It has attracted large-scale interest due to its crucial role in mitochondrial bioenergy, antioxidation, antiaging, and immune system regulation. Upon aging, the production of CoQ10 declines, so it is necessary to supply additional amounts through foods such as meats, fatty fish (e.g., trout) and nuts (e.g., pistachios) or through dietary supplements. It has been reported to exert positive effects in enhancing age-produced deterioration of oocyte quality. 376 CoQ10 and selenium supplementation have been reported to increase serum sirtuin1 levels 377 and to improve heart function in the elderly. 378

l -Glutathione (GSH, CAS RN 70-18-8) is an abundant antioxidant playing an essential role in protecting cells against oxidative stress-caused cellular damage. Declined glutathione levels are related to the typical characteristics of aging, as well as of a wide variety of pathological conditions, including neurodegenerative disorders. Glutathione depletion seems to be important for the onset of Parkinson’s disease. 379 Furthermore, glutathione is important for body detoxification, and it is also a successful immunostimulant and skin rejuvenator. 380

Fermented Papaya Preparation (FPP), a product resulting from yeast fermentation of Carica Papaya , is a powerful antioxidant and nutraceutical adjuvant. 381 Its major reported actions are as a free radical regulator, 382 immunomodulator, 383 , 384 and antioxidant. 385 , 386 An animal model study has indicated that daily FPP assumption caused an increase in telomeres length in bone marrow and ovary, along with an increase in the plasmatic levels of telomerase activity and the antioxidant levels, accompanied by a decrease of ROS. 381

Antioxidant Intake Controversy

The reported inverse correlation between systemic levels of antioxidants and certain age-associated diseases has resulted in the perception that antioxidant supplementation is an effective prophylactic and therapeutic intervention for such aging pathologies. However, the therapeutic results of this strategy in clinical trials have been frequently disappointing. 387 The interplay of both endogenous and exogenous antioxidants is complex and still not well understood. To successfully maintain the redox homeostasis, exogenous and endogenous antioxidants need to act synergistically. 388 A fine-tuned equilibrium between the oxidative and antioxidative processes in the organism is vital in preserving homeostatic stability. Excessive antioxidant supplementation might turn out to be damaging for the delicate homeostatic control mechanisms resulting in health decline. 389 Similarly to the hormesis-causing agents, antioxidants perform beneficially in certain concentration range, and their higher concentrations are typically toxic to organisms. The excessive levels of exogenous antioxidants may perturb the endogenous signaling pathways and thereby be harmful. 390 In view of these contradictions, it is not surprising that conflicting data have been reported on the health outcomes of long-term antioxidant intake. This ambiguity is often referred to as “antioxidant paradox”. 283 While benefits of dietary antioxidant supplementation appear to be clear in cases of high oxidative stress and endogenous antioxidant insufficiency, further research is necessary to clarify the potential risks and advantages linked to the supplement of antioxidants by healthy people.

Antiaging Peptides

Peptides have been mainly used in antiaging cosmetics and cosmeceuticals to repair skin aging signs like wrinkles and sagging. They have been found effective also at hair regrowth stimulation as well as weight loss. 391 − 393 Furthermore, peptides were reported useful for treating rheumatoid arthritis 394 and as analgesics. 395 Peptide supplementation modified energy metabolism and oxidative stress, improved endurance, and decreased fatigue in experimental animals. 396 Because of their hydrophilicity, peptides for use in skin cosmetics are commonly lipidated by esterification with an alkyl (most often palmitoyl) chain to enhance their penetration through the highly lipophilic stratum corneum. Exemplary antiaging peptides are shown in Table 2 .

The mechanism of action of many antiagent agents is often related to multiple aging hallmarks and refers to several antiaging strategies. In Figure 11 we have exemplified certain correlations between some antiaging drugs, hallmarks of aging (A), and antiaging strategies (B).

In Tables 3 and 4 we have summarized the natural ( Table 3 ) and synthetic ( Table 4 ) antiaging agents most widely represented in the CAS Content Collection, 45 , 283 , 288 − 291 , 397 − 408 complete with their chemical structures and the number of documents (journal articles and patents) in the CAS Content Collection, in which their antiaging performance has been documented and discussed. A more extensive collection of antiaging compounds represented in CAS Content Collection is provided in the Supporting Information, Tables S1 and S2 .

Private Investment

Examining the overall global private investment activities of the antiaging field provides insight into the commercial interest into this area. Performing a search of antiaging within PitchBook, 409 an online source for investment data, reveals the overall venture capital activities. Antiaging field refers to companies, which perform research and development of restorative treatments to prevent or treat the effects of aging and enhance lifespan. Research areas include genomic instability, telomere attrition, epigenetic alteration, loss of proteostasis, impaired nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. The search revealed capital steadily raised within this industry ( Figure 12 A). 409 From 2012 through 2018, the total venture capital raised increased from $1.4B to over $12.2B. 2019 revealed the overall venture capital raised fell to just $7.0B. Capital raised continued to grow for 2019 to 2022 totaling over $30.6B in 2022 in total venture capital investment ( Figure 12 A). In the years 2013–2015 and 2020–2022 the investments were dominated by the United States, while in 2016–2019 investments from Asia were dominating. The venture capital investment data in this area clearly show a recent and increasing commercial interest surrounding antiaging agents, revealing its potential promise for therapeutic applications.

In addition to the venture capital investments, in 2020 there was an investment of over $97B from the European Union, for the Horizon 2020 SME Instrument. 410 The SME Instrument supports high-risk and high-potential small and medium-sized initiatives to develop and provide new products, services, and business models able to drive economic growth. This large investment enhanced significantly the Europe contribution in the total capital investments distribution ( Figure 12 B).

Clinical Trials

A representative selection of therapeutic antiaging clinical trials is examined within this section to gain an overall view of the past, present, and future state of clinical development. A selection of the top 10 000 antiaging clinical trials 411 from https://clinicaltrials.gov are examined against time, clinical trial phase, status, disease indication, and antiaging strategy. Antiaging therapeutics are well established in clinical development, with Figure 13 showing a steady growth starting in the early 1990s and continuing through 2022.

Analysis of therapeutic antiaging clinical trial phases reveals that close to half of all trials are in phases III and IV with the other half filtering into earlier phases. Phase II trials contain the highest percentage of all categories encompassing 33% of all trials ( Figure 14 A). Examining clinical trials a step further, by disease indication, shows that bone, cardiovascular, and skin diseases along with sleep disorders and obesity are well established in the development pipeline having the highest percentage of clinical trials further along in phase III and phase IV clinical trials ( Figure 14 B). Balance disorders, cancer, frailty, along with eye and neurological disease are the indications less established in the pipeline with the largest percentage of trials in earlier phases ( Figure 14 B).

Next, we review therapeutic antiaging clinical trial statuses, characterized by age-related disease indications. Current therapeutic antiaging clinical trials in early phase trials such as neurological disease, frailty, sleep disorders, and cancer also have the highest percentage in active, recruiting, and not yet recruiting statuses ( Figure 15 ). These early phase trials are active or getting ready to be active in the pipeline. On the other hand, it is no surprise that disease indications more well established in the development pipeline such as skin, bone, and eye diseases along with obesity also contain the highest percentage of completed trials. There is however still current advancement in these areas reflected by greater than 20% of their trials in active, recruiting, or not yet recruiting status ( Figure 15 ).

Finally, representative clinical trials examining antiaging therapeutics are highlighted in Tables 5 – 12 categorized by antiaging strategy. These are examined in further detail below to showcase a variety of antiaging strategies, interventions, and targeted conditions in clinical development along with their status and any published results.

mTOR inhibition is widely explored in clinical trials for antiaging therapeutics ( Table 5 ). The National Eye Institute researched the use of rapamycin for the treatment of geographic atrophy (GA) as part of late-stage age-related macular degeneration (AMD) in phase I/II clinical trial NCT01445548 . Six participants with bilateral GA were enrolled and received intravitreal sirolimus, but no benefit was detected. 412 A following phase II study NCT01675947 enrolled 52 participants with GA for monthly intravitreal sirolimus treatment. The study was terminated early due to lack of efficacy and the adverse event of sterile endophthalmitis in three participants. 413 It was determined that while immunosuppression may play some role in AMD, it might not be the main pathway for GA development. The Mayo Clinic also researched at the use of rapamycin in phase I clinical trial NCT01649960 . They focused on rapamycin treatment effects on senescence markers and frailty in elderly subjects undergoing cardiac rehabilitation. Thirteen participants received low doses (0.5–2 mg) of rapamycin daily for 12 weeks. While correlation between some senescence markers and physical performance were observed, the primary end point measurement of frailty saw no improvement. 414

mTOR inhibition research continues however with the University of Texas Health Science Center at San Antonio currently investigating the use of rapamycin for inflammation reduction and epigenetic reversal in an active clinical trial ( NCT04608448 ). Subjects aged 65–95 will topically apply rapamycin 8% ointment to a forearm daily for 6 months. Both epigenetic and inflammatory markers will be measured. The University of Nottingham is recruiting for another study ( NCT05414292 ) looking at the use of rapamycin and resistance exercise on age related muscle loss. The study aims to recruit 16 healthy male participants over 50 years old who will take a 1 mg rapamycin oral tablet daily for 16 weeks along with performing a 14-week unilateral resistance exercise program. Measurements such as changes in muscle mass, strength, power, and function will be recorded.

Targeting aging senescent cells to combat aging with senotherapy is currently undergoing research in clinical trials ( Table 6 ). One such study researched the use of Carlson fish oil to improve immune senescence biomarkers CD28, CD57, on the surface of CD4+ and CD8+ T lymphocytes in aging participants 40–70 years old with HIV infection. The intervention groups received 1.6 g of ω3 fatty acids daily for 12 weeks. 415 Published results were less than encouraging however with no significant difference in immune senescence measurements in participants. 416 Another phase I/II clinical trial NCT04063124 researching targeting aging senescent cells was recently completed by the University of Texas Health Science Center at San Antonio. Five early stage AD patients were enrolled and received 100 mg of dasatinib and 1000 mg of quercetin every 2 weeks for 12 weeks. The outcome measurements of brain penetration for both compounds and AD and senescence biomarkers were collected. 417 Interpretative results have yet to be published, but the results of this pilot study will guide researchers in developing a larger phase II trial researching senolytic agents for the modulation of Alzheimer’s disease progression. 418 Lastly, we examine phase II clinical trial NCT04733534 currently recruiting 60 participants. St. Jude Children’s Research Hospital will evaluate two senolytic regimens for their cellular senescence biomarker reduction and frailty improvement in adult survivors of childhood cancer. Treatment groups will receive either oral dasatinib (100 mg/day) and quercetin (500 mg twice daily) on days 1, 2, 3, 30, 31, and 32 or oral fisetin (20 mg/kg/day) on days 1, 2, 30, and 31. Outcome measurement of walking speed and blood senescent cells (p16INK4A) levels will be recorded. If this pilot study is successful, it too will provide evidence needed for a continued phase II trial to determine further efficacy. 419

Hormonal replacement trials in the clinical pipeline have shown promising results ( Table 7 ). A large phase III clinical study ( NCT00799617 ) sponsored by the University of Pennsylvania called the testosterone trials is a coordinated set of seven clinical trials including 788 male participants with a mean age of 72. The treatment group applied 5–15 g of AndroGel once daily for 12 months to determine the efficacy of increasing the testosterone levels of older men with low testosterone. 420 Results from these trials are highlighted below. 421

Testosterone Level: increased the median testosterone level from low to normal

Sexual Function Trial: increased sexual activity, sexual desire, and erectile function

Physical Function Trial: increased distance walked

Vitality Trial: slight increase in mood and depression; did not increase energy

Anemia Trial: increased hemoglobin

Bone Trial: increased volumetric bone mineral density and strength of the spine and hip bones

Cardiovascular Trial: increased coronary artery noncalcified plaque

The testosterone trials have shown that increasing testosterone levels in older men with low testosterone has documented benefits. This trial paves the way for larger trials to explore the risks and efficacy deeper and has helped influence physician decisions regarding testosterone treatment in older men.

The University of California, San Diego researched the use of estrogen with two separate drug delivery systems for the prevention of recurrent urinary tract infections (UTIs) in postmenopausal women. Their phase IV clinical trial NCT01958073 had an intervention of 0.5 g of estrogen vaginal cream 2 times weekly or an estradiol ring every 3 months for 6 months. 422 More encouraging results were revealed in this trial with vaginal estrogen preventing UTIs in postmenopausal women who have been diagnosed with recurrent UTIs. 423 The University of Southern California is recruiting for its phase II trial NCT04103476 which will look at the effects of a tissue selective estrogen complex therapy on the progression of atherosclerosis and cognitive decline in 360 postmenopausal women aged 45–59 years. The treatment group will receive bazedoxifene 20 mg/conjugated equine estrogen 0.45 mg for up to a total of 3 years. Measurement outcomes will include carotid artery intima-media thickness, arterial stiffness, and three composite cognitive measures to determine cognitive decline. 424

Aging induces various gut microbiota changes especially the reduction in health promoting species. Researchers in the clinic are looking at gut microbiota modulation for disease treatment of various age-related indications ( Table 8 ). A few of these studies examined the use of prebiotics and probiotics along with fecal microbiota transplant (FMT) to aid a variety of conditions such as immune function, skin health, infection, and neurological disease. One such study sponsored by Clasado discovered that their Bimuno galacto oligosaccharide (GOS) mixture product has the potential to increase Bacteroides and Bifidobacterium fecal bacteria during an early phase I clinical trial ( NCT01303484 ). Forty participants (65–80 years old) with a dose group of 5 g/day of GOS mixture for 10 weeks revealed that supplementation with a GOS prebiotic positively affects the gut microbiota and biomarkers for immune function among the elderly. 425

On the other hand, the University of Antwerp, Belgium, saw no immune improvement when looking at the use of Lactobacillus casei Shirota (LcS) probiotic for the prevention of respiratory infection and immune boost in elderly nursing home residents ( NCT00849277 ). 737 volunteers aged 65 and older were enrolled and the treatment group received a daily fermented milk drink that contained greater than 6.5B live LcS cultures for 176 days with a flu vaccine given on day 21. The results showed no significant effect on the protection against respiratory infections or regarding flu vaccine immune response. 426

Currently in the pipeline, Chr Hansen is recruiting for their research ( NCT05529693 ) on the use of Bifidobacterium adolescentis Bif-038 on low grade inflammation biomarkers. Subjects aged 65–85 years old with low and high treatment groups of 1 and 10 billion CFU for 12 weeks will be tested and various biomarkers such as C-reactive protein and TNFα will be measured. 427 Another method of gut microbiota modulation, FMT, is currently only approved for the treatment of recurrent Clostridioides difficile infection, but researchers are branching out and researching its use for other indications with a gut–brain access connection. The University of Ghent has recently completed a clinical trial researching the effect of nasojejunal FMT ( NCT03808389 ) on subjects with Parkinson’s disease. 49 subjects aged 50–65 were enrolled, and the treatment group received donor fecal microbiota with published results forthcoming. 428

Caloric restriction is well researched as an antiaging strategy with its clinical development widely established. The 2-year clinical trial NCT00427193 by Duke University enrolled over 200 people to research the effect of a 25% calorie restricted diet on aging and age-related disease processes. Outcome measures included change in core body temperature, resting metabolic rate, inflammatory marker TNFα, along with fat mass. 429 The effect of calorie restriction included significant decreases in both inflammatory markers and cardiometabolic risk factors which suggests potential benefits for aging and age-related disease processes. 430 The University of Alabama also researched the use of caloric restriction along with exercise for the reduction of cardiometabolic risk. Phase III clinical trial NCT00955903 enrolled 167 participants with outcome measurements of change in abdominal fat mass, cardiometabolic risk factors, and weight change. Study results show significant improvement to relative fat mass, biomarker adiponectin and leptin, and cardiometabolic risk measurements for the intervention arm. 431

Researchers are also currently investigating how caloric restriction can affect biological aging and neurodegenerative diseases such as cognitive impairment and Alzheimer’s disease ( Table 9 ). TruDiagnositic is conducting an active phase II trial with 50 subjects enrolled to investigate the use of Peak Human Labs calorie mimetic supplement along with a fasting mimicking diet to see their effect on biological aging. The intervention group will take the supplement for 90 days mixing in a 5-day fasting diet, three times. Outcome measurements include the epigenetic age biomarkers which will test methylation at 850 000 locations on the DNA and body max index. 432 Another active study performed by the University of Kansas hopes to learn how the Mediterranean diet compared to a low-fat diet for 12 months affects cardiometabolic biomarkers, brain antioxidant status, brain volume, and memory in cognitive normal adults aged 65 or greater. Researchers plan to examine brain processes to understand health and how the Mediterranean diet may help treat Alzheimer’s disease in the future. 433 The University of Genova is also currently recruiting for its phase I/II study which will investigate the use of a specific 5-day low protein fasting diet called Prolon ADTM. 40 participants will be enrolled, and the treatment group will consume the diet once a month for 12 months. Metabolic, inflammatory, and regenerative pathways will be monitored to see the diet’s effect on mild cognitive impairment and early Alzheimer’s disease. 434

Research on physical exercise as an intervention for aging indications is well established, and clinical trials are seeing promising results. The Central Arkansas Veterans Healthcare System has completed a clinical trial on the use of Wii-Fit exercises to improve unsteady gait and postural balance in 30 veterans aged 65 and over. The intervention was performed for 45 min, 3 days a week for 8 weeks. 435 Outcome measurements of gait and balance improved significantly in the intervention group, showing that the Wii-Fit exercise program was effective. 436 Another study from the University of Kansas Medical Center recently published results for its clinical trial ( NCT04009629 ) researching moderately intensive aerobic exercise and its effects on brain blood flow and biological factors after exercise (15 min) in participants with a genetic risk factor for developing Alzheimer’s disease. 61 participants aged 65–80 years old with the apolipoprotein e4 (APOE4) gene were enrolled. 437 The results revealed increases in cerebral blood flow and neurotrophic response to acute aerobic exercise for all participants regardless of APOE4 status. 438 The long-term goal of the study team with this acquired knowledge is to create a personalized exercise prescription for the treatment of Alzheimer’s disease.

Upcoming clinical trials are also continuing to examine physical exercise and its effects on the cognitive function in the aging population with heart failure ( Table 10 ). The Montreal Heart Institute is recruiting 218 participants aged 60 years and older to research physical exercise and cognitive training interventions on cognition and brain health in patients with heart failure for clinical trial NCT04970888 . Cognitive training sessions will be 30 min and physical exercise sessions will be 60 min, three times a week for 6 months. 439 This combined intervention method has not been widely studied, so results should be of particular interest. Another indication of post-traumatic stress disorder (PTSD) among elderly veterans is also currently in the clinical development pipeline ( NCT04199182 ). The VA Office of Research and Development is recruiting to investigate this quickly emerging field of study. A three times a week supervised exercise program will continue for 6 months to see its effects on PTSD symptoms and related conditions such as sleep disorders among 188 older veterans. 440

Stem cell transplantation has shown promising results in clinical trials for aging-related conditions ( Table 11 ). Longeveron studied the use of allogeneic mesenchymal stem cells (allo-MSCs) for the condition of frailty in a successful clinical trial ( NCT02065245 ). Thirty patients with a mean age of 75.5 years received either a 100-million or 200-million cell dose infusion. Significant reduction of inflammatory marker TNF-α and early and late-stage T-cells activation occurred. B cell intracellular TNF-α and physical performance among participants was also improved in both treatment groups. 441 Longeveron also explored the use of MSCs through its biotherapeutic candidate Lomecel-B for the treatment of Alzheimer’s disease (AD) in phase I clinical trial NCT02600130 . Thirty participants were enrolled with low and high dose infusion groups of 30 and 100 million cells. Significant improvement was seen for inflammatory and AD biomarkers along with neurocognitive assessments. 442 Due to these encouraging results, Alzheimer’s disease treatment with Lomecel-B is further researched in phase II trial NCT05233774 currently recruiting participants.

The Vinmec Research Institute of Stem Cell and Gene Technology are exploring the use of MSC for male sexual dysfunction in a phase I/II clinical trial ( NCT05345418 ). They are currently recruiting male subjects aged 50–70 years old with sexual functional deficiency. Treatment groups will receive two iv doses of 1.5 million cells/kg body weight spaced out by 3 months. Various biomarkers, testosterone levels, and sexual life quality information will be measured. The First Affiliated Hospital with Nanjing Medical University has an upcoming phase I clinical trial ( NCT04706312 ) researching the use of amniotic mesenchymal stem cells (AMSCs) for the treatment of infertility is people with diminished ovarian response. Subjects will receive an iv injection of AMSCs and measurements recorded for ovarian function and in vitro fertilization such as stimulated follicles, number of oocyte retrieval, fertilization rate, etc. 443

Dietary supplementation is an antiaging strategy that targets a wide range of indications ( Table 12 ). The University of Sherbrooke, Canada, researched the use of medium chain triglycerides (MCT) combined with aerobic (AE) exercise on ketone production in a group of 20 women (prediabetic and healthy) over the age of 60 years through clinical trial NCT02678390 . They discovered that MCT (30 g/day for 5 days) combined with AE (30 min) was more ketogenic in older women than MCT or AE alone. 444 A clinical trial ( NCT02446314 ) researching the use of two different blueberry formulations for the treatment of cognitive decline in 125 participants 65–80 years old. Treatment groups consisted of a 6-month daily regime of 450–900 mg of blueberry powder or 100 mg of blueberry extract. The results reveal that the blueberry extract intervention can improve episodic memory and cardiovascular biomarkers over 6 months. The same effects were not observed for the blueberry powder intervention or with the measurements of executive function, working memory, or mood. 445

Several current studies are exploring the use of collagen for age-related indications. NovoBliss Research, India, is researching the effect of vegetable, bovine, fish, and chicken collagen peptide for indications such as skin elasticity, wrinkles, and hydration, hair thickness and density, along with joint pain and osteoarthritis. 125 participants are currently enrolled with treatment groups of 0.5–10 g/day. 446 Shenzhen Precision Health Food, China, also has a registered trial ( NCT05682092 ) researching the use of collagen peptide to increase skin moisture and elasticity. The trial is not yet recruiting but plans to enroll 70 middle aged (30–50 years old) women who will consume 25 mL twice a day for two months if in the treatment group. Lastly, we discuss Medical College of Wisconsin’s clinical trial NCT05598359 that is not yet recruiting but will be researching the use of TA-65, a purified small molecule extracted from Astragalus root. 180 participants will be recruited to investigate the use of TA-64 (250 U) taken once per day on microvascular function and blood pressure. 447

Outlook and Perspectives

Aging is generally defined as the accumulation of detrimental changes taking place in cells and tissues with advancing age, which bring about the increased risk of disease and death. The emerging standpoint defines aging as a particularly complex, multifactorial process. Antiaging research aims to identify strategies to promote healthy aging and extend lifespan. The major perspectives in the antiaging exploration generally fall into two groups: (i) lifestyle modifications and (ii) pharmacological/genetic manipulations. More specifically, the foremost approaches in antiaging research include the following:

Extensive current research explores the genetic basis of aging and age-related diseases and investigates the potential of genetic interventions , such as gene therapy, to prevent or reverse age-related damage.

Lifestyle interventions , such as caloric restriction, exercise, and stress reduction, have been believed to promote healthy aging and extend lifespan. Widespread research is currently exploring the mechanisms underlying these effects and developing strategies to promote healthy behaviors.

Pharmaceutical interventions explore the potential of drugs that target age-related pathways or senescent cells, to prevent or delay age-related diseases.

Regenerative medicine aims to restore or replace damaged tissues and organs and has the potential to promote healthy aging and extend lifespan.

Social and environmental factors , such as social support, access to healthcare, and exposure to toxins, can influence the aging process. The effects of these factors are being explored, and interventions to promote healthy aging are being currently developed.

Artificial intelligence (AI) is being used to analyze large amounts of data and identify patterns that could be used to predict or prevent age-related diseases. AI is also being used to develop personalized antiaging interventions based on an individual’s genetic and lifestyle factors.

More specifically, with particular attention to brain health maintenance, the following antiaging lifestyle strategies can help prevent or slow down age-associated brain function decline:

Physical exercise has been shown to improve brain function, increase brain volume, and reduce the risk of cognitive decline.

Mental stimulation: Engaging in mentally stimulating activities can help maintain cognitive function and reduce the risk of age-related cognitive decline.

Eating a healthy diet rich in fruits, vegetables, whole grains, and lean protein can help reduce inflammation and oxidative stress in the brain.

Stress reduction: Chronic stress has been linked to accelerated brain aging, so finding ways to manage stress like practicing mindfulness and meditation can be beneficial.

Staying socially active and connected can help maintain cognitive function and reduce the risk of cognitive decline.

Getting adequate sleep is essential for brain health and has been linked to improved cognitive function and a reduced risk of cognitive decline.

All these strategies are not mutually exclusive, and antiaging research often involves a multidisciplinary approach that combines different approaches to promote healthy aging and extend lifespan. Yet, regardless of the extensive research for antiaging therapeutics, based on the general understanding that aging is malleable in diverse species, to date, no convincing evidence has been provided indicating that the administration of existing antiaging remedies can markedly slow aging or increase longevity in humans. The major roadblocks that antiaging research and development is currently facing are summarized in Table 13 .

Despite these multiple difficulties and complexities, antiaging research is a rapidly growing field, and researchers are working to overcome these challenges to develop effective interventions to promote healthy aging and extend lifespan. Certain important steps forward toward the understanding of the aging process have been made so that it is no more an incomprehensible issue. The extensive efforts and research activities in the antiaging strategies field has led to several important outcomes:

Identification of biomarkers of aging . Researchers have identified biomarkers that can predict biological age and the risk of age-related diseases. These biomarkers can be used to develop personalized antiaging interventions and monitor the effectiveness of these interventions.

Development of interventions to promote healthy aging . Antiaging research has led to the development of interventions, such as caloric restriction, exercise, and stress reduction, that can promote healthy aging and extend lifespan.

Identification of potential drug targets . Researchers have identified several pathways and targets that could be targeted by drugs to prevent or delay age-related diseases.

Development of regenerative medicine therapies . Antiaging research has led to the development of regenerative medicine therapies that can restore or replace damaged tissues and organs, which could have important implications for treating age-related diseases.

Extension of lifespan in animal models . Antiaging interventions have been shown to extend lifespan in animal models, which provides proof-of-concept for the potential of these interventions to promote healthy aging in humans.

Improved understanding of the biology of aging . Antiaging research has led to a better understanding of the biological mechanisms underlying aging and age-related diseases, which could lead to the development of new interventions and therapies.

The progress in antiaging research has shown the potential to improve health and quality of life for older adults by promoting healthy aging and delaying the onset of age-related diseases. In pursuing a solution to the aging issues, it is necessary to keep clear in mind that the goal of research on aging hallmarks and antiaging strategies is not to enhance human longevity but to enhance healthy, active longevity, free from disability and functional incapacity. 403 , 448 Such understanding of aging has resulted in a shift in the approach for aging interventions from antiaging to healthy aging. Focusing on prevention may lead to new successes in achieving healthy aging. 449

Acknowledgments

The authors sincerely appreciate the CAS Data, Analytics & Insights team for their assistance in data extraction and Dharmini Patel for project coordination. The authors are grateful to Manuel Guzman, Gilles Georges, Michael Dennis, Dawn Riedel, Dawn George, and Hong Xie for executive sponsorship. The authors also appreciate the rest of the Science Connect team at CAS for their support and insightful discussions.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acschemneuro.3c00532 .

Table S1 listing antiaging drugs included in the CAS Content Collection (extended list); Table S2 listing ntural antiaging agents most widely represented in the CAS Content Collection including structures; Table S3 listing synthetic antiaging agents most widely represented in the CAS Content Collection including structures; Figure S1 showing yearly NIH funding for projects related to antiaging research ( PDF )

Author Contributions

R.T. and J.M.S: conceptualization, investigation, methodology, data acquisition, writing, editing. X.W.: investigation, writing, editing. Q.A.Z.: Conceptualization, investigation, methodology, validation, data and resource acquisition. All authors have approved the submitted final version.

The authors declare no competing financial interest.

Published ASAP January 12, 2024; Table 3 graphic reprocessed January 17, 2024 to correct production error.

Supplementary Material

cn3c00532_si_001.pdf

References

World Population Ageing. https://www.un.org/en/development/desa/population/publications/pdf/ageing/WPA2017_Highlights.pdf (accessed Jan 30, 2023).

Melzer D.; Pilling L. C.; Ferrucci L. The genetics of human ageing. Nat. Rev. Genet 2020, 21, 88–101. 10.1038/s41576-019-0183-6.

Cardano G.Opus novum cunctis de Sanitate tuenda ac vita producenda studiosis apprime necessarium; Apud Franciscum Zanettum, 1580.

Bernard C.Introduction à l’étude de la médecine expérimentale; JB Baillière, 1865.

Metchnikoff E.The Prolongation of Life: Optimistic Studies; 1923.

Harman D. Aging: a theory based on free radical and radiation chemistry. J. Gerontol 1956, 11, 298–300. 10.1093/geronj/11.3.298.

Metchnikoff E.The Nature of Man; Studies in Optimistic Philosophy; G. P. Putnam’s Sons: New York, 1903.

Müller H. The remaking of chromosomes. Collecting Net (Woods Hole) 1938, 8, 181–198.

McCay C. M.; Maynard L. A.; Sperling G.; Barnes L. L. Retarded Growth, Life Span, Ultimate Body Size and Age Changes in the Albino Rat after Feeding Diets Restricted in Calories: Four Figures. Journal of Nutrition 1939, 18, 1–13. 10.1093/jn/18.1.1.

Takaoka M. Resveratrol, a new phenolic compound, from Veratrum grandiflorum. Journal of the Chemical Society of Japan 1939, 60, 1090–1100. 10.1246/nikkashi1921.60.1090.

Medawar P. B.An Unsolved Problem of Biology; H. K. Lewis & Co.: London, 1952.

Williams G. C. Pleiotropy, Natural Selection, and the Evolution of Senescence. Evolution 1957, 11, 398–411. 10.1111/j.1558-5646.1957.tb02911.x.

Hayflick L. The Limited in Vitro Lifetime of Human Diploid Cell Strains. Exp. Cell Res. 1965, 37, 614–636. 10.1016/0014-4827(65)90211-9.

Hayflick L.; Moorhead P. S. The serial cultivation of human diploid cell strains. Exp. Cell Res. 1961, 25, 585–621. 10.1016/0014-4827(61)90192-6.

Watson J. D. Origin of concatemeric T7 DNA. Nat. New Biol. 1972, 239, 197–201. 10.1038/newbio239197a0.

Olovnikov A. M. A theory of marginotomy. The incomplete copying of template margin in enzymic synthesis of polynucleotides and biological significance of the phenomenon. J. Theor. Biol. 1973, 41, 181–190. 10.1016/0022-5193(73)90198-7.

National Institute on Aging (NIA). https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-institute-aging-nia (accessed Mar 5, 2023).

Johnson T. E.; Wood W. B. Genetic analysis of life-span in Caenorhabditis elegans. Proc. Natl. Acad. Sci. U. S. A. 1982, 79, 6603–6607. 10.1073/pnas.79.21.6603.

Greider C. W.; Blackburn E. H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 1985, 43, 405–413. 10.1016/0092-8674(85)90170-9.

Rose M. R.Evolutionary Biology of Aging; Oxford University Press: New York, 1991.

Rose M. R. Life history evolution with antagonistic pleiotropy and overlapping generations. Theoretical Population Biology 1985, 28, 342–358. 10.1016/0040-5809(85)90034-6.

Friedman D. B.; Johnson T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 1988, 118, 75–86. 10.1093/genetics/118.1.75.

Rudman D.; Feller A. G.; Nagraj H. S.; Gergans G. A.; Lalitha P. Y.; Goldberg A. F.; Schlenker R. A.; Cohn L.; Rudman I. W.; Mattson D. E. Effects of human growth hormone in men over 60 years old. New England journal of medicine 1990, 323, 1–6. 10.1056/NEJM199007053230101.

American Academy of Anti Aging Medicine. https://www.a4m.com/ (accessed May 5, 2023).

Kenyon C.; Chang J.; Gensch E.; Rudner A.; Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature 1993, 366, 461–464. 10.1038/366461a0.

Dimri G. P.; Lee X.; Basile G.; Acosta M.; Scott G.; Roskelley C.; Medrano E. E.; Linskens M.; Rubelj I.; Pereira-Smith O.; et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl. Acad. Sci. U. S. A. 1995, 92, 9363–9367. 10.1073/pnas.92.20.9363.

Ogg S.; Paradis S.; Gottlieb S.; Patterson G. I.; Lee L.; Tissenbaum H. A.; Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 1997, 389, 994–999. 10.1038/40194.

Frye R. A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem. Biophys. Res. Commun. 2000, 273, 793–798. 10.1006/bbrc.2000.3000.

Fabrizio P.; Pozza F.; Pletcher S. D.; Gendron C. M.; Longo V. D. Regulation of longevity and stress resistance by Sch9 in yeast. Science (New York, N.Y.) 2001, 292, 288–290. 10.1126/science.1059497.

Tatar M.; Kopelman A.; Epstein D.; Tu M. P.; Yin C. M.; Garofalo R. S. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science (New York, N.Y.) 2001, 292, 107–110. 10.1126/science.1057987.

Clancy D. J.; Gems D.; Harshman L. G.; Oldham S.; Stocker H.; Hafen E.; Leevers S. J.; Partridge L. Extension of life-span by loss of CHICO, a Drosophila insulin receptor substrate protein. Science (New York, N.Y.) 2001, 292, 104–106. 10.1126/science.1057991.

Interventions Testing Program. https://www.nia.nih.gov/research/dab/interventions-testing-program-itp/about-itp (accessed Mar 5, 2023).

Howitz K. T.; Bitterman K. J.; Cohen H. Y.; Lamming D. W.; Lavu S.; Wood J. G.; Zipkin R. E.; Chung P.; Kisielewski A.; Zhang L. L.; et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003, 425, 191–196. 10.1038/nature01960.

Wong K.-K.; Maser R. S.; Bachoo R. M.; Menon J.; Carrasco D. R.; Gu Y.; Alt F. W.; DePinho R. A. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 2003, 421, 643–648. 10.1038/nature01385.

Kennedy B. K.; Berger S. L.; Brunet A.; Campisi J.; Cuervo A. M.; Epel E. S.; Franceschi C.; Lithgow G. J.; Morimoto R. I.; Pessin J. E.; et al. Geroscience: linking aging to chronic disease. Cell 2014, 159, 709–713. 10.1016/j.cell.2014.10.039.

Hubbard B. P.; Sinclair D. A. Small molecule SIRT1 activators for the treatment of aging and age-related diseases. Trends Pharmacol. Sci. 2014, 35, 146–154. 10.1016/j.tips.2013.12.004.

Milne J. C.; Lambert P. D.; Schenk S.; Carney D. P.; Smith J. J.; Gagne D. J.; Jin L.; Boss O.; Perni R. B.; Vu C. B.; et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature 2007, 450, 712–716. 10.1038/nature06261.

Bartke A. Impact of reduced insulin-like growth factor-1/insulin signaling on aging in mammals: novel findings. Aging Cell 2008, 7, 285–290. 10.1111/j.1474-9726.2008.00387.x.

Harrison D. E.; Strong R.; Sharp Z. D.; Nelson J. F.; Astle C. M.; Flurkey K.; Nadon N. L.; Wilkinson J. E.; Frenkel K.; Carter C. S.; et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009, 460, 392–395. 10.1038/nature08221.

The Nobel Prize in Physiology or Medicine 2009. https://www.nobelprize.org/prizes/medicine/2009/press-release/ (accessed Mar 5, 2023).

Sahin E.; Colla S.; Liesa M.; Moslehi J.; Müller F. L.; Guo M.; Cooper M.; Kotton D.; Fabian A. J.; Walkey C.; et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 2011, 470, 359–365. 10.1038/nature09787.

Jaskelioff M.; Muller F. L.; Paik J. H.; Thomas E.; Jiang S.; Adams A. C.; Sahin E.; Kost-Alimova M.; Protopopov A.; Cadiñanos J.; et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature 2011, 469, 102–106. 10.1038/nature09603.

The Nobel Prize in Physiology or Medicine 2012. https://www.nobelprize.org/prizes/medicine/2012/press-release/ (accessed Mar 5, 2023).

Martin-Montalvo A.; Mercken E. M.; Mitchell S. J.; Palacios H. H.; Mote P. L.; Scheibye-Knudsen M.; Gomes A. P.; Ward T. M.; Minor R. K.; Blouin M. J.; et al. Metformin improves healthspan and lifespan in mice. Nat. Commun. 2013, 4, 2192. 10.1038/ncomms3192.

Sinclair D. A.; Guarente L. Small-Molecule Allosteric Activators of Sirtuins. Annual Review of Pharmacology and Toxicology 2014, 54, 363–380. 10.1146/annurev-pharmtox-010611-134657.

Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013, 14, R115. 10.1186/gb-2013-14-10-r115.

Mitchell S. J.; Martin-Montalvo A.; Mercken E. M.; Palacios H. H.; Ward T. M.; Abulwerdi G.; Minor R. K.; Vlasuk G. P.; Ellis J. L.; Sinclair D. A.; et al. The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet. Cell Rep 2014, 6, 836–843. 10.1016/j.celrep.2014.01.031.

Zhu Y.; Tchkonia T.; Pirtskhalava T.; Gower A. C.; Ding H.; Giorgadze N.; Palmer A. K.; Ikeno Y.; Hubbard G. B.; Lenburg M.; et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015, 14, 644–658. 10.1111/acel.12344.

Barzilai N.; Crandall J. P.; Kritchevsky S. B.; Espeland M. A. Metformin as a Tool to Target Aging. Cell Metab 2016, 23, 1060–1065. 10.1016/j.cmet.2016.05.011.

Wissler Gerdes E. O.; Misra A.; Netto J. M. E.; Tchkonia T.; Kirkland J. L. Strategies for late phase preclinical and early clinical trials of senolytics. Mechanisms of Ageing and Development 2021, 200, 111591. 10.1016/j.mad.2021.111591.

Hong J.; Yun C. O. Telomere Gene Therapy: Polarizing Therapeutic Goals for Treatment of Various Diseases. Cells 2019, 8, 392. 10.3390/cells8050392.

Suda M.; Shimizu I.; Katsuumi G.; Yoshida Y.; Hayashi Y.; Ikegami R.; Matsumoto N.; Yoshida Y.; Mikawa R.; Katayama A.; et al. Senolytic vaccination improves normal and pathological age-related phenotypes and increases lifespan in progeroid mice. Nature Aging 2021, 1, 1117–1126. 10.1038/s43587-021-00151-2.

Raghavachari N.; Dutta C. In search of better biomarkers of aging. https://www.nia.nih.gov/research/blog/2021/11/search-better-biomarkers-aging (accessed Mar 5, 2023).

Meer M.; Sehgal R.; Levine M. Aging Biomarkers for Clinical Trials and Drug Discovery. Innovation in Aging 2021, 5, 4–5. 10.1093/geroni/igab046.014.

Hartmann A.; Hartmann C.; Secci R.; Hermann A.; Fuellen G.; Walter M. Ranking Biomarkers of Aging by Citation Profiling and Effort Scoring. Front. Genet. 2021, 12, 686320. 10.3389/fgene.2021.686320.

Ziegler D. A.; Anguera J. A.; Gallen C. L.; Hsu W.-Y.; Wais P. E.; Gazzaley A. Leveraging technology to personalize cognitive enhancement methods in aging. Nature Aging 2022, 2, 475–483. 10.1038/s43587-022-00237-5.

Kalmukova O.; Kyryk V.; Dzerzhynsky M. CIRCADIAN RHYTHMS AND PERSONALIZED STRATEGIES FOR ANTI-AGING THERAPIES. Anti-Aging Eastern Europe 2022, 1, 19–27. 10.56543/aaeeu.2022.1.1.03.

Mattison J. A.; Colman R. J.; Beasley T. M.; Allison D. B.; Kemnitz J. W.; Roth G. S.; Ingram D. K.; Weindruch R.; de Cabo R.; Anderson R. M. Caloric restriction improves health and survival of rhesus monkeys. Nat. Commun. 2017, 8, 14063. 10.1038/ncomms14063.

Pifferi F.; Terrien J.; Marchal J.; Dal-Pan A.; Djelti F.; Hardy I.; Chahory S.; Cordonnier N.; Desquilbet L.; Hurion M.; et al. Caloric restriction increases lifespan but affects brain integrity in grey mouse lemur primates. Commun. Biol. 2018, 1, 30. 10.1038/s42003-018-0024-8.

Omodei D.; Fontana L. Calorie restriction and prevention of age-associated chronic disease. FEBS Lett. 2011, 585, 1537–1542. 10.1016/j.febslet.2011.03.015.

Campisi J.; Kapahi P.; Lithgow G. J.; Melov S.; Newman J. C.; Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature 2019, 571, 183–192. 10.1038/s41586-019-1365-2.

Creighton H. B.; McClintock B. A Correlation of Cytological and Genetical Crossing-Over in Zea Mays. Proc. Natl. Acad. Sci. U. S. A. 1931, 17, 492–497. 10.1073/pnas.17.8.492.

Harley C. B.; Futcher A. B.; Greider C. W. Telomeres shorten during ageing of human fibroblasts. Nature 1990, 345, 458–460. 10.1038/345458a0.

Cooke H. J.; Smith B. A. Variability at the telomeres of the human X/Y pseudoautosomal region. Cold Spring Harbor Symp. Quant. Biol. 1986, 51 (Part 1), 213–219. 10.1101/SQB.1986.051.01.026.

Aubert G.; Lansdorp P. M. Telomeres and Aging. Physiol. Rev. 2008, 88, 557–579. 10.1152/physrev.00026.2007.

Hayflick L. Living forever and dying in the attempt. Experimental Gerontology 2003, 38, 1231–1241. 10.1016/j.exger.2003.09.003.

Hornsby P. J. Short telomeres: cause or consequence of aging?. Aging Cell 2006, 5, 577–578. 10.1111/j.1474-9726.2006.00249.x.

Chakravarti D.; LaBella K. A.; DePinho R. A. Telomeres: history, health, and hallmarks of aging. Cell 2021, 184, 306–322. 10.1016/j.cell.2020.12.028.

Lee H. W.; Blasco M. A.; Gottlieb G. J.; Horner J. W. 2nd; Greider C. W.; DePinho R. A. Essential role of mouse telomerase in highly proliferative organs. Nature 1998, 392, 569–574. 10.1038/33345.

Rudolph K. L.; Chang S.; Lee H. W.; Blasco M.; Gottlieb G. J.; Greider C.; DePinho R. A. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell 1999, 96, 701–712. 10.1016/S0092-8674(00)80580-2.

Wu D.; Prives C. Relevance of the p53–MDM2 axis to aging. Cell Death & Differentiation 2018, 25, 169–179. 10.1038/cdd.2017.187.

Feng Z.; Lin M.; Wu R. The Regulation of Aging and Longevity: A New and Complex Role of p53. Genes Cancer 2011, 2, 443–452. 10.1177/1947601911410223.

Kapahi P.; Chen D.; Rogers A. N.; Katewa S. D.; Li P. W.; Thomas E. L.; Kockel L. With TOR, less is more: a key role for the conserved nutrient-sensing TOR pathway in aging. Cell Metab 2010, 11, 453–465. 10.1016/j.cmet.2010.05.001.

Sinclair D. A.; Guarente L. Extrachromosomal rDNA circles--a cause of aging in yeast. Cell 1997, 91, 1033–1042. 10.1016/S0092-8674(00)80493-6.

Ran F. A.; Hsu P. D.; Wright J.; Agarwala V.; Scott D. A.; Zhang F. Genome engineering using the CRISPR-Cas9 system. Nat. Protoc. 2013, 8, 2281–2308. 10.1038/nprot.2013.143.

Walker R. F. On the evolution of anti-aging medicine. Clin Interv Aging 2006, 1, 201–203. 10.2147/ciia.2006.1.3.201.

CAS Content Collection. https://www.cas.org/about/cas-content (accessed January 18, 2023).

Mahmoudi S.; Xu L.; Brunet A. Turning back time with emerging rejuvenation strategies. Nat. Cell Biol. 2019, 21, 32–43. 10.1038/s41556-018-0206-0.

López-Otín C.; Blasco M. A.; Partridge L.; Serrano M.; Kroemer G. The hallmarks of aging. Cell 2013, 153, 1194–1217. 10.1016/j.cell.2013.05.039.

López-Otín C.; Blasco M. A.; Partridge L.; Serrano M.; Kroemer G. Hallmarks of aging: An expanding universe. Cell 2023, 186, 243–278. 10.1016/j.cell.2022.11.001.

Shetty A. K.; Kodali M.; Upadhya R.; Madhu L. N. Emerging Anti-Aging Strategies - Scientific Basis and Efficacy. Aging Dis 2018, 9, 1165–1184. 10.14336/AD.2018.1026.

Tenchov R.; Sasso J. M.; Wang X.; Zhou Q. A. Aging Hallmarks and Progression and Age-Related Diseases: A Landscape View of Research Advancement. ACS Chem. Neurosci. 2024, 15, 1–30. 10.1021/acschemneuro.3c00531.

Conese M.; Carbone A.; Beccia E.; Angiolillo A. The Fountain of Youth: A Tale of Parabiosis, Stem Cells, and Rejuvenation. Open Med. (Wars) 2017, 12, 376–383. 10.1515/med-2017-0053.

Jack H.Anti-Aging: State of the Art. https://www.lesswrong.com/posts/RcifQCKkRc9XTjxC2/anti-aging-state-of-the-art (accessed Feb 3, 2023).

Conboy I. M.; Conboy M. J.; Wagers A. J.; Girma E. R.; Weissman I. L.; Rando T. A. Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 2005, 433, 760–764. 10.1038/nature03260.

Loffredo F. S.; Steinhauser M. L.; Jay S. M.; Gannon J.; Pancoast J. R.; Yalamanchi P.; Sinha M.; Dall’Osso C.; Khong D.; Shadrach J. L.; et al. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell 2013, 153, 828–839. 10.1016/j.cell.2013.04.015.

Katsimpardi L.; Litterman N. K.; Schein P. A.; Miller C. M.; Loffredo F. S.; Wojtkiewicz G. R.; Chen J. W.; Lee R. T.; Wagers A. J.; Rubin L. L. Vascular and neurogenic rejuvenation of the aging mouse brain by young systemic factors. Science (New York, N.Y.) 2014, 344, 630–634. 10.1126/science.1251141.

Sinha M.; Jang Y. C.; Oh J.; Khong D.; Wu E. Y.; Manohar R.; Miller C.; Regalado S. G.; Loffredo F. S.; Pancoast J. R.; et al. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle.. Science (New York, N.Y.) 2014, 344, 649–652. 10.1126/science.1251152.

Villeda S. A.; Luo J.; Mosher K. I.; Zou B.; Britschgi M.; Bieri G.; Stan T. M.; Fainberg N.; Ding Z.; Eggel A.; et al. The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011, 477, 90–94. 10.1038/nature10357.

Ludwig F. C.; Elashoff R. M. Mortality in syngeneic rat parabionts of different chronological age. Trans N Y Acad. Sci. 1972, 34, 582–587. 10.1111/j.2164-0947.1972.tb02712.x.

The PLasma for Alzheimer SymptoM Amelioration (PLASMA) Study (PLASMA). https://clinicaltrials.gov/ct2/show/NCT02256306 (accessed Feb 27, 2023).

Sha S. J.; Deutsch G. K.; Tian L.; Richardson K.; Coburn M.; Gaudioso J. L.; Marcal T.; Solomon E.; Boumis A.; Bet A.; et al. Safety, Tolerability, and Feasibility of Young Plasma Infusion in the Plasma for Alzheimer Symptom Amelioration Study: A Randomized Clinical Trial. JAMA Neurol 2019, 76, 35–40. 10.1001/jamaneurol.2018.3288.

Papadopoli D.; Boulay K.; Kazak L.; Pollak M.; Mallette F.; Topisirovic I.; Hulea L. mTOR as a central regulator of lifespan and aging. F1000Res 2019, 8, 998. 10.12688/f1000research.17196.1.

Saxton R. A.; Sabatini D. M. mTOR Signaling in Growth, Metabolism, and Disease. Cell 2017, 168, 960–976. 10.1016/j.cell.2017.02.004.

Uchenunu O.; Pollak M.; Topisirovic I.; Hulea L. Oncogenic kinases and perturbations in protein synthesis machinery and energetics in neoplasia. J. Mol. Endocrinol 2019, 62, R83–r103. 10.1530/JME-18-0058.

Noureldein M. H.; Eid A. A. Gut microbiota and mTOR signaling: Insight on a new pathophysiological interaction. Microb Pathog 2018, 118, 98–104. 10.1016/j.micpath.2018.03.021.

Heitman J.; Movva N. R.; Hall M. N. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science (New York, N.Y.) 1991, 253, 905–909. 10.1126/science.1715094.

Bhat M.; Robichaud N.; Hulea L.; Sonenberg N.; Pelletier J.; Topisirovic I. Targeting the translation machinery in cancer. Nature reviews. Drug discovery 2015, 14, 261–278. 10.1038/nrd4505.

Childs B. G.; Durik M.; Baker D. J.; van Deursen J. M. Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nat. Med. 2015, 21, 1424–1435. 10.1038/nm.4000.

Zhavoronkov A. Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections. Aging (Albany NY) 2020, 12, 6492–6510. 10.18632/aging.102988.

Byun H. O.; Lee Y. K.; Kim J. M.; Yoon G. From cell senescence to age-related diseases: differential mechanisms of action of senescence-associated secretory phenotypes. BMB Rep 2015, 48, 549–558. 10.5483/BMBRep.2015.48.10.122.

Young A. R.; Narita M. SASP reflects senescence. EMBO Rep 2009, 10, 228–230. 10.1038/embor.2009.22.

Laberge R. M.; Zhou L.; Sarantos M. R.; Rodier F.; Freund A.; de Keizer P. L.; Liu S.; Demaria M.; Cong Y. S.; Kapahi P.; et al. Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell 2012, 11, 569–578. 10.1111/j.1474-9726.2012.00818.x.

Liu S.; Uppal H.; Demaria M.; Desprez P.-Y.; Campisi J.; Kapahi P. Simvastatin suppresses breast cancer cell proliferation induced by senescent cells. Sci. Rep. 2016, 5, 17895. 10.1038/srep17895.

Xu M.; Tchkonia T.; Ding H.; Ogrodnik M.; Lubbers E. R.; Pirtskhalava T.; White T. A.; Johnson K. O.; Stout M. B.; Mezera V.; et al. JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl. Acad. Sci. U. S. A. 2015, 112, E6301–E6310. 10.1073/pnas.1515386112.

Xu M.; Palmer A. K.; Ding H.; Weivoda M. M.; Pirtskhalava T.; White T. A.; Sepe A.; Johnson K. O.; Stout M. B.; Giorgadze N.; et al. Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife 2015, 4, e12997 10.7554/eLife.12997.

Zhu Y.; Tchkonia T.; Fuhrmann-Stroissnigg H.; Dai H. M.; Ling Y. Y.; Stout M. B.; Pirtskhalava T.; Giorgadze N.; Johnson K. O.; Giles C. B.; et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 2016, 15, 428–435. 10.1111/acel.12445.

Soto-Gamez A.; Quax W. J.; Demaria M. Regulation of Survival Networks in Senescent Cells: From Mechanisms to Interventions. J. Mol. Biol. 2019, 431, 2629–2643. 10.1016/j.jmb.2019.05.036.

Khosla S.; Farr J. N.; Tchkonia T.; Kirkland J. L. The role of cellular senescence in ageing and endocrine disease. Nat. Rev. Endocrinol 2020, 16, 263–275. 10.1038/s41574-020-0335-y.

Fuhrmann-Stroissnigg H.; Ling Y. Y.; Zhao J.; McGowan S. J.; Zhu Y.; Brooks R. W.; Grassi D.; Gregg S. Q.; Stripay J. L.; Dorronsoro A.; et al. Identification of HSP90 inhibitors as a novel class of senolytics. Nat. Commun. 2017, 8, 422. 10.1038/s41467-017-00314-z.

Xiong S.; Patrushev N.; Forouzandeh F.; Hilenski L.; Alexander R. W. PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases. Cell Rep 2015, 12, 1391–1399. 10.1016/j.celrep.2015.07.047.

Hofmann J. W.; Zhao X.; De Cecco M.; Peterson A. L.; Pagliaroli L.; Manivannan J.; Hubbard G. B.; Ikeno Y.; Zhang Y.; Feng B.; et al. Reduced expression of MYC increases longevity and enhances healthspan. Cell 2015, 160, 477–488. 10.1016/j.cell.2014.12.016.

Xu Y.; Sun Z. Molecular Basis of Klotho: From Gene to Function in Aging. Endocrine Reviews 2015, 36, 174–193. 10.1210/er.2013-1079.

Buchanan S.; Combet E.; Stenvinkel P.; Shiels P. G. Klotho, Aging, and the Failing Kidney. Front. Endocrinol. 2020, 11, 560. 10.3389/fendo.2020.00560.

Takahashi K.; Yamanaka S. A decade of transcription factor-mediated reprogramming to pluripotency. Nat. Rev. Mol. Cell Biol. 2016, 17, 183–193. 10.1038/nrm.2016.8.

Takahashi K.; Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006, 126, 663–676. 10.1016/j.cell.2006.07.024.

Singh P. B.; Zacouto F. Nuclear reprogramming and epigenetic rejuvenation. J. Biosci 2010, 35, 315–319. 10.1007/s12038-010-0034-2.

Hou P.; Li Y.; Zhang X.; Liu C.; Guan J.; Li H.; Zhao T.; Ye J.; Yang W.; Liu K.; et al. Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds. Science (New York, N.Y.) 2013, 341, 651–654. 10.1126/science.1239278.

Ye J.; Ge J.; Zhang X.; Cheng L.; Zhang Z.; He S.; Wang Y.; Lin H.; Yang W.; Liu J.; et al. Pluripotent stem cells induced from mouse neural stem cells and small intestinal epithelial cells by small molecule compounds. Cell Res. 2016, 26, 34–45. 10.1038/cr.2015.142.

Kim Y.; Jeong J.; Choi D. Small-molecule-mediated reprogramming: a silver lining for regenerative medicine. Exp Mol. Med. 2020, 52, 213–226. 10.1038/s12276-020-0383-3.

Moradi S.; Mahdizadeh H.; Šarić T.; Kim J.; Harati J.; Shahsavarani H.; Greber B.; Moore J. B. Research and therapy with induced pluripotent stem cells (iPSCs): social, legal, and ethical considerations. Stem Cell Res. Ther. 2019, 10, 341. 10.1186/s13287-019-1455-y.

Olova N.; Simpson D. J.; Marioni R. E.; Chandra T. Partial reprogramming induces a steady decline in epigenetic age before loss of somatic identity. Aging Cell 2019, 18, e12877 10.1111/acel.12877.

Kuszel L.; Trzeciak T.; Richter M.; Czarny-Ratajczak M. Osteoarthritis and telomere shortening. Journal of Applied Genetics 2015, 56, 169–176. 10.1007/s13353-014-0251-8.

Carlquist J. F.; Knight S.; Cawthon R. M.; Le V. T.; Jared Bunch T.; Horne B. D.; Rollo J. S.; Huntinghouse J. A.; Brent Muhlestein J.; Anderson J. L. Shortened telomere length is associated with paroxysmal atrial fibrillation among cardiovascular patients enrolled in the Intermountain Heart Collaborative Study. Heart Rhythm 2016, 13, 21–27. 10.1016/j.hrthm.2015.07.032.

Hunt S. C.; Kimura M.; Hopkins P. N.; Carr J. J.; Heiss G.; Province M. A.; Aviv A. Leukocyte Telomere Length and Coronary Artery Calcium. American Journal of Cardiology 2015, 116, 214–218. 10.1016/j.amjcard.2015.03.060.

Blasco M. A. Telomere length, stem cells and aging. Nat. Chem. Biol. 2007, 3, 640–649. 10.1038/nchembio.2007.38.

Pereira B.; Ferreira M. G. Sowing the seeds of cancer: telomeres and age-associated tumorigenesis. Curr. Opin. Oncol. 2013, 25, 93. 10.1097/CCO.0b013e32835b6358.

Wang S.; Madu C. O.; Lu Y. Telomere and Its Role in Diseases. Oncomedicine 2019, 4, 1–9. 10.7150/oncm.28210.

de Jesus B. B.; Schneeberger K.; Vera E.; Tejera A.; Harley C. B.; Blasco M. A. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell 2011, 10, 604–621. 10.1111/j.1474-9726.2011.00700.x.

Bar C.; Huber N.; Beier F.; Blasco M. A. Therapeutic effect of androgen therapy in a mouse model of aplastic anemia produced by short telomeres. Haematologica 2015, 100, 1267–1274. 10.3324/haematol.2015.129239.

Calado R. T.; Yewdell W. T.; Wilkerson K. L.; Regal J. A.; Kajigaya S.; Stratakis C. A.; Young N. S. Sex hormones, acting on the TERT gene, increase telomerase activity in human primary hematopoietic cells. Blood 2009, 114, 2236–2243. 10.1182/blood-2008-09-178871.

Bernardes de Jesus B.; Vera E.; Schneeberger K.; Tejera A. M.; Ayuso E.; Bosch F.; Blasco M. A. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Molecular Medicine 2012, 4, 691–704. 10.1002/emmm.201200245.

Kouda K.; Iki M. Beneficial effects of mild stress (hormetic effects): dietary restriction and health. J. Physiol Anthropol 2010, 29, 127–132. 10.2114/jpa2.29.127.

Rattan S. I. Applying hormesis in aging research and therapy. Human & experimental toxicology 2001, 20, 281–285. (discussion 293–284) 10.1191/096032701701548034.

Rattan S. I. S. Rationale and methods of discovering hormetins as drugs for healthy ageing. Expert Opinion on Drug Discovery 2012, 7, 439–448. 10.1517/17460441.2012.677430.

Rattan S. I. Anti-ageing strategies: prevention or therapy? Showing ageing from within. EMBO Rep 2005, 6, S25–S29. 10.1038/sj.embor.7400401.

Hercus M. J.; Loeschcke V.; Rattan S. I. Lifespan extension of Drosophila melanogaster through hormesis by repeated mild heat stress. Biogerontology 2003, 4, 149–156. 10.1023/A:1024197806855.

Minois N. Longevity and aging: beneficial effects of exposure to mild stress. Biogerontology 2000, 1, 15–29. 10.1023/A:1010085823990.

Rattan S. I. The Future of Aging Interventions: Aging intervention, prevention, and therapy through hormesis. J. Gerontol., Ser. A 2004, 59, B705–B709. 10.1093/gerona/59.7.B705.

Wood J. G.; Rogina B.; Lavu S.; Howitz K.; Helfand S. L.; Tatar M.; Sinclair D. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004, 430, 686–689. 10.1038/nature02789.

Calabrese V.; Giordano J.; Ruggieri M.; Berritta D.; Trovato A.; Ontario M. L.; Bianchini R.; Calabrese E. J. Hormesis, cellular stress response, and redox homeostasis in autism spectrum disorders. J. Neurosci Res. 2016, 94, 1488–1498. 10.1002/jnr.23893.

Calabrese E. J.; Mattson M. P. How does hormesis impact biology, toxicology, and medicine?. npj Aging Mech. Dis. 2017, 3, 13. 10.1038/s41514-017-0013-z.

Calabrese V.; Cornelius C.; Dinkova-Kostova A. T.; Iavicoli I.; Di Paola R.; Koverech A.; Cuzzocrea S.; Rizzarelli E.; Calabrese E. J. Cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2012, 1822, 753–783. 10.1016/j.bbadis.2011.11.002.

Calabrese V.; Cornelius C.; Cuzzocrea S.; Iavicoli I.; Rizzarelli E.; Calabrese E. J. Hormesis, cellular stress response and vitagenes as critical determinants in aging and longevity. Mol. Aspects Med. 2011, 32, 279–304. 10.1016/j.mam.2011.10.007.

Zouboulis C. C.; Makrantonaki E. Hormonal therapy of intrinsic aging. Rejuvenation Res. 2012, 15, 302–312. 10.1089/rej.2011.1249.

Xu L.; Zhao Q.; Li K.; Zhang Y.; Wang C.; Hind K.; Wang L.; Liu Y.; Cheng X. The Role of Sex Hormones on Bone Mineral Density, Marrow Adiposity, and Muscle Adiposity in Middle-Aged and Older Men. Front Endocrinol (Lausanne) 2022, 13, 817418. 10.3389/fendo.2022.817418.

Tsujimura A. The Relationship between Testosterone Deficiency and Men’s Health. World J. Mens Health 2013, 31, 126–135. 10.5534/wjmh.2013.31.2.126.

Conde D. M.; Verdade R. C.; Valadares A. L. R.; Mella L. F. B.; Pedro A. O.; Costa-Paiva L. Menopause and cognitive impairment: A narrative review of current knowledge. World J. Psychiatry 2021, 11, 412–428. 10.5498/wjp.v11.i8.412.

AlAwlaqi A.; Amor H.; Hammadeh M. E. Role of hormones in hypoactive sexual desire disorder and current treatment. J. Turk Ger Gynecol Assoc 2017, 18, 210–218. 10.4274/jtgga.2017.0071.

Son D. H.; Park W. J.; Lee Y. J. Recent Advances in Anti-Aging Medicine. Korean J. Fam Med. 2019, 40, 289–296. 10.4082/kjfm.19.0087.

Perimenopause. https://my.clevelandclinic.org/health/diseases/21608-perimenopause (accessed Oct 25, 2023).

Santoro N.; Braunstein G. D.; Butts C. L.; Martin K. A.; McDermott M.; Pinkerton J. V. Compounded Bioidentical Hormones in Endocrinology Practice: An Endocrine Society Scientific Statement. J. Clin Endocrinol Metab 2016, 101, 1318–1343. 10.1210/jc.2016-1271.

Stuenkel C. A.; Manson J. E. Compounded Bioidentical Hormone Therapy: The National Academies Weigh In. JAMA Internal Medicine 2021, 181, 370–371. 10.1001/jamainternmed.2020.7232.

National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Health Sciences Policy; Committee on the Clinical Utility of Treating Patients with Compounded Bioidentical Hormone Replacement Therapy . In The Clinical Utility of Compounded Bioidentical Hormone Therapy: A Review of Safety, Effectiveness, and Use; Jackson L. M., Parker R. M., Mattison D. R., Eds.; National Academies Press (US): Washington. D.C., Copyright 2020. by the National Academy of Sciences. All rights reserved.

Stuenkel C. A.; Manson J. E. Compounded Bioidentical Hormone Therapy: Does the Regulatory Double Standard Harm Women?. JAMA Intern Med. 2017, 177, 1719–1720. 10.1001/jamainternmed.2017.5141.

Rossouw J. E.; Anderson G. L.; Prentice R. L.; LaCroix A. Z.; Kooperberg C.; Stefanick M. L.; Jackson R. D.; Beresford S. A.; Howard B. V.; Johnson K. C.; et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002, 288, 321–333. 10.1001/jama.288.3.321.

Samaras N.; Papadopoulou M. A.; Samaras D.; Ongaro F. Off-label use of hormones as an antiaging strategy: a review. Clin Interv Aging 2014, 9, 1175–1186. 10.2147/CIA.S48918.

Samaras N.; Samaras D.; Lang P. O.; Forster A.; Pichard C.; Frangos E.; Meyer P. A view of geriatrics through hormones. What is the relation between andropause and well-known geriatric syndromes?. Maturitas 2013, 74, 213–219. 10.1016/j.maturitas.2012.11.009.

Bain J. Andropause. Testosterone replacement therapy for aging men. Can. Fam. Physician 2001, 47, 91–97.

Emmelot-Vonk M. H.; Verhaar H. J.; Nakhai Pour H. R.; Aleman A.; Lock T. M.; Bosch J. L.; Grobbee D. E.; van der Schouw Y. T. Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial. JAMA 2008, 299, 39–52. 10.1001/jama.2007.51.

Kenny A. M.; Kleppinger A.; Annis K.; Rathier M.; Browner B.; Judge J. O.; McGee D. Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, low bone mass, and physical frailty. J. Am. Geriatr Soc. 2010, 58, 1134–1143. 10.1111/j.1532-5415.2010.02865.x.

Pierorazio P. M.; Ferrucci L.; Kettermann A.; Longo D. L.; Metter E. J.; Carter H. B. Serum testosterone is associated with aggressive prostate cancer in older men: results from the Baltimore Longitudinal Study of Aging. BJU Int. 2010, 105, 824–829. 10.1111/j.1464-410X.2009.08853.x.

Gao W.; Kim J.; Dalton J. T. Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands. Pharm. Res. 2006, 23, 1641–1658. 10.1007/s11095-006-9024-3.

Vignali J. D.; Pak K. C.; Beverley H. R.; DeLuca J. P.; Downs J. W.; Kress A. T.; Sadowski B. W.; Selig D. J. Systematic Review of Safety of Selective Androgen Receptor Modulators in Healthy Adults: Implications for Recreational Users. J. Xenobiot 2023, 13, 218–236. 10.3390/jox13020017.

Valenti G.; Denti L.; Maggio M.; Ceda G.; Volpato S.; Bandinelli S.; Ceresini G.; Cappola A.; Guralnik J. M.; Ferrucci L. Effect of DHEAS on skeletal muscle over the life span: the InCHIANTI study. J. Gerontol., Ser. A 2004, 59, 466–472. 10.1093/gerona/59.5.M466.

Clarke B. L.; Ebeling P. R.; Jones J. D.; Wahner H. W.; O’Fallon W. M.; Riggs B. L.; Fitzpatrick L. A. Predictors of bone mineral density in aging healthy men varies by skeletal site. Calcif Tissue Int. 2002, 70, 137–145. 10.1007/s00223-001-1072-4.

Barrett-Connor E.; Goodman-Gruen D.; Patay B. Endogenous sex hormones and cognitive function in older men. J. Clin. Endocrinol. Metab. 1999, 84, 3681–3685. 10.1210/jcem.84.10.6086.

Michael A.; Jenaway A.; Paykel E. S.; Herbert J. Altered salivary dehydroepiandrosterone levels in major depression in adults. Biol. Psychiatry 2000, 48, 989–995. 10.1016/S0006-3223(00)00955-0.

Tang J.; Chen L. R.; Chen K. H. The Utilization of Dehydroepiandrosterone as a Sexual Hormone Precursor in Premenopausal and Postmenopausal Women: An Overview. Pharmaceuticals (Basel) 2022, 15, 46. 10.3390/ph15010046.

Lazar M. A.; McIntyre R. S.. Chapter 34 - Novel Therapeutic Targets for Major Depressive Disorder. In Neurobiology of Depression; Quevedo J., Carvalho A. F., Zarate C. A., Eds.; Academic Press, 2019; pp 383–400.

Chimote B. N.; Chimote N. M.. Chapter Eight - Dehydroepiandrosterone (DHEA) and Its Sulfate (DHEA-S) in Mammalian Reproduction: Known Roles and Novel Paradigms. In Vitamins and Hormones; Litwack G., Ed.; Academic Press, 2018; Vol. 108, pp 223–250.

Genazzani A. D.; Lanzoni C.; Genazzani A. R. Might DHEA be considered a beneficial replacement therapy in the elderly?. Drugs Aging 2007, 24, 173–185. 10.2165/00002512-200724030-00001.

Nair K. S.; Rizza R. A.; O’Brien P.; Dhatariya K.; Short K. R.; Nehra A.; Vittone J. L.; Klee G. G.; Basu A.; Basu R.; et al. DHEA in elderly women and DHEA or testosterone in elderly men. New England journal of medicine 2006, 355, 1647–1659. 10.1056/NEJMoa054629.

Baquero F.; Nombela C. The microbiome as a human organ. Clin. Microbiol. Infect. 2012, 18 (Suppl. 4), 2–4. 10.1111/j.1469-0691.2012.03916.x.

Evans J. M.; Morris L. S.; Marchesi J. R. The gut microbiome: the role of a virtual organ in the endocrinology of the host. Journal of Endocrinology 2013, 218, R37–R47. 10.1530/JOE-13-0131.

Haseeb A.; Shahzad I.; Ghulam H.; Muhammad Naeem F.; Humaira M.; Imtiaz M.; Imran M.; Saima M.; Muhammad Irfan U.. Gut Microbiome: A New Organ System in Body. In Parasitology and Microbiology Research; Gilberto Antonio Bastidas P., Asghar Ali K., Eds.; IntechOpen: Rijeka, Croatia, 2019; Chapter 10.

Binstock R. H. Anti-aging medicine and research: a realm of conflict and profound societal implications. J. Gerontol A Biol. Sci. Med. Sci. 2004, 59, B523–533. 10.1093/gerona/59.6.B523.

Sasso J. M.; Ammar R. M.; Tenchov R.; Lemmel S.; Kelber O.; Grieswelle M.; Zhou Q. A. Gut Microbiome–Brain Alliance: A Landscape View into Mental and Gastrointestinal Health and Disorders. ACS Chem. Neurosci. 2023, 14, 1717–1763. 10.1021/acschemneuro.3c00127.

Cat L. A.The Decade Of The Microbiome. https://www.forbes.com/sites/linhanhcat/2019/12/31/decade-of-the-microbiome/?sh=7e621a679961 (accessed Oct 11, 2022).

Biagi E.; Franceschi C.; Rampelli S.; Severgnini M.; Ostan R.; Turroni S.; Consolandi C.; Quercia S.; Scurti M.; Monti D.; et al. Gut Microbiota and Extreme Longevity. Curr. Biol. 2016, 26, 1480–1485. 10.1016/j.cub.2016.04.016.

Perez Martínez G. P.; Bäuerl C.; Collado M. C. Understanding gut microbiota in elderly’s health will enable intervention through probiotics. Benefic. Microbes 2014, 5, 235–246. 10.3920/BM2013.0079.

Rondanelli M.; Giacosa A.; Faliva M. A.; Perna S.; Allieri F.; Castellazzi A. M. Review on microbiota and effectiveness of probiotics use in older. World J. Clin Cases 2015, 3, 156–162. 10.12998/wjcc.v3.i2.156.

Young V. B.; Hayden M. K. Environmental management in the gut: fecal transplantation to restore the intestinal ecosystem. Infect Dis (Lond) 2016, 48, 593–595. 10.1080/23744235.2016.1177200.

Konturek P. C.; Haziri D.; Brzozowski T.; Hess T.; Heyman S.; Kwiecien S.; Konturek S. J.; Koziel J. Emerging role of fecal microbiota therapy in the treatment of gastrointestinal and extra-gastrointestinal diseases. J. Physiol. Pharmacol. 2015, 66, 483–491.

Choi H. H.; Cho Y. S. Fecal Microbiota Transplantation: Current Applications, Effectiveness, and Future Perspectives. Clin Endosc 2016, 49, 257–265. 10.5946/ce.2015.117.

Martin B.; Mattson M. P.; Maudsley S. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res. Rev. 2006, 5, 332–353. 10.1016/j.arr.2006.04.002.

Cantó C.; Auwerx J. Calorie restriction: is AMPK a key sensor and effector?. Physiology (Bethesda) 2011, 26, 214–224. 10.1152/physiol.00010.2011.

Imai S. I.; Guarente L. It takes two to tango: NAD(+) and sirtuins in aging/longevity control. npj Aging Mech. Dis. 2016, 2, 16017. 10.1038/npjamd.2016.17.

Chio U. S.; Rechiche O.; Bryll A. R.; Zhu J.; Leith E. M.; Feldman J. L.; Peterson C. L.; Tan S.; Armache J.-P. Cryo-EM structure of the human Sirtuin 6–nucleosome complex. Sci. Adv. 2023, 9, eadf7586 10.1126/sciadv.adf7586.

Mitchell S. E.; Delville C.; Konstantopedos P.; Hurst J.; Derous D.; Green C.; Chen L.; Han J. J.; Wang Y.; Promislow D. E.; et al. The effects of graded levels of calorie restriction: II. Impact of short term calorie and protein restriction on circulating hormone levels, glucose homeostasis and oxidative stress in male C57BL/6 mice. Oncotarget 2015, 6, 23213–23237. 10.18632/oncotarget.4003.

Yang F.; Chu X.; Yin M.; Liu X.; Yuan H.; Niu Y.; Fu L. mTOR and autophagy in normal brain aging and caloric restriction ameliorating age-related cognition deficits. Behav Brain Res. 2014, 264, 82–90. 10.1016/j.bbr.2014.02.005.

Lee S. H.; Min K. J. Caloric restriction and its mimetics. BMB Rep 2013, 46, 181–187. 10.5483/BMBRep.2013.46.4.033.

Ingram D. K.; Roth G. S. Calorie restriction mimetics: can you have your cake and eat it, too?. Ageing Res. Rev. 2015, 20, 46–62. 10.1016/j.arr.2014.11.005.

Rebelo-Marques A.; De Sousa Lages A.; Andrade R.; Ribeiro C. F.; Mota-Pinto A.; Carrilho F.; Espregueira-Mendes J. Aging Hallmarks: The Benefits of Physical Exercise. Front. Endocrinol. 2018, 9, 258. 10.3389/fendo.2018.00258.

Garatachea N.; Pareja-Galeano H.; Sanchis-Gomar F.; Santos-Lozano A.; Fiuza-Luces C.; Morán M.; Emanuele E.; Joyner M. J.; Lucia A. Exercise attenuates the major hallmarks of aging. Rejuvenation research 2015, 18, 57–89. 10.1089/rej.2014.1623.

Nelson M. E.; Rejeski W. J.; Blair S. N.; Duncan P. W.; Judge J. O.; King A. C.; Macera C. A.; Castaneda-Sceppa C. Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association. Circulation 2007, 116, 1094. 10.1161/CIRCULATIONAHA.107.185650.

American College of Sports Medicine . ACSM’s Guidelines for Exercise Testing and Prescription. Lippincott Williams & Wilkins, 2013.

Brown W. M. Exercise-associated DNA methylation change in skeletal muscle and the importance of imprinted genes: a bioinformatics meta-analysis. British Journal of Sports Medicine 2015, 49, 1567–1578. 10.1136/bjsports-2014-094073.

Arsenis N. C.; You T.; Ogawa E. F.; Tinsley G. M.; Zuo L. Physical activity and telomere length: Impact of aging and potential mechanisms of action. Oncotarget 2017, 8, 45008. 10.18632/oncotarget.16726.

Morton J. P.; Kayani A. C.; McArdle A.; Drust B. The exercise-induced stress response of skeletal muscle, with specific emphasis on humans. Sports medicine 2009, 39, 643–662. 10.2165/00007256-200939080-00003.

Cona L. A.Stem Cells: Anti-Aging Treatment Breakthrough in 2023? https://www.dvcstem.com/post/anti-aging-stem-cells (accessed Mar 1, 2023).

Chang L.; Fan W.; Pan X.; Zhu X. Stem cells to reverse aging. Chin Med. J. (Engl) 2022, 135, 901–910. 10.1097/CM9.0000000000001984.

Alle Q.; Le Borgne E.; Milhavet O.; Lemaitre J. M. Reprogramming: Emerging Strategies to Rejuvenate Aging Cells and Tissues. Int. J. Mol. Sci. 2021, 22, 3990. 10.3390/ijms22083990.

Rauch C.; Feifel E.; Kern G.; Murphy C.; Meier F.; Parson W.; Beilmann M.; Jennings P.; Gstraunthaler G.; Wilmes A. Differentiation of human iPSCs into functional podocytes. PloS one 2018, 13, e0203869 10.1371/journal.pone.0203869.

Song B.; Smink A. M.; Jones C. V.; Callaghan J. M.; Firth S. D.; Bernard C. A.; Laslett A. L.; Kerr P. G.; Ricardo S. D. The directed differentiation of human iPS cells into kidney podocytes. PloS one 2012, 7, e46453 10.1371/journal.pone.0046453.

Fernandopulle M. S.; Prestil R.; Grunseich C.; Wang C.; Gan L.; Ward M. E. Transcription Factor-Mediated Differentiation of Human iPSCs into Neurons. Curr. Protoc. Cell Biol. 2018, 79, e51 10.1002/cpcb.51.

Yoder M. C. Differentiation of pluripotent stem cells into endothelial cells. Curr. Opin Hematol 2015, 22, 252–257. 10.1097/MOH.0000000000000140.

Acimovic I.; Vilotic A.; Pesl M.; Lacampagne A.; Dvorak P.; Rotrekl V.; Meli A. C. Human pluripotent stem cell-derived cardiomyocytes as research and therapeutic tools. BioMed Res. Int. 2014, 2014, 512831. 10.1155/2014/512831.

Deng Y. I.; Verron E.; Rohanizadeh R. Molecular Mechanisms of Anti-metastatic Activity of Curcumin. Anticancer Res. 2016, 36, 5639–5647. 10.21873/anticanres.11147.

Qin Y.; Xiao L.; Zhan X. B.; Zhou H. X. Pdxl and its role in activating Ngn3 and Pax6 to induce differentiation of iPSCs into islet β cells. Genet Mol. Res. 2015, 14, 8892–8900. 10.4238/2015.August.3.12.

Mianné J.; Ahmed E.; Bourguignon C.; Fieldes M.; Vachier I.; Bourdin A.; Assou S.; De Vos J. Induced Pluripotent Stem Cells for Primary Ciliary Dyskinesia Modeling and Personalized Medicine. Am. J. Respir. Cell Mol. Biol. 2018, 59, 672–683. 10.1165/rcmb.2018-0213TR.

Di Lullo E.; Kriegstein A. R. The use of brain organoids to investigate neural development and disease. Nat. Rev. Neurosci 2017, 18, 573–584. 10.1038/nrn.2017.107.

Heide M.; Huttner W. B.; Mora-Bermúdez F. Brain organoids as models to study human neocortex development and evolution. Curr. Opin Cell Biol. 2018, 55, 8–16. 10.1016/j.ceb.2018.06.006.

Seto Y.; Eiraku M. Human brain development and its in vitro recapitulation. Neurosci Res. 2019, 138, 33–42. 10.1016/j.neures.2018.09.011.

Serra D.; Mayr U.; Boni A.; Lukonin I.; Rempfler M.; Challet Meylan L.; Stadler M. B.; Strnad P.; Papasaikas P.; Vischi D.; et al. Self-organization and symmetry breaking in intestinal organoid development. Nature 2019, 569, 66–72. 10.1038/s41586-019-1146-y.

Yin Y. B.; de Jonge H. R.; Wu X.; Yin Y. L. Mini-gut: a promising model for drug development. Drug Discov Today 2019, 24, 1784–1794. 10.1016/j.drudis.2019.06.006.

Nishinakamura R. Human kidney organoids: progress and remaining challenges. Nat. Rev. Nephrol 2019, 15, 613–624. 10.1038/s41581-019-0176-x.

Hulot J. S. Modeling Cardiac Arrhythmias With Organoids. J. Am. Coll Cardiol 2019, 73, 2325–2327. 10.1016/j.jacc.2019.01.076.

Nugraha B.; Buono M. F.; von Boehmer L.; Hoerstrup S. P.; Emmert M. Y. Human Cardiac Organoids for Disease Modeling. Clin Pharmacol Ther 2019, 105, 79–85. 10.1002/cpt.1286.

Pesl M.; Acimovic I.; Pribyl J.; Hezova R.; Vilotic A.; Fauconnier J.; Vrbsky J.; Kruzliak P.; Skladal P.; Kara T.; et al. Forced aggregation and defined factors allow highly uniform-sized embryoid bodies and functional cardiomyocytes from human embryonic and induced pluripotent stem cells. Heart Vessels 2014, 29, 834–846. 10.1007/s00380-013-0436-9.

Brooks M. J.; Chen H. Y.; Kelley R. A.; Mondal A. K.; Nagashima K.; De Val N.; Li T.; Chaitankar V.; Swaroop A. Improved Retinal Organoid Differentiation by Modulating Signaling Pathways Revealed by Comparative Transcriptome Analyses with Development In Vivo. Stem Cell Reports 2019, 13, 891–905. 10.1016/j.stemcr.2019.09.009.

Lee J. S.; Kim B. S.; Seo D.; Park J. H.; Cho D. W. Three-Dimensional Cell Printing of Large-Volume Tissues: Application to Ear Regeneration. Tissue Eng. Part C Methods 2017, 23, 136–145. 10.1089/ten.tec.2016.0362.

Liu T. K.; Pang Y.; Zhou Z. Z.; Yao R.; Sun W. An integrated cell printing system for the construction of heterogeneous tissue models. Acta Biomater 2019, 95, 245–257. 10.1016/j.actbio.2019.05.052.

Zhang K.; Chou C. K.; Xia X.; Hung M. C.; Qin L. Block-Cell-Printing for live single-cell printing. Proc. Natl. Acad. Sci. U. S. A. 2014, 111, 2948–2953. 10.1073/pnas.1313661111.

Chen Y.; Hamidu S.; Yang X.; Yan Y.; Wang Q.; Li L.; Oduro P. K.; Li Y. Dietary Supplements and Natural Products: An Update on Their Clinical Effectiveness and Molecular Mechanisms of Action During Accelerated Biological Aging. Front. Genet. 2022, 13, 880421. 10.3389/fgene.2022.880421.

Garay R. P. Investigational drugs and nutrients for human longevity. Recent clinical trials registered in ClinicalTrials.gov and clinicaltrialsregister.eu. Expert Opin Investig Drugs 2021, 30, 749–758. 10.1080/13543784.2021.1939306.

Bima A. I.; Mahdi A. S.; Al Fayez F. F.; Khawaja T. M.; Abo El-Khair S. M.; Elsamanoudy A. Z. Cellular Senescence and Vitamin D Deficiency Play a Role in the Pathogenesis of Obesity-Associated Subclinical Atherosclerosis: Study of the Potential Protective Role of Vitamin D Supplementation. Cells 2021, 10, 920. 10.3390/cells10040920.

He J.; Wang H.; Shi J.; Shi M.; Sun W. 1,25-Dihydroxyvitamin D deficiency accelerates male reproductive senescence in aging mice and 1,25(OH)2D3 alleviates oxidative stress via NF-κB/SOD. American Journal of Physiology-Endocrinology and Metabolism 2021, 320, E732–E746. 10.1152/ajpendo.00531.2020.

Yang R.; Zhang J.; Li J.; Qin R.; Chen J.; Wang R.; Goltzman D.; Miao D. Inhibition of Nrf2 degradation alleviates age-related osteoporosis induced by 1,25-Dihydroxyvitamin D deficiency. Free Radic Biol. Med. 2022, 178, 246–261. 10.1016/j.freeradbiomed.2021.12.010.

Jolliffe D. A.; Camargo C. A. Jr.; Sluyter J. D.; Aglipay M.; Aloia J. F.; Ganmaa D.; Bergman P.; Bischoff-Ferrari H. A.; Borzutzky A.; Damsgaard C. T.; et al. Vitamin D supplementation to prevent acute respiratory infections: a systematic review and meta-analysis of aggregate data from randomised controlled trials. Lancet Diabetes Endocrinol 2021, 9, 276–292. 10.1016/S2213-8587(21)00051-6.

Crosta F.; Stefani A.; Melani F.; Fabrizzi P.; Nizzardo A.; Grassi D.; Bocale R.; Necozione S.; Lombardi F.; Castelli V.; et al. Improvement of Executive Function after Short-Term Administration of an Antioxidants Mix Containing Bacopa, Lycopene, Astaxanthin and Vitamin B12: The BLAtwelve Study. Nutrients 2021, 13, 56. 10.3390/nu13010056.

Iuliano S.; Poon S.; Robbins J.; Bui M.; Wang X.; De Groot L.; Van Loan M.; Zadeh A. G.; Nguyen T.; Seeman E. Effect of dietary sources of calcium and protein on hip fractures and falls in older adults in residential care: cluster randomised controlled trial. Bmj 2021, 375, n2364. 10.1136/bmj.n2364.

Wallace T. C.; Bailey R. L.; Lappe J.; O’Brien K. O.; Wang D. D.; Sahni S.; Weaver C. M. Dairy intake and bone health across the lifespan: a systematic review and expert narrative. Crit Rev. Food Sci. Nutr 2021, 61, 3661–3707. 10.1080/10408398.2020.1810624.

de Almeida Brasiel P. G. The key role of zinc in elderly immunity: A possible approach in the COVID-19 crisis. Clin Nutr ESPEN 2020, 38, 65–66. 10.1016/j.clnesp.2020.06.003.

Emri E.; Kortvely E.; Dammeier S.; Klose F.; Simpson D.; Consortium E.-R.; den Hollander A. I.; Ueffing M.; Lengyel I. A Multi-Omics Approach Identifies Key Regulatory Pathways Induced by Long-Term Zinc Supplementation in Human Primary Retinal Pigment Epithelium. Nutrients 2020, 12, 3051. 10.3390/nu12103051.

Wu J.; Cho E.; Giovannucci E. L.; Rosner B. A.; Sastry S. M.; Willett W. C.; Schaumberg D. A. Dietary Intakes of Eicosapentaenoic Acid and Docosahexaenoic Acid and Risk of Age-Related Macular Degeneration. Ophthalmology 2017, 124, 634–643. 10.1016/j.ophtha.2016.12.033.

Arslan S.; Kadayifçilar S.; Samur G. The Potential Role of Dietary Antioxidant Capacity in Preventing Age-Related Macular Degeneration. Journal of the American College of Nutrition 2019, 38, 424–432. 10.1080/07315724.2018.1538830.

Harris W. S.; Tintle N. L.; Imamura F.; Qian F.; Korat A. V. A.; Marklund M.; Djoussé L.; Bassett J. K.; Carmichael P. H.; Chen Y. Y.; et al. Blood n-3 fatty acid levels and total and cause-specific mortality from 17 prospective studies. Nat. Commun. 2021, 12, 2329. 10.1038/s41467-021-22370-2.

Del Brutto O. H.; Mera R. M.; Gillman J.; Zambrano M.; Ha J. E. Oily Fish Intake and Cognitive Performance in Community-Dwelling Older Adults: The Atahualpa Project. J. Community Health 2016, 41, 82–86. 10.1007/s10900-015-0070-9.

Kuszewski J. C.; Wong R. H. X.; Howe P. R. C. Effects of Long-Chain Omega-3 Polyunsaturated Fatty Acids on Endothelial Vasodilator Function and Cognition-Are They Interrelated?. Nutrients 2017, 9, 487. 10.3390/nu9050487.

Bagherniya M.; Butler A. E.; Barreto G. E.; Sahebkar A. The effect of fasting or calorie restriction on autophagy induction: A review of the literature. Ageing Res. Rev. 2018, 47, 183–197. 10.1016/j.arr.2018.08.004.

Redmann M.; Darley-Usmar V.; Zhang J. The Role of Autophagy, Mitophagy and Lysosomal Functions in Modulating Bioenergetics and Survival in the Context of Redox and Proteotoxic Damage: Implications for Neurodegenerative Diseases. Aging Dis 2016, 7, 150–162. 10.14336/AD.2015.0820.

Scrivo A.; Bourdenx M.; Pampliega O.; Cuervo A. M. Selective autophagy as a potential therapeutic target for neurodegenerative disorders. Lancet Neurol 2018, 17, 802–815. 10.1016/S1474-4422(18)30238-2.

Moors T. E.; Hoozemans J. J.; Ingrassia A.; Beccari T.; Parnetti L.; Chartier-Harlin M. C.; van de Berg W. D. Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease. Mol. Neurodegener 2017, 12, 11. 10.1186/s13024-017-0154-3.

Li Y.; Wang K.; Zhou K.; Guo W.; Dai B.; Liang Y.; Dai J.; Cui M. Novel D-A-D based near-infrared probes for the detection of β-amyloid and Tau fibrils in Alzheimer’s disease. Chem. Commun. (Camb) 2018, 54, 8717–8720. 10.1039/C8CC05259J.

Hamano T.; Hayashi K.; Shirafuji N.; Nakamoto Y. The Implications of Autophagy in Alzheimer’s Disease. Curr. Alzheimer Res. 2018, 15, 1283–1296. 10.2174/1567205015666181004143432.

Gelino S.; Chang J. T.; Kumsta C.; She X.; Davis A.; Nguyen C.; Panowski S.; Hansen M. Intestinal Autophagy Improves Healthspan and Longevity in C. elegans during Dietary Restriction. PLoS Genet 2016, 12, e1006135 10.1371/journal.pgen.1006135.

Madeo F.; Zimmermann A.; Maiuri M. C.; Kroemer G. Essential role for autophagy in life span extension. J. Clin Invest 2015, 125, 85–93. 10.1172/JCI73946.

Shakeri A.; Cicero A. F. G.; Panahi Y.; Mohajeri M.; Sahebkar A. Curcumin: A naturally occurring autophagy modulator. J. Cell Physiol 2019, 234, 5643–5654. 10.1002/jcp.27404.

Revuelta M.; Matheu A. Autophagy in stem cell aging. Aging Cell 2017, 16, 912–915. 10.1111/acel.12655.

Ferreira L. K.; Busatto G. F. Resting-state functional connectivity in normal brain aging. Neurosci Biobehav Rev. 2013, 37, 384–400. 10.1016/j.neubiorev.2013.01.017.

Damoiseaux J. S. Effects of aging on functional and structural brain connectivity. NeuroImage 2017, 160, 32–40. 10.1016/j.neuroimage.2017.01.077.

Cognitive Health and Older Adults. https://www.nia.nih.gov/health/cognitive-health-and-older-adults (accessed Apr 26, 2023).

Trajano G. S.; Blazevich A. J. Static Stretching Reduces Motoneuron Excitability: The Potential Role of Neuromodulation. Exerc Sport Sci. Rev. 2021, 49, 126–132. 10.1249/JES.0000000000000243.

Wahl D.; Solon-Biet S. M.; Cogger V. C.; Fontana L.; Simpson S. J.; Le Couteur D. G.; Ribeiro R. V. Aging, lifestyle and dementia. Neurobiol Dis 2019, 130, 104481. 10.1016/j.nbd.2019.104481.

Mattson M. P.; Arumugam T. V. Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab 2018, 27, 1176–1199. 10.1016/j.cmet.2018.05.011.

Berchtold N. C.; Prieto G. A.; Phelan M.; Gillen D. L.; Baldi P.; Bennett D. A.; Buchman A. S.; Cotman C. W. Hippocampal gene expression patterns linked to late-life physical activity oppose age and AD-related transcriptional decline. Neurobiol Aging 2019, 78, 142–154. 10.1016/j.neurobiolaging.2019.02.012.

van Praag H.; Christie B. R.; Sejnowski T. J.; Gage F. H. Running enhances neurogenesis, learning, and long-term potentiation in mice. Proc. Natl. Acad. Sci. U. S. A. 1999, 96, 13427–13431. 10.1073/pnas.96.23.13427.

van Praag H.; Shubert T.; Zhao C.; Gage F. H. Exercise enhances learning and hippocampal neurogenesis in aged mice. J. Neurosci. 2005, 25, 8680–8685. 10.1523/JNEUROSCI.1731-05.2005.

Parker A.; Romano S.; Ansorge R.; Aboelnour A.; Le Gall G.; Savva G. M.; Pontifex M. G.; Telatin A.; Baker D.; Jones E.; et al. Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome 2022, 10, 68. 10.1186/s40168-022-01243-w.

Koene S.; Smeitink J. Metabolic manipulators: a well founded strategy to combat mitochondrial dysfunction. J. Inherit Metab Dis 2011, 34, 315–325. 10.1007/s10545-010-9162-y.

Rastaldo R.; Vitale E.; Giachino C. Dual Role of Autophagy in Regulation of Mesenchymal Stem Cell Senescence. Front. Cell Dev. Biol. 2020, 8, 276. 10.3389/fcell.2020.00276.

Hussey B.; Lindley M. R.; Mastana S. Epigenetics and epigenomics: the future of nutritional interventions? Future. Science 2017, 3, FSO237. 10.4155/fsoa-2017-0088.

Nicodemus-Johnson J.; Sinnott R. A. Fruit and Juice Epigenetic Signatures Are Associated with Independent Immunoregulatory Pathways. Nutrients 2017, 9, 752. 10.3390/nu9070752.

Wesselink E.; Koekkoek W. A. C.; Grefte S.; Witkamp R. F.; van Zanten A. R. H. Feeding mitochondria: Potential role of nutritional components to improve critical illness convalescence. Clinical Nutrition 2019, 38, 982–995. 10.1016/j.clnu.2018.08.032.

Perico N.; Casiraghi F.; Remuzzi G. Clinical Translation of Mesenchymal Stromal Cell Therapies in Nephrology. J. Am. Soc. Nephrol 2018, 29, 362–375. 10.1681/ASN.2017070781.

Yang H.-C.; Rossini M.; Ma L.-J.; Zuo Y.; Ma J.; Fogo A. B. Cells Derived from Young Bone Marrow Alleviate Renal Aging. J. Am. Soc. Nephrol. 2011, 22, 2028. 10.1681/ASN.2010090982.

Special Issue “Nutritional Regulation of Lipid Metabolism and Health”. Nutrients 2021, 13.

Stem Cell Transplants in Cancer Treatment. https://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant#1 (accessed Mar 24, 2023).

Chu D. T.; Nguyen T. T.; Tien N. L. B.; Tran D. K.; Jeong J. H.; Anh P. G.; Thanh V. V.; Truong D. T.; Dinh T. C. Recent Progress of Stem Cell Therapy in Cancer Treatment: Molecular Mechanisms and Potential Applications. Cells 2020, 9, 563. 10.3390/cells9030563.

Chen H. J., Thakur A.. How stem cell therapies can provide new ways to stop tumors from spreading or growing back. https://pme.uchicago.edu/news/how-stem-cell-therapies-can-provide-new-ways-stop-tumors-spreading-or-growing-back (accessed Mar 24, 2023).

Jin X.; Jin X.; Kim H. Cancer stem cells and differentiation therapy. Tumor Biol. 2017, 39, 1010428317729933 10.1177/1010428317729933.

Mao Z.; Zhang W. Role of mTOR in Glucose and Lipid Metabolism. Int. J. Mol. Sci. 2018, 19, 2043. 10.3390/ijms19072043.

Warburton D. E.; Nicol C. W.; Bredin S. S. Health benefits of physical activity: the evidence. Cmaj 2006, 174, 801–809. 10.1503/cmaj.051351.

Kivipelto M.; Solomon A.; Ahtiluoto S.; Ngandu T.; Lehtisalo J.; Antikainen R.; Bäckman L.; Hänninen T.; Jula A.; Laatikainen T. The Finnish geriatric intervention study to prevent cognitive impairment and disability (FINGER): study design and progress. Alzheimer’s Dementia 2013, 9, 657–665. 10.1016/j.jalz.2012.09.012.

Lehtisalo J.; Levälahti E.; Lindström J.; Hänninen T.; Paajanen T.; Peltonen M.; Antikainen R.; Laatikainen T.; Strandberg T.; Soininen H.; et al. Dietary changes and cognition over 2 years within a multidomain intervention trial—The Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER). Alzheimer’s Dementia 2019, 15, 410–417. 10.1016/j.jalz.2018.10.001.

Ho M.; Ho J. W.; Fong D. Y.; Lee C.; Macfarlane D. J.; Cerin E.; Lee A. M.; Leung S.; Chan W. Y.; Leung I. P.; et al. Effects of dietary and physical activity interventions on generic and cancer-specific health-related quality of life, anxiety, and depression in colorectal cancer survivors: a randomized controlled trial. J. Cancer Survivorship 2020, 14, 424–433. 10.1007/s11764-020-00864-0.

Gambacciani M.; Levancini M. Hormone replacement therapy and the prevention of postmenopausal osteoporosis. Przegl. Menopauzalny 2014, 13, 213–220. 10.5114/pm.2014.44996.

Camacho P. M.Estrogen Replacement Therapy for Osteoporosis. https://www.endocrineweb.com/conditions/osteoporosis/estrogen-replacement-therapy-osteoporosis (accessed Mar 24, 2023).

Osteoporosis: Diagnosis and Treatment. https://www.webmd.com/osteoporosis/guide/understanding-osteoporosis-treatment (accessed Mar 24, 2023).

Vaiserman A. M.; Lushchak O. V.. Chapter 1 - Geroscience—The concept. In Anti-Aging Pharmacology; Koltover V. K., Ed.; Academic Press, 2023; pp 1–12.

Martel J.; Chang S.-H.; Wu C.-Y.; Peng H.-H.; Hwang T.-L.; Ko Y.-F.; Young J. D.; Ojcius D. M. Recent advances in the field of caloric restriction mimetics and anti-aging molecules. Ageing Research Reviews 2021, 66, 101240. 10.1016/j.arr.2020.101240.

Vaiserman A. M.; Lushchak O. V.; Koliada A. K. Anti-aging pharmacology: Promises and pitfalls. Ageing Res. Rev. 2016, 31, 9–35. 10.1016/j.arr.2016.08.004.

Kirkland J.; Tchkonia T. Senolytic drugs: from discovery to translation. Journal of internal medicine 2020, 288, 518–536. 10.1111/joim.13141.

Vaiserman A.; Pasyukova E. G.. Epigenetic Drugs: A Novel Anti-Aging Strategy?; Frontiers Media SA:, 2012; Vol. 3, p 224.

Vaiserman A.; Koliada A.; Lushchak O.; Castillo M. J. Repurposing drugs to fight aging: The difficult path from bench to bedside. Medicinal Research Reviews 2021, 41, 1676–1700. 10.1002/med.21773.

Binic I.; Lazarevic V.; Ljubenovic M.; Mojsa J.; Sokolovic D. Skin ageing: natural weapons and strategies. Evidence-Based Complementary Altern. Med. 2013, 2013, 827248. 10.1155/2013/827248.

Shen C. Y.; Jiang J. G.; Yang L.; Wang D. W.; Zhu W. Anti-ageing active ingredients from herbs and nutraceuticals used in traditional Chinese medicine: pharmacological mechanisms and implications for drug discovery. Br. J. Pharmacol. 2017, 174, 1395–1425. 10.1111/bph.13631.

Corrêa R. C. G.; Peralta R. M.; Haminiuk C. W. I.; Maciel G. M.; Bracht A.; Ferreira I. New phytochemicals as potential human anti-aging compounds: Reality, promise, and challenges. Crit Rev. Food Sci. Nutr 2018, 58, 942–957. 10.1080/10408398.2016.1233860.

Ding A. J.; Zheng S. Q.; Huang X. B.; Xing T. K.; Wu G. S.; Sun H. Y.; Qi S. H.; Luo H. R. Current Perspective in the Discovery of Anti-aging Agents from Natural Products. Nat. Prod Bioprospect 2017, 7, 335–404. 10.1007/s13659-017-0135-9.

Martel J.; Ojcius D. M.; Ko Y. F.; Chang C. J.; Young J. D. Antiaging effects of bioactive molecules isolated from plants and fungi. Med. Res. Rev. 2019, 39, 1515–1552. 10.1002/med.21559.

Lane M.; Ingram D.; Roth G. 2-Deoxy-D-Glucose Feeding in Rats Mimics Physiologic Effects of Calorie Restriction. Journal of Anti-Aging Medicine 1998, 1, 327–337. 10.1089/rej.1.1998.1.327.

Madeo F.; Carmona-Gutierrez D.; Hofer S. J.; Kroemer G. Caloric restriction mimetics against age-associated disease: targets, mechanisms, and therapeutic potential. Cell metabolism 2019, 29, 592–610. 10.1016/j.cmet.2019.01.018.

Johnson S. C.; Rabinovitch P. S.; Kaeberlein M. mTOR is a key modulator of ageing and age-related disease. Nature 2013, 493, 338–345. 10.1038/nature11861.

Kennedy B. K.; Lamming D. W. The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell metabolism 2016, 23, 990–1003. 10.1016/j.cmet.2016.05.009.

Boutouja F.; Stiehm C. M.; Platta H. W. mTOR: a cellular regulator interface in health and disease. Cells 2019, 8, 18. 10.3390/cells8010018.

SciFinder-n. https://scifinder-n.cas.org/ (accessed Apr 14, 2022).

Benade V.; Jayarajan P.; Krishnadas N.; Kamuju V.; Gandipudi S.; Nirogi R. Metformin, a calorie restriction mimetic for the treatment of Alzheimer’s disease: A preclinical investigation. Alzheimer’s Dementia 2021, 17, e051635 10.1002/alz.051635.

Foretz M.; Guigas B.; Bertrand L.; Pollak M.; Viollet B. Metformin: from mechanisms of action to therapies. Cell metabolism 2014, 20, 953–966. 10.1016/j.cmet.2014.09.018.

Greenhill C. Metformin improves survival and recurrence rate in patients with diabetes and gastric cancer. Nature reviews Gastroenterology & hepatology 2015, 12, 124–124. 10.1038/nrgastro.2015.9.

Campbell J. M.; Bellman S. M.; Stephenson M. D.; Lisy K. Metformin reduces all-cause mortality and diseases of ageing independent of its effect on diabetes control: a systematic review and meta-analysis. Ageing Res. Rev. 2017, 40, 31–44. 10.1016/j.arr.2017.08.003.

Porter K. M.; Ward M.; Hughes C. F.; O’Kane M.; Hoey L.; McCann A.; Molloy A. M.; Cunningham C.; Casey M. C.; Tracey F.; et al. Hyperglycemia and metformin use are associated with B vitamin deficiency and cognitive dysfunction in older adults. J. Clin. Endocrinol. Metab. 2019, 104, 4837–4847. 10.1210/jc.2018-01791.

Ozata M.; Oktenli C.; Bingol N.; Ozdemir I. C. The effects of metformin and diet on plasma testosterone and leptin levels in obese men. Obesity research 2001, 9, 662–667. 10.1038/oby.2001.90.

de Ligt M.; Timmers S.; Schrauwen P. Resveratrol and obesity: Can resveratrol relieve metabolic disturbances?. Biochimica et biophysica acta (BBA)-molecular basis of disease 2015, 1852, 1137–1144. 10.1016/j.bbadis.2014.11.012.

Valenzano D. R.; Terzibasi E.; Genade T.; Cattaneo A.; Domenici L.; Cellerino A. Resveratrol prolongs lifespan and retards the onset of age-related markers in a short-lived vertebrate. Current biology 2006, 16, 296–300. 10.1016/j.cub.2005.12.038.

Yu X.; Li G. Effects of resveratrol on longevity, cognitive ability and aging-related histological markers in the annual fish Nothobranchius guentheri. Experimental gerontology 2012, 47, 940–949. 10.1016/j.exger.2012.08.009.

Bhullar K. S.; Hubbard B. P. Lifespan and healthspan extension by resveratrol. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 2015, 1852, 1209–1218. 10.1016/j.bbadis.2015.01.012.

Kaeberlein M.; McDonagh T.; Heltweg B.; Hixon J.; Westman E. A.; Caldwell S. D.; Napper A.; Curtis R.; DiStefano P. S.; Fields S.; et al. Substrate-specific activation of sirtuins by resveratrol. J. Biol. Chem. 2005, 280, 17038–17045. 10.1074/jbc.M500655200.

Rajman L.; Chwalek K.; Sinclair D. A. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell metabolism 2018, 27, 529–547. 10.1016/j.cmet.2018.02.011.

Lagouge M.; Argmann C.; Gerhart-Hines Z.; Meziane H.; Lerin C.; Daussin F.; Messadeq N.; Milne J.; Lambert P.; Elliott P.; et al. Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. Cell 2006, 127, 1109–1122. 10.1016/j.cell.2006.11.013.

Price N. L.; Gomes A. P.; Ling A. J.; Duarte F. V.; Martin-Montalvo A.; North B. J.; Agarwal B.; Ye L.; Ramadori G.; Teodoro J. S.; et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012, 15, 675–690. 10.1016/j.cmet.2012.04.003.

Morselli E.; Mariño G.; Bennetzen M. V.; Eisenberg T.; Megalou E.; Schroeder S.; Cabrera S.; Bénit P.; Rustin P.; Criollo A.; et al. Spermidine and resveratrol induce autophagy by distinct pathways converging on the acetylproteome. J. Cell Biol. 2011, 192, 615–629. 10.1083/jcb.201008167.

Pietrocola F.; Mariño G.; Lissa D.; Vacchelli E.; Malik S. A.; Niso-Santano M.; Zamzami N.; Galluzzi L.; Maiuri M. C.; Kroemer G. Pro-autophagic polyphenols reduce the acetylation of cytoplasmic proteins. Cell cycle 2012, 11, 3851–3860. 10.4161/cc.22027.

Eisenberg T.; Abdellatif M.; Schroeder S.; Primessnig U.; Stekovic S.; Pendl T.; Harger A.; Schipke J.; Zimmermann A.; Schmidt A.; et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 2016, 22, 1428–1438. 10.1038/nm.4222.

Pietrocola F.; Lachkar S.; Enot D.; Niso-Santano M.; Bravo-San Pedro J. M.; Sica V.; Izzo V.; Maiuri M.; Madeo F.; Mariño G.; Kroemer G. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 2015, 22, 509–516. 10.1038/cdd.2014.215.

Qi Y.; Qiu Q.; Gu X.; Tian Y.; Zhang Y. ATM mediates spermidine-induced mitophagy via PINK1 and Parkin regulation in human fibroblasts. Sci. Rep. 2016, 6, 24700. 10.1038/srep24700.

Strong R.; Miller R. A.; Astle C. M.; Floyd R. A.; Flurkey K.; Hensley K. L.; Javors M. A.; Leeuwenburgh C.; Nelson J. F.; Ongini E.; et al. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell 2008, 7, 641–650. 10.1111/j.1474-9726.2008.00414.x.

Balfour J. A.; McTavish D. Acarbose. An update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 1993, 46, 1025–1054. 10.2165/00003495-199346060-00007.

Harrison D. E.; Strong R.; Allison D. B.; Ames B. N.; Astle C. M.; Atamna H.; Fernandez E.; Flurkey K.; Javors M. A.; Nadon N. L.; et al. Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell 2014, 13, 273–282. 10.1111/acel.12170.

Harrison D. E.; Strong R.; Alavez S.; Astle C. M.; DiGiovanni J.; Fernandez E.; Flurkey K.; Garratt M.; Gelfond J. A. L.; Javors M. A.; et al. Acarbose improves health and lifespan in aging HET3 mice. Aging Cell 2019, 18, e12898 10.1111/acel.12898.

Gupta S.; Jiang Z.; Ladiges W. The antidiabetic drug acarbose suppresses age-related lesions in C57BL/6 mice in an organ dependent manner. Aging Pathobiol. Ther. 2021, 3, 41–42. 10.31491/APT.2021.06.060.

Wu B.; Yan J.; Yang J.; Xia Y.; Li D.; Zhang F.; Cao H. Extension of the Life Span by Acarbose: Is It Mediated by the Gut Microbiota?. Aging Dis 2022, 13, 1005–1014. 10.14336/AD.2022.0117.

Robbins P. D.; Jurk D.; Khosla S.; Kirkland J. L.; LeBrasseur N. K.; Miller J. D.; Passos J. F.; Pignolo R. J.; Tchkonia T.; Niedernhofer L. J. Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span. Annual Review of Pharmacology and Toxicology 2021, 61, 779–803. 10.1146/annurev-pharmtox-050120-105018.

Wang E. Senescent human fibroblasts resist programmed cell death, and failure to suppress bcl2 is involved. Cancer Res. 1995, 55, 2284–2292.

Zhu Y.; Tchkonia T.; Pirtskhalava T.; Gower A. C.; Ding H.; Giorgadze N.; Palmer A. K.; Ikeno Y.; Hubbard G. B.; Lenburg M.; et al. The Achilles’ heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015, 14, 644–658. 10.1111/acel.12344.

van Deursen J. M. Senolytic therapies for healthy longevity. Science (New York, N.Y.) 2019, 364, 636–637. 10.1126/science.aaw1299.

Zhang L.; Pitcher L. E.; Prahalad V.; Niedernhofer L. J.; Robbins P. D. Targeting cellular senescence with senotherapeutics: senolytics and senomorphics. FEBS journal 2023, 290, 1362–1383. 10.1111/febs.16350.

Marotta F.; Balakrishnan B.; Yazdani A.; Ayala A.; He F.; Catanzaro R.. Chapter 13 - Gut stem cells: Interplay with immune system, microbiota, and aging. In Stem Cells and Aging; Pathak S., Banerjee A., Eds.; Academic Press, 2021; pp 177–186.

Marotta F.; Thandavan P. S.; Pathak S.; Sriramulu S.; Jothimani G.; Gunasekaran D.; Markandeyan D.; Banerjee A. Vitagenic Effect of Specific Bioactive Fractions of Rhodiola with Trachurus sp. Extract Against Oxidative Stress-Induced Aging in Human Amnion Derived Epithelial Cell Line: In View of a Novel Senolytic. Curr. Aging Sci. 2021, 14, 139–153. 10.2174/1874609814666210114094030.

Wong F.; Omori S.; Donghia N. M.; Zheng E. J.; Collins J. J. Discovering small-molecule senolytics with deep neural networks. Nat. Aging 2023, 3, 734. 10.1038/s43587-023-00415-z.

Li W.; Qin L.; Feng R.; Hu G.; Sun H.; He Y.; Zhang R. Emerging senolytic agents derived from natural products. Mechanisms of Ageing and Development 2019, 181, 1–6. 10.1016/j.mad.2019.05.001.

Deledda A.; Giordano E.; Velluzzi F.; Flore G.; Franceschelli S.; Speranza L.; Ripari P. Mitochondrial Aging and Senolytic Natural Products with Protective Potential. Int. J. Mol. Sci. 2022, 23, 16219. 10.3390/ijms232416219.

Chiodi I.; Mondello C. Telomere and telomerase stability in human diseases and cancer. Front. Biosci. 2016, 21, 203–224. 10.2741/4385.

Zhang J.; Rane G.; Dai X.; Shanmugam M. K.; Arfuso F.; Samy R. P.; Lai M. K. P.; Kappei D.; Kumar A. P.; Sethi G. Ageing and the telomere connection: An intimate relationship with inflammation. Ageing research reviews 2016, 25, 55–69. 10.1016/j.arr.2015.11.006.

Sishc B. J.; Nelson C. B.; McKenna M. J.; Battaglia C. L.; Herndon A.; Idate R.; Liber H. L.; Bailey S. M. Telomeres and telomerase in the radiation response: implications for instability, reprograming, and carcinogenesis. Front. Oncol. 2015, 5, 257. 10.3389/fonc.2015.00257.

Raghavan P. R. Metadichol: A Novel Nanolipid Formulation That Inhibits SARS-CoV-2 and a Multitude of Pathological Viruses In Vitro. BioMed Res. Int. 2022, 2022, 1558860. 10.1155/2022/1558860.

Tsoukalas D.; Fragkiadaki P.; Docea A. O.; Alegakis A. K.; Sarandi E.; Thanasoula M.; Spandidos D. A.; Tsatsakis A.; Razgonova M. P.; Calina D. Discovery of potent telomerase activators: Unfolding new therapeutic and anti-aging perspectives. Mol. Med. Rep. 2019, 20, 3701–3708. 10.3892/mmr.2019.10614.

Minocha T.; Dwivedi N.; Panda C.; Misra A.; Nayak B. B.; Yadav S. K.; Birla H.; Singh S. K.. Chapter 7 - Epigenetic drugs based on antiaging approach: an overview. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging; Singh S. K., Lin C.-L., Mishra S. K., Eds.; Academic Press, 2022; pp 127–138.

Arguelles A. O.; Meruvu S.; Bowman J. D.; Choudhury M. Are epigenetic drugs for diabetes and obesity at our door step?. Drug discovery today 2016, 21, 499–509. 10.1016/j.drudis.2015.12.001.

Cacabelos R. Epigenomic networking in drug development: from pathogenic mechanisms to pharmacogenomics. Drug Dev. Res. 2014, 75, 348–365. 10.1002/ddr.21219.

Zhong B.; Vatolin S.; Idippily N. D.; Lama R.; Alhadad L. A.; Reu F. J.; Su B. Structural optimization of non-nucleoside DNA methyltransferase inhibitor as anti-cancer agent. Bioorg. Med. Chem. Lett. 2016, 26, 1272–1275. 10.1016/j.bmcl.2016.01.020.

Ghoshal K.; Bai S. DNA methyltransferases as targets for cancer therapy. Drugs Today 2007, 43, 395–422. 10.1358/dot.2007.43.6.1062666.

Lakshmaiah K.; Jacob L. A.; Aparna S.; Lokanatha D.; Saldanha S. C. Epigenetic therapy of cancer with histone deacetylase inhibitors. Journal of cancer research and therapeutics 2014, 10, 469–478. 10.4103/0973-1482.137937.

Arking R. Independent chemical regulation of health and senescent spans in Drosophila. Invertebrate reproduction & development 2015, 59, 28–32. 10.1080/07924259.2014.978028.

McDonald P.; Maizi B. M.; Arking R. Chemical regulation of mid-and late-life longevities in Drosophila. Experimental gerontology 2013, 48, 240–249. 10.1016/j.exger.2012.09.006.

Ma N.; Luo Y.; Wang Y.; Liao C.; Ye W.-C.; Jiang S. Selective histone deacetylase inhibitors with anticancer activity. Current topics in medicinal chemistry 2015, 16, 415–426. 10.2174/1568026615666150813145629.

Chun P. Histone deacetylase inhibitors in hematological malignancies and solid tumors. Archives of pharmacal research 2015, 38, 933–949. 10.1007/s12272-015-0571-1.

Liu Y.; Long J.; Liu J. Mitochondrial free radical theory of aging: Who moved my premise?. Geriatrics & gerontology international 2014, 14, 740–749. 10.1111/ggi.12296.

Payne B. A.; Chinnery P. F. Mitochondrial dysfunction in aging: Much progress but many unresolved questions. Biochimica et Biophysica Acta (BBA)-Bioenergetics 2015, 1847, 1347–1353. 10.1016/j.bbabio.2015.05.022.

Pinto M.; Moraes C. T. Mechanisms linking mtDNA damage and aging. Free Radical Biol. Med. 2015, 85, 250–258. 10.1016/j.freeradbiomed.2015.05.005.

Anik M. I.; Mahmud N.; Masud A. A.; Khan M. I.; Islam M. N.; Uddin S.; Hossain M. K. Role of Reactive Oxygen Species in Aging and Age-Related Diseases: A Review. ACS Applied Bio Materials 2022, 5, 4028–4054. 10.1021/acsabm.2c00411.

Hossen S.; Hossain M. K.; Basher M. K.; Mia M. N. H.; Rahman M. T.; Uddin M. J. Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: A review. Journal of Advanced Research 2019, 15, 1–18. 10.1016/j.jare.2018.06.005.

Anik M. I.; Hossain M. K.; Hossain I.; Mahfuz A. M. U. B.; Rahman M. T.; Ahmed I. Recent progress of magnetic nanoparticles in biomedical applications: A review. Nano Select 2021, 2, 1146–1186. 10.1002/nano.202000162.

Koliada A. K.; Krasnenkov D. S.; Vaiserman A. M. Telomeric aging: mitotic clock or stress indicator?. Front. Genet. 2015, 6, 82. 10.3389/fgene.2015.00082.

KAGAN V. E.; KISIN E. R.; KAWAI K.; SERINKAN B. F.; OSIPOV A. N.; SERBINOVA E. A.; WOLINSKY I.; SHVEDOVA A. A. Toward Mechanism-based Antioxidant Interventions. Ann. N.Y. Acad. Sci. 2002, 959, 188–198. 10.1111/j.1749-6632.2002.tb02093.x.

Packer L.; Ong A. S. H.. Biological Oxidants and Antioxidants: Molecular Mechanisms and Health Effects; AOCS Publishing, 1998.

Jacob R. A.; Sotoudeh G. Vitamin C function and status in chronic disease. Nutr Clin Care 2002, 5, 66–74. 10.1046/j.1523-5408.2002.00005.x.

Li Y.; Schellhorn H. E. New developments and novel therapeutic perspectives for vitamin C. J. Nutr. 2007, 137, 2171–2184. 10.1093/jn/137.10.2171.

Carr A. C.; Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am. J. Clin. Nutr. 1999, 69, 1086–1107. 10.1093/ajcn/69.6.1086.

Jurenka J. S. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med. Rev. 2009, 14, 141–153.

Aggarwal B. B.; Sundaram C.; Malani N.; Ichikawa H. Curcumin: the Indian solid gold. Adv. Exp. Med. Biol. 2007, 595, 1–75. 10.1007/978-0-387-46401-5_1.

Zhang M.; Tang J.; Li Y.; Xie Y.; Shan H.; Chen M.; Zhang J.; Yang X.; Zhang Q.; Yang X. Curcumin attenuates skeletal muscle mitochondrial impairment in COPD rats: PGC-1α/SIRT3 pathway involved. Chem. Biol. Interact 2017, 277, 168–175. 10.1016/j.cbi.2017.09.018.

Miao Y.; Zhao S.; Gao Y.; Wang R.; Wu Q.; Wu H.; Luo T. Curcumin pretreatment attenuates inflammation and mitochondrial dysfunction in experimental stroke: The possible role of Sirt1 signaling. Brain Res. Bull. 2016, 121, 9–15. 10.1016/j.brainresbull.2015.11.019.

Queen B. L.; Tollefsbol T. O. Polyphenols and aging. Curr. Aging Sci. 2010, 3, 34–42. 10.2174/1874609811003010034.

Hardeland R.; Cardinali D. P.; Brown G. M.; Pandi-Perumal S. R. Melatonin and brain inflammaging. Prog. Neurobiol 2015, 127–128, 46–63. 10.1016/j.pneurobio.2015.02.001.

Cristòfol R.; Porquet D.; Corpas R.; Coto-Montes A.; Serret J.; Camins A.; Pallàs M.; Sanfeliu C. Neurons from senescence-accelerated SAMP8 mice are protected against frailty by the sirtuin 1 promoting agents melatonin and resveratrol. J. Pineal Res. 2012, 52, 271–281. 10.1111/j.1600-079X.2011.00939.x.

Kireev R. A.; Vara E.; Tresguerres J. A. Growth hormone and melatonin prevent age-related alteration in apoptosis processes in the dentate gyrus of male rats. Biogerontology 2013, 14, 431–442. 10.1007/s10522-013-9443-6.

Hadad N.; Levy R. The synergistic anti-inflammatory effects of lycopene, lutein, β-carotene, and carnosic acid combinations via redox-based inhibition of NF-κB signaling. Free Radical Biol. Med. 2012, 53, 1381–1391. 10.1016/j.freeradbiomed.2012.07.078.

Zheng W. V.; Xu W.; Li Y.; Qin J.; Zhou T.; Li D.; Xu Y.; Cheng X.; Xiong Y.; Chen Z. Anti-aging effect of β-carotene through regulating the KAT7-P15 signaling axis, inflammation and oxidative stress process. Cell. Mol. Biol. Lett. 2022, 27, 86. 10.1186/s11658-022-00389-7.

Niki E.; Noguchi N.; Tsuchihashi H.; Gotoh N. Interaction among vitamin C, vitamin E, and beta-carotene. Am. J. Clin. Nutr. 1995, 62, 1322s–1326s. 10.1093/ajcn/62.6.1322S.

Skibska B.; Goraca A. The protective effect of lipoic acid on selected cardiovascular diseases caused by age-related oxidative stress. Oxid, Med. Cell, Longev, 2015, 2015, 313021. 10.1155/2015/313021.

Tibullo D.; Li Volti G.; Giallongo C.; Grasso S.; Tomassoni D.; Anfuso C. D.; Lupo G.; Amenta F.; Avola R.; Bramanti V. Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential. Inflamm Res. 2017, 66, 947–959. 10.1007/s00011-017-1079-6.

Shay K. P.; Moreau R. F.; Smith E. J.; Smith A. R.; Hagen T. M. Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim. Biophys. Acta 2009, 1790, 1149–1160. 10.1016/j.bbagen.2009.07.026.

Valdecantos M. P.; Pérez-Matute P.; González-Muniesa P.; Prieto-Hontoria P. L.; Moreno-Aliaga M. J.; Martínez J. A. Lipoic acid improves mitochondrial function in nonalcoholic steatosis through the stimulation of sirtuin 1 and sirtuin 3. Obesity (Silver Spring) 2012, 20, 1974–1983. 10.1038/oby.2012.32.

Zhang L.; Zou J.; Chai E.; Qi Y.; Zhang Y. Alpha-lipoic acid attenuates cardiac hypertrophy via downregulation of PARP-2 and subsequent activation of SIRT-1. Eur. J. Pharmacol. 2014, 744, 203–210. 10.1016/j.ejphar.2014.09.037.

Yang L.; Wang H.; Song S.; Xu H.; Chen Y.; Tian S.; Zhang Y.; Zhang Q. Systematic Understanding of Anti-Aging Effect of Coenzyme Q10 on Oocyte Through a Network Pharmacology Approach. Front. Endocrinol. 2022, 13, 813772. 10.3389/fendo.2022.813772.

Alexander J.Coenzyme Q10 and Selenium Supplementation Increases Serum Sirtuin1 Levels. https://www.q10facts.com/coenzyme-q10-and-selenium-supplementation-increases-serum-sirtuin1-levels/ (accessed Apr 18, 2023).

Morrill R.Coenzyme Q10 Benefits Heart Health. https://www.q10facts.com/coenzyme-q10-benefits-heart-health/ (accessed Apr 18, 2023).

Homma T.; Fujii J. Application of Glutathione as Anti-Oxidative and Anti-Aging Drugs. Curr. Drug Metab 2015, 16, 560–571. 10.2174/1389200216666151015114515.

5 Anti-aging Benefits of L-Glutathione. https://wellbeingnutrition.com/blogs/listing/anti-aging-benefits-of-glutathione (accessed Apr 18, 2023).

Logozzi M.; Di Raimo R.; Mizzoni D.; Andreotti M.; Spada M.; Macchia D.; Fais S. Beneficial Effects of Fermented Papaya Preparation (FPP) Supplementation on Redox Balance and Aging in a Mouse Model. Antioxidants (Basel) 2020, 9, 144. 10.3390/antiox9020144.

Marotta F.; Koike K.; Lorenzetti A.; Naito Y.; Fayet F.; Shimizu H.; Marandola P. Nutraceutical strategy in aging: targeting heat shock protein and inflammatory profile through understanding interleukin-6 polymorphism. Ann. N.Y. Acad. Sci. 2007, 1119, 196–202. 10.1196/annals.1404.011.

Collard E.; Roy S. Improved function of diabetic wound-site macrophages and accelerated wound closure in response to oral supplementation of a fermented papaya preparation. Antioxid Redox Signal 2010, 13, 599–606. 10.1089/ars.2009.3039.

Rimbach G.; Guo Q.; Akiyama T.; Matsugo S.; Moini H.; Virgili F.; Packer L. Ferric nitrilotriacetate induced DNA and protein damage: inhibitory effect of a fermented papaya preparation. Anticancer Res. 2000, 20, 2907–2914.

Prus E.; Fibach E. The antioxidant effect of fermented papaya preparation involves iron chelation. J. Biol. Regul. Homeostatic Agents 2012, 26, 203–210.

Rimbach G.; Park Y. C.; Guo Q.; Moini H.; Qureshi N.; Saliou C.; Takayama K.; Virgili F.; Packer L. Nitric oxide synthesis and TNF-alpha secretion in RAW 264.7 macrophages: mode of action of a fermented papaya preparation. Life Sci. 2000, 67, 679–694. 10.1016/S0024-3205(00)00664-0.

Conti V.; Izzo V.; Corbi G.; Russomanno G.; Manzo V.; De Lise F.; Di Donato A.; Filippelli A. Antioxidant Supplementation in the Treatment of Aging-Associated Diseases. Front. Pharmacol. 2016, 7, 24. 10.3389/fphar.2016.00024.

Bouayed J.; Bohn T. Exogenous antioxidants—double-edged swords in cellular redox state: health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxidative medicine and cellular longevity 2010, 3, 228–237. 10.4161/oxim.3.4.12858.

Vaiserman A. M.Aging-Modulating Treatments: From Reductionism to a System-Oriented Perspective; Frontiers Media SA, 2014; Vol. 5, p 446.

Halliwell B. Free radicals and antioxidants–quo vadis?. Trends in pharmacological sciences 2011, 32, 125–130. 10.1016/j.tips.2010.12.002.

10 Best Peptides For Anti Aging For 2023. https://www.operationmilitarykids.org/best-peptides-for-anti-aging/ (accessed Apr 20, 2023).

Kobiela T.; Milner-Krawczyk M.; Pasikowska-Piwko M.; Bobecka-Wesołowska K.; Eris I.; Święszkowski W.; Dulinska-Molak I. The Effect of Anti-aging Peptides on Mechanical and Biological Properties of HaCaT Keratinocytes. Int. J. Pept Res. Ther 2018, 24, 577–587. 10.1007/s10989-017-9648-7.

Ahsan H. The biomolecules of beauty: biochemical pharmacology and immunotoxicology of cosmeceuticals. J. Immunoassay Immunochem 2019, 40, 91–108. 10.1080/15321819.2018.1555766.

Bosch X. Researchers discover peptide that may reduce rheumatoid arthritis. BMJ. 2001, 322, 1084. 10.1136/bmj.322.7294.1084/a.

Zhao L.; Luo H.; Ma Y.; Zhu S.; Wu Y.; Lu M.; Yao X.; Liu X.; Chen G. An analgesic peptide H-20 attenuates chronic pain via the PD-1 pathway with few adverse effects. Proc. Natl. Acad. Sci. U. S. A. 2022, 119, e2204114119 10.1073/pnas.2204114119.

Zhong H.; Shi J.; Zhang J.; Wang Q.; Zhang Y.; Yu P.; Guan R.; Feng F. Soft-Shelled Turtle Peptide Supplementation Modifies Energy Metabolism and Oxidative Stress, Enhances Exercise Endurance, and Decreases Physical Fatigue in Mice. Foods 2022, 11, 600. 10.3390/foods11040600.

Liu L.; Guo P.; Wang P.; Zheng S.; Qu Z.; Liu N. The Review of Anti-aging Mechanism of Polyphenols on Caenorhabditis elegans. Front Bioeng Biotechnol 2021, 9, 635768. 10.3389/fbioe.2021.635768.

Partridge L.; Fuentealba M.; Kennedy B. K. The quest to slow ageing through drug discovery. Nat. Rev. Drug Discovery 2020, 19, 513–532. 10.1038/s41573-020-0067-7.

Blagosklonny M. V. An anti-aging drug today: from senescence-promoting genes to anti-aging pill. Drug Discov Today 2007, 12, 218–224. 10.1016/j.drudis.2007.01.004.

Yodhaanjali J. R.; Surya R.; Sumukha K. C.; Harini G.; Deshpande G.; Chandan S.; Achar R. R.. Chapter 10 - Antiaging drugs, candidates, and food supplements: the journey so far. In Anti-Aging Drug Discovery on the Basis of Hallmarks of Aging; Singh S. K., Lin C.-L., Mishra S. K., Eds.; Academic Press, 2022; pp 191–239.

Wang T. -y.; Li Q.; Bi K. -s. Bioactive flavonoids in medicinal plants: Structure, activity and biological fate. Asian Journal of Pharmaceutical Sciences 2018, 13, 12–23. 10.1016/j.ajps.2017.08.004.

Cătană C.-S.; Atanasov A. G.; Berindan-Neagoe I. Natural products with anti-aging potential: Affected targets and molecular mechanisms. Biotechnology Advances 2018, 36, 1649–1656. 10.1016/j.biotechadv.2018.03.012.

Klimova B.; Novotny M.; Kuca K. Anti-Aging Drugs - Prospect of Longer Life?. Curr. Med. Chem. 2018, 25, 1946–1953. 10.2174/0929867325666171129215251.

Arora B. P. Anti-aging medicine. Indian J. Plast. Surg. 2008, 41, 130–133. 10.1055/s-0039-1700483.

Pilcher H.Anti-ageing pills are real, and some of us are taking them without knowing it. https://www.sciencefocus.com/the-human-body/anti-ageing-medication-health/ (accessed Apr 11, 2023).

Wesinka Top Ten Life Extension Drugs. https://www.esculape.com/bricabrac/toptenlifeextensiondrugs.html (accessed Apr 11, 2023).

The 14 Best Anti-Aging Vitamins and Supplements. https://www.healthline.com/nutrition/anti-aging-supplements (accessed Apr 11, 2023).

Thanapairoje K.; Junsiritrakhoon S.; Wichaiyo S.; Osman M. A.; Supharattanasitthi W. Anti-ageing effects of FDA-approved medicines: a focused review. J. Basic Clin. Physiol. Pharmacol. 2023, 34, 277. 10.1515/jbcpp-2022-0242.

PitchBook. https://www.pitchbook.com/ (accessed Mar 30, 2023).

Horizon 2020 - SME Instrument. https://www.techfunding.eu/sme-instrument (accessed Mar 29, 2023).

Clinical Trials. https://www.clinicaltrials.gov/ (accessed Apr 20, 2023).

Petrou P. A.; Cunningham D.; Shimel K.; Harrington M.; Hammel K.; Cukras C. A.; Ferris F. L.; Chew E. Y.; Wong W. T. Intravitreal sirolimus for the treatment of geographic atrophy: results of a phase I/II clinical trial. Invest Ophthalmol Vis Sci. 2015, 56, 330–338. 10.1167/iovs.14-15877.

Gensler G.; Clemons T. E.; Domalpally A.; Danis R. P.; Blodi B.; Wells J.; Rauser M.; Hoskins J.; Hubbard G. B.; Elman M. J.; et al. Treatment of Geographic Atrophy with Intravitreal Sirolimus: The Age-Related Eye Disease Study 2 Ancillary Study. Ophthalmology Retina 2018, 2, 441–450. 10.1016/j.oret.2017.08.015.

Singh M.; Jensen M. D.; Lerman A.; Kushwaha S.; Rihal C. S.; Gersh B. J.; Behfar A.; Tchkonia T.; Thomas R. J.; Lennon R. J.; et al. Effect of Low-Dose Rapamycin on Senescence Markers and Physical Functioning in Older Adults with Coronary Artery Disease: Results of a Pilot Study. J. Frailty Aging 2016, 5, 204–207. 10.14283/jfa.2016.112.

Fish Oil for HIV-Related Inflamm-aging and Immune Senescence. https://clinicaltrials.gov/ct2/show/NCT02102724 (accessed Apr 20, 2023).

Swanson B.; Keithley J.; Baum L.; Leurgans S.; Adeyemi O.; Barnes L. L.; Mata M.; Rosdil A. Effects of Fish Oil on HIV-Related Inflammation and Markers of Immunosenescence: A Randomized Clinical Trial. J. Altern Complement Med. 2018, 24, 709–716. 10.1089/acm.2017.0222.

Senolytic Therapy to Modulate Progression of Alzheimer’s Disease (SToMP-AD). https://clinicaltrials.gov/ct2/show/study/NCT04063124 (accessed Apr 20, 2023).

Gonzales M. M.; Garbarino V. R.; Marques Zilli E.; Petersen R. C.; Kirkland J. L.; Tchkonia T.; Musi N.; Seshadri S.; Craft S.; Orr M. E. Senolytic Therapy to Modulate the Progression of Alzheimer’s Disease (SToMP-AD): A Pilot Clinical Trial. J. Prev. Alzheimer's Dis. 2022, 9, 22–29. 10.14283/jpad.2021.62.

An Open-Label Intervention Trial to Reduce Senescence and Improve Frailty in Adult Survivors of Childhood Cancer. https://clinicaltrials.gov/ct2/show/NCT04733534 (accessed Apr 20, 2023).

The Testosterone Trials in Older Men. https://clinicaltrials.gov/ct2/show/NCT00799617 (accessed Apr 20, 2023).

Snyder P. J.; Bhasin S.; Cunningham G. R.; Matsumoto A. M.; Stephens-Shields A. J.; Cauley J. A.; Gill T. M.; Barrett-Connor E.; Swerdloff R. S.; Wang C.; et al. Lessons From the Testosterone Trials. Endocr Rev. 2018, 39, 369–386. 10.1210/er.2017-00234.

Vaginal Estrogen for the Prevention of Recurrent Urinary Tract Infection in Postmenopausal Women (VESPR). https://clinicaltrials.gov/ct2/show/NCT01958073 (accessed Apr 20, 2023).

Ferrante K. L.; Wasenda E. J.; Jung C. E.; Adams-Piper E. R.; Lukacz E. S. Vaginal Estrogen for the Prevention of Recurrent Urinary Tract Infection in Postmenopausal Women: A Randomized Clinical Trial. Female Pelvic Med. Reconstr Surg 2021, 27, 112–117. 10.1097/SPV.0000000000000749.

Advancing Postmenopausal Preventive Therapy (APPT). https://clinicaltrials.gov/ct2/show/NCT04103476 (accessed Apr 20, 2023).

Vulevic J.; Juric A.; Walton G. E.; Claus S. P.; Tzortzis G.; Toward R. E.; Gibson G. R. Influence of galacto-oligosaccharide mixture (B-GOS) on gut microbiota, immune parameters and metabonomics in elderly persons. Br. J. Nutr. 2015, 114, 586–595. 10.1017/S0007114515001889.

Van Puyenbroeck K.; Hens N.; Coenen S.; Michiels B.; Beunckens C.; Molenberghs G.; Van Royen P.; Verhoeven V. Efficacy of daily intake of Lactobacillus casei Shirota on respiratory symptoms and influenza vaccination immune response: a randomized, double-blind, placebo-controlled trial in healthy elderly nursing home residents. American Journal of Clinical Nutrition 2012, 95, 1165–1171. 10.3945/ajcn.111.026831.

Efficacy of a Probiotic Strain on Level of Markers of Inflammation in an Elderly Population. https://clinicaltrials.gov/ct2/show/NCT05529693 (accessed Apr 20, 2023).

Fecal Microbiota Transplantation for Parkinson’s Disease. https://clinicaltrials.gov/ct2/show/NCT03808389 (accessed Apr 20, 2023).

CALERIE: Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy. https://clinicaltrials.gov/ct2/show/NCT00427193 (accessed Apr 20, 2023).

Ravussin E.; Redman L. M.; Rochon J.; Das S. K.; Fontana L.; Kraus W. E.; Romashkan S.; Williamson D. A.; Meydani S. N.; Villareal D. T.; et al. A 2-Year Randomized Controlled Trial of Human Caloric Restriction: Feasibility and Effects on Predictors of Health Span and Longevity. Journals of Gerontology: Series A 2015, 70, 1097–1104. 10.1093/gerona/glv057.

Senkus K. E.; Crowe-White K. M.; Locher J. L.; Ard J. D. Relative fat mass assessment estimates changes in adiposity among female older adults with obesity after a 12-month exercise and diet intervention. Ann. Med. 2022, 54, 1160–1166. 10.1080/07853890.2022.2067352.

The Impact of a Fast Diet and Calorie Mimetic Supplements on Epigenetic Aging. https://clinicaltrials.gov/ct2/show/NCT04962464 (accessed Apr 20, 2023).

Nutrition Interventions for Cognitive Enhancement (NICE). https://clinicaltrials.gov/ct2/show/NCT03841539 (accessed Apr 20, 2023).

Clinical Trial of a Low Protein Diet in Patients With Cognitive Impairment. https://clinicaltrials.gov/ct2/show/NCT05480358 (accessed Apr 20, 2023).

Wii-Fit For Balance And Gait In Elderly Veterans. https://clinicaltrials.gov/ct2/show/NCT02190045 (accessed Apr 20, 2023).

Padala K. P.; Padala P. R.; Lensing S. Y.; Dennis R. A.; Bopp M. M.; Parkes C. M.; Garrison M. K.; Dubbert P. M.; Roberson P. K.; Sullivan D. H. Efficacy of Wii-Fit on Static and Dynamic Balance in Community Dwelling Older Veterans: A Randomized Controlled Pilot Trial. J. Aging Res. 2017, 2017, 4653635. 10.1155/2017/4653635.

Dementia Risk and Dynamic Response to Exercise (DYNAMIC). https://clinicaltrials.gov/ct2/show/NCT04009629 (accessed Apr 20, 2023).

Vidoni E. D.; Morris J. K.; Palmer J. A.; Li Y.; White D.; Kueck P. J.; John C. S.; Honea R. A.; Lepping R. J.; Lee P.; et al. Dementia risk and dynamic response to exercise: A non-randomized clinical trial. PloS one 2022, 17, e0265860 10.1371/journal.pone.0265860.

Comparing the Effects of Cognitive Training and Physical Exercise on Cognition, Cerebral Autoregulation and Cerebral Vasoreactivity in Men and Women With Heart Failure (ReCARDIO). https://clinicaltrials.gov/ct2/show/NCT04970888 (accessed Apr 20, 2023).

Exercise Training to Improve PTSD Symptoms and Health in Older Veterans. https://clinicaltrials.gov/ct2/show/NCT04199182 (accessed Apr 20, 2023).

Tompkins B. A.; DiFede D. L.; Khan A.; Landin A. M.; Schulman I. H.; Pujol M. V.; Heldman A. W.; Miki R.; Goldschmidt-Clermont P. J.; Goldstein B. J.; et al. Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Journals of Gerontology: Series A 2017, 72, 1513–1522. 10.1093/gerona/glx137.

Brody M.; Agronin M.; Herskowitz B. J.; Bookheimer S. Y.; Small G. W.; Hitchinson B.; Ramdas K.; Wishard T.; McInerney K. F.; Vellas B.; et al. Results and insights from a phase I clinical trial of Lomecel-B for Alzheimer’s disease. Alzheimer’s Dementia 2023, 19, 261–273. 10.1002/alz.12651.

Transplantation of hAMSCs for Woman With DOR. https://clinicaltrials.gov/ct2/show/NCT04706312 (accessed Apr 20, 2023).

Vandenberghe C.; Castellano C.-A.; Maltais M.; Fortier M.; St-Pierre V.; Dionne I. J.; Cunnane S. C. A short-term intervention combining aerobic exercise with medium-chain triglycerides (MCT) is more ketogenic than either MCT or aerobic exercise alone: a comparison of normoglycemic and prediabetic older women. Applied Physiology, Nutrition, and Metabolism 2019, 44, 66–73. 10.1139/apnm-2018-0367.

Whyte A. R.; Cheng N.; Fromentin E.; Williams C. M. A Randomized, Double-Blinded, Placebo-Controlled Study to Compare the Safety and Efficacy of Low Dose Enhanced Wild Blueberry Powder and Wild Blueberry Extract (ThinkBlue) in Maintenance of Episodic and Working Memory in Older Adults. Nutrients 2018, 10, 660. 10.3390/nu10060660.

A Proof of Science, Dose-Response Study to Evaluate the Safety, Efficacy of Different Dosages of Test Treatments. https://clinicaltrials.gov/ct2/show/NCT05613660 (accessed Apr 20, 2023).

TA-65 and Aging Associated Microvascular Dysfunction. https://clinicaltrials.gov/ct2/show/NCT05598359 (accessed Apr 20, 2023).

Hayflick L. The future of ageing. Nature 2000, 408, 267–269. 10.1038/35041709.

Rattan S. I. Healthy ageing, but what is health?. Biogerontology 2013, 14, 673–677. 10.1007/s10522-013-9442-7.

Associated Data

Supplementary Materials

cn3c00532_si_001.pdf