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Chimeric Antigen Receptor T Cells as Living Therapeutics Targeting Senescence and Age-Related Diseases.

The aging of the global population exacerbates the burden of age-related diseases; however, therapies that can intervene in fundamental aging processes are lacking. Senescent cells drive chronic inflammation and multitissue dysfunction through the secretion of proinflammatory and profibrotic senescence-associated secretory phenotype cells, making them emerging therapeutic targets. Although first-generation senolytic drugs have entered clinical trials, they face limitations such as insufficient targeting specificity and transient efficacy. The success of chimeric antigen receptor T cell (CAR T

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… Aging of the cells: Insight into cellular senescence and detection methods . Eur J Cell Biol . 2020 ; 99 ( 6 ): Article 151108 . 32800277 10.1016/j.ejcb.2020.151108 47. Hernandez-Segura A , Nehme J , Demaria M . Hallmarks of cellular senescence . … Cellular senescence: What, why, and how . Wounds . 2017 ; 29 ( 6 ): 168 – 174 . 28682291 56. Salama R , Sadaie M , Hoare M , Narita M . Cellular senescence and its effector programs . Genes Dev . 2014 ; 28 ( 2 ): 99 – 114 . 24449267 10.1101/gad.235184.113 PMC3909793 57. …

Senescent T cells: Beneficial and detrimental roles.

As the thymus involutes during aging, the T-cell pool has to be maintained by the periodic expansion of preexisting T cells during adulthood. A conundrum is that repeated episodes of activation and proliferation drive the differentiation of T cells toward replicative senescence, due to telomere erosion. This review discusses mechanisms that regulate the end-stage differentiation (senescence) of T cells. Although these cells, within both CD4 and CD8 compartments, lose proliferative activity after antigen-specific challenge, they acquire innate-like immune function. While this may confer broad i

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… Mechanisms of cellular senescence: cell cycle arrest and senescence associated secretory phenotype. Front Cell Dev Biol. 2021;9(29):645593. doi: 10.3389/fcell.2021.645593 8. Kuilman T, Peeper DS. Senescence‐messaging secretome: SMS‐ing cellular stress. … Cellular senescence and senolytics: the path to the clinic. Nat Med. 2022;28(8):1556‐1568. doi: 10.1038/s41591-022-01923-y 160. Novais EJ, Tran VA, Johnston SN, et al. …

Chondroprotection and Molecular Mechanism of Action of Phytonutraceuticals on Osteoarthritis.

Osteoarthritis (OA) is a degenerative joint disease and an important cause of incapacitation. There is a lack of drugs and effective treatments that stop or slow the OA progression. Modern pharmacological treatments, such as analgesics, have analgesic effects but do not affect the course of OA. Long-term use of these drugs can lead to serious side effects. Given the OA nature, it is likely that lifelong treatment will be required to stop or slow its progression. Therefore, there is an urgent need for disease-modifying OA treatments that are also safe for clinical use over long periods. Phytonu

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… Cellular senescence: A translational perspective. EBioMedicine. 2017;21:21–28. doi: 10.1016/j.ebiom.2017.04.013. 134. Kim S.R., Jiang K., Ogrodnik M., Chen X., Zhu X.-Y., Lohmeier H., Ahmed L., Tang H., Tchkonia T., Hickson L.J., et al. … Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun. 2017;8:1–12. doi: 10.1038/ncomms15691. 136. Baker D.J., Childs B.G., Durik M., Wijers M.E., Sieben C.J., Zhong J., Saltness R.A., Jeganathan K.B., Verzosa G.C., Pezeshki A., et al. …

Aging modulation of the immune system and immunotherapy efficacy in cancer.

Immunosenescence is characterized by immune decline and chronic inflammation. With advancing age, the incidence of tumors increases significantly. Understanding how immunosenescence influences the initiation and progression of tumors, as well as its implications for tumor immunotherapy, has become a matter of urgent importance. This review begins with an analysis of the phenotypic changes and underlying mechanisms associated with immune system and immune cell aging, and further explores the interplay between immunosenescence and tumorigenesis. Evidence indicates that cytokines, cell interactio

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… This leads to a state of oxidative damage and cellular senescence, a metabolic reprogramming that parallels features observed in tumor cells ( 23 ). … Cellular senescence in traumatic brain injury: Evidence and perspectives. Front Aging Neurosci. (2021) 13:742632. doi: 10.3389/fnagi.2021.742632, PMID: 58. Hoechst B, Gamrekelashvili J, Manns MP, Greten TF, Korangy F. …

Exposome and unhealthy aging: environmental drivers from air pollution to occupational exposures.

The aging population worldwide is facing a significant increase in age-related non-communicable diseases, including cardiovascular and brain pathologies. This comprehensive review paper delves into the impact of the exposome, which encompasses the totality of environmental exposures, on unhealthy aging. It explores how environmental factors contribute to the acceleration of aging processes, increase biological age, and facilitate the development and progression of a wide range of age-associated diseases. The impact of environmental factors on cognitive health and the development of chronic age

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… Oxidative stress is also associated with DNA damage and DNA damage–induced cellular senescence, which are additional mechanisms of aging contributing to vascular pathologies [ 37 , 60 , 61 ]. … Secondly, exposure to these pollutants can induce increased DNA damage and cellular senescence [ 159 – 163 ]. DNA damage can occur due to direct interaction with the genetic material or through the generation of ROS. …

Concept of natural genome reconstruction.Part 5. Analysis of changes in the lifespan of old animals after reinfusion of bone marrow cells derived from old animals and treated with hDNAgr in combination with recombinant human angiogenin.

Two series of tests were performed, on mice and rats, to assess the lifespan of old animals reinfused with bone marrow cells from old animals treated with fragmented human DNA (hDNAgr), recombinant human angiogenin, and both preparations together. Animals reinfused with untreated bone marrow cells from old animals or bone marrow cells from young animals were used as comparison groups. Using both outbred mice and CBA/Lac mice, no significant increase in the lifespan of animals reinfused with bone marrow cells treated with the hDNAgr was found compared with the group of mice reinfused with untre

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… Cellular senescence, the primary trigger of organismal involution and numerous age-related diseases, is initiated and sustained (He, Sharpless, 2017). … Hence, the inability to restore the lost telomeric heterochromatin content is among the causal events behind cellular senescence and its propagation throughout the organism. …

Drug delivery for age-related bone diseases: From therapeutic targets to common and emerging therapeutic strategies.

With the accumulation of knowledge on aging, people have gradually realized that among the many factors that cause individual aging, the accumulation of aging cells is an essential cause of organ degeneration and, ultimately, age-related diseases. Most cells present in the bone microenvironment gradually age over time, leading to an imbalance of osteogenesis, osteoclastogenesis, adipogenesis, and chondrogenesis. This imbalance contributes to age-related bone loss and the development of age-related bone diseases, such as osteoporosis. Bone aging can prolong the lifespan and delay the developmen

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… Targeting cellular senescence prevents age-related bone loss in mice. Nat. Med. 2017;23(9):1072–1079. doi: 10.1038/nm.4385. Farr J.N., et al. Osteocyte cellular senescence. Curr. Osteoporos. Rep. 2020;18(5):559–567. doi: 10.1007/s11914-020-00619-x. Ferreira-Faria I., et al. … CD9 monoclonal antibody-conjugated PEGylated liposomes for targeted delivery of rapamycin in the treatment of cellular senescence. Nanotechnology. 2017;28(9) doi: 10.1088/1361-6528/aa57b3. …

Progress of immune senescence in multiple myeloma treatment resistance.

Multiple myeloma has become the second most common hematologic malignancy threatening human health with the increasing incidence in the population, and the emergence of drug resistance in its treatment has become a problem that needs to be solved urgently. Recent studies have shown that the immune system is closely related to the development of multiple myeloma, and immune senescence plays an extremely critical role in MM treatment resistance. In this paper, we review the connection between immune senescence and the development of MM and its possible role in the drug resistance of MM treatment

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… senescence. … Figure 1 summarizes cellular senescence's developmental process and MM therapeutic resistance's emergence (Fig. 1 ). Fig. 1 The development process of cellular senescence and MM therapy resistance. 1. …

Immunosenescence and cancer predisposition in pediatric transplant recipients: An emerging paradigm.

Pediatric solid organ and hematopoietic stem cell transplant recipients paradoxically experience accelerated immune aging despite chronological youth, establishing a paradigm with profound implications for cancer risk and long-term outcomes. This comprehensive review synthesizes current evidence demonstrating how transplantation-related factors, anti-thymocyte globulin-mediated T cell depletion, cytomegalovirus reactivation, chronic immunosuppression, and thymic dysfunction, induce premature immunosenescent phenotypes. These processes converge to generate T cell populations exhibiting CD28 los

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… Molecular consequences of telomere dysfunction: Critically short telomeres trigger cellular senescence through activation of p53 and p16INK4a/Rb pathways, resulting in irreversible cell cycle arrest[ 28 ]. … Cellular senescence and the tumour microenvironment. Mol Oncol 2022; 16: 3333-3351. ©2022 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. …

Immunotherapies for Aging and Age-Related Diseases: Advances, Pitfalls, and Prospects.

Aging is characterized by a gradual decline in the functionality of all the organs and tissues, leading to various diseases. As the global population ages, the urgency to develop effective anti-aging strategies becomes increasingly critical due to the growing severity of associated health problems. Immunotherapy offers novel and promising approaches to combat aging by utilizing approaches including vaccines, antibodies, and cytokines to target specific aging-related molecules and pathways. In this review, we summarize the recent advancements of immunotherapies to eliminate senescence cells and

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… Immunotherapies Targeting Aging Itself Cellular senescence is an irreversible process affecting various pathways, leading to morphological, cyclical, metabolic, and oxidative damage changes (Fig. 1 ). … This imbalance is further compounded by age-related physiological changes such as hormone disorder, cellular senescence, and chronic low-grade inflammation [ 141 ]. …

Exploring the Complexity and Promise of Tumor Immunotherapy in Drug Development.

Cancer represents a significant threat to human health, and traditional chemotherapy or cytotoxic therapy is no longer the sole or preferred approach for managing malignant tumors. With advanced research into the immunogenicity of tumor cells and the growing elderly population, tumor immunotherapy has emerged as a prominent therapeutic option. Its significance in treating elderly cancer patients is increasingly recognized. In this study, we review the conceptual classifications and benefits of immunotherapy, and discuss recent developments in new drugs and clinical progress in cancer treatment

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… Cellular senescence is at the heart of this inflammatory process. According to Effros RB et al., senescent CD8 + T cells accumulate in vivo during immune senescence [ 104 ]. … Immunosenescence and Cancer Immunosenescence is a critical hallmark of aging, strongly associated with cancer and cellular senescence, often leading to a poor prognosis for patients [ 122 ]. …

Иммунометаболизм в старении мозга и нейродегенерации: преодоление метаболических путей и иммунные ответные меры.

Сложный набор взаимодействий между иммунной системой и метаболизмом, известный как иммунометаболизм, стал критическим регулятором последствий заболеваний в центральной нервной системе. В ходе многочисленных исследований метаболические расстройства увязывались с ослабленной иммунной реакцией при старении мозга, нейродегенеративных расстройствах и травме мозга. В этом обзоре мы обсудим вопрос о том, как нарушения баланса иммунометаболизма мозга способствуют патофизиологии дисфункции мозга. В первой части обзора резюмируется вклад таких критических групп иммунной клетки, как микроглии, астроциты,

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… Various cellular stresses or macromolecular damage can induce irreversible cell cycle arrest, resulting in cellular senescence, preventing proliferation into damaged tissue, and oncogenesis [ 15 ]. Normally, immune cells remove these senescent cells. … Different metabolic changes in NAD can modulate cellular senescence. CD38, a NAD-ase present on the surface of cells, including immune cells, is stimulated by SASP factors and is responsible for aging-related declines in NAD levels [ 23 ]. …

Influence of the Mediterranean Diet on Healthy Aging.

The life expectancy of the global population has increased. Aging is a natural physiological process that poses major challenges in an increasingly long-lived and frail population. Several molecular mechanisms are involved in aging. Likewise, the gut microbiota, which is influenced by environmental factors such as diet, plays a crucial role in the modulation of these mechanisms. The Mediterranean diet, as well as the components present in it, offer some proof of this. Achieving healthy aging should be focused on the promotion of healthy lifestyle habits that reduce the development of pathologi

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… In addition, the Aβ peptide was identified as a potent inducer of cellular senescence [ 258 , 259 , 260 , 261 , 262 ]. … Is Cellular Senescence an Example of Antagonistic Pleiotropy? Aging Cell. 2012;11:378–383. doi: 10.1111/j.1474-9726.2012.00807.x. 13. 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. …

Advancements in antibody-drug conjugates as cancer therapeutics.

Antibody-drug conjugates (ADCs) represent a promising approach in targeted cancer therapy, combining the targeted precision of antibodies with the potency of cytotoxic payloads to selectively target tumour cell whilst minimising off-target effects. This review provides a comprehensive analysis of ADCs, encompassing their structural components, mechanisms of action, and clinical applications. It also examines recent technological advancements, particularly in antibody engineering and linker design, aimed at enhancing therapeutic efficacy and safety. The current clinical landscape is outlined, h

Inflammaging in periodontal, periapical, and malignancy-associated disease: drivers of alveolar bone loss and repair.

BACKGROUND: Aging significantly impacts bone metabolism through altered osteoblast/osteoclast dynamics, reduced stem cell regeneration, and chronic inflammaging. This narrative review explores how these age-related changes influence alveolar bone loss and regeneration in the oral cavity. METHODS: The review investigates key mechanisms-including immunosenescence and inflammasome activation-across three specific pathological contexts: (1) periodontitis, (2) periapical bone resorption, and (3) malignancy-associated osteolysis. Preclinical and clinical evidence were integrated to analyze the bone

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… Key mechanisms underlying these changes include cellular senescence, stem cell exhaustion, hormonal alterations, and chronic low-grade inflammation [ 14 , 15 ]. … Farr JN, Khosla S (2019) Cellular senescence in bone. Bone 121:121–133. 10.1016/j.bone.2019.01.015 25. …

Multiple myeloma, a quintessential malignant disease of aging: a geroscience perspective on pathogenesis and treatment.

Multiple myeloma (MM) is an incurable plasma cell malignancy, which is predominantly a disease of older adults (the median age at diagnosis is 70 years). The slow progression from asymptomatic stages and the late-onset of MM suggest fundamental differences compared to many other hematopoietic system-related malignancies. The concept discussed in this review is that age-related changes at the level of terminally differentiated plasma cells act as the main risk factors for the development of MM. Epigenetic and genetic changes that characterize both MM development and normal aging are highlighted

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… Cellular senescence Cellular senescence, an evolutionarily conserved, DNA damage-associated cellular stress response, is a critical biological process underlying aging [ 71 ]. … Cellular senescence and chromatin structure. Chromosoma. 2007;116(5):431–40. 10.1007/s00412-007-0115-7 17579878 76. …

Histone modifications: Unveiling the epigenetic enigma of degenerative skeletal diseases.

Degenerative skeletal diseases, including osteoporosis, osteoarthritis, and intervertebral disc degeneration, are prevalent age-related conditions characterized by progressive tissue degeneration and functional decline. Histone modifications are covalent modifications of histone residues, catalyzed by specific enzymes, that modulate chromatin architecture and transcriptional activity. Accumulating evidence highlights the critical involvement of histone modifications in orchestrating disease-associated transcriptional programs. In osteoporosis, histone modifications regulate osteoblast and oste

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… In addition, by triggering the senescence signaling pathway, histone modification accelerates the cellular senescence of BMSCs, which decreases their osteogenic differentiation and proliferation abilities, promotes apoptosis, and disrupts bone homeostasis [ 147 , 148 ]. … Histone modifications in nucleus pulposus cell senescence Intervertebral disc degeneration, an age-related affliction, is intricately intertwined with cellular senescence. …

Inflammaging, an Imbalanced Immune Response That Needs to Be Restored for Cancer Prevention and Treatment in the Elderly.

Nowadays, new advances in society and health have brought an increased life expectancy. However, at the same time, aging comes with complications that impact the development of autoimmunity, neurodegenerative diseases and cancer. These complications affect the quality of life and impact the public health system. Specifically, with aging, a low-grade chronic sterile systemic inflammation with self-reactivity in the absence of acute infection occurs termed inflammaging. Inflammaging is related to an imbalanced immune response that can be either naturally acquired with aging or accelerated due to

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… Indeed, it has been observed that cGVHD-derived T-cells present high expression of genes that positively regulate cellular senescence ( CDKN2A , SERPINB9 , LYPLA1 and CKTM1A/B ) [ 88 ]. … Cellular Senescence: From Physiology to Pathology. Nat. Rev. Mol. Cell Biol. 2014;15:482–496. doi: 10.1038/nrm3823. 21. Jeyapalan J.C., Ferreira M., Sedivy J.M., Herbig U. Accumulation of Senescent Cells in Mitotic Tissue of Aging Primates. Mech. …

Ремонтные механизмы центральной нервной системы: от вырастания аксона до воспроизводства.

Центральная нервная система (КНС), состоящая из мозга, спинного мозга и зрительного нерва, имеет ограниченную регенеративную способность, что создает значительные трудности в лечении неврологических расстройств. Последние достижения в области нейрофизики и нейротерапевтии ввели перспективные стратегии стимулирования восстановления CNS, особенно в контексте нейродегенеративных заболеваний, таких, как множественный склероз. В настоящем обзоре рассматривается сложная взаимосвязь между воспалением, обезвоживанием и возможностями воспоминания. Глиальные клетки, включая прекурсоры олигодендроцитов,

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… One of the most important processes contributing to neurodegeneration is cellular senescence [ 124 , 125 ]. Senescent cells, which are typically in a state of irreversible growth arrest, accumulate in tissues with age and play a pivotal role in age-related pathology. …

Engagement of Mesenchymal Stromal Cells in the Remodeling of the Bone Marrow Microenvironment in Hematological Cancers.

Mesenchymal stromal cells (MSCs) are a subset of heterogeneous, non-hematopoietic fibroblast-like cells which play important roles in tissue repair, inflammation, and immune modulation. MSCs residing in the bone marrow microenvironment (BMME) functionally interact with hematopoietic stem progenitor cells regulating hematopoiesis. However, MSCs have also emerged in recent years as key regulators of the tumor microenvironment. Indeed, they are now considered active players in the pathophysiology of hematologic malignancies rather than passive bystanders in the hematopoietic microenvironment. Onc

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… As MDS stromal cells, both AML and ALL-MSCs show accelerated cellular senescence, contributing to their impairment in functions associated with HSPC support and stemness properties [ 19 , 91 ]. … Dicer1, an RNAse III endonuclease essential for miRNA biogenesis, has been demonstrated to be one of the key promoters of cellular senescence in MSCs [ 11 , 165 ]. Specifically, the upregulation of Dicer1 in MM-MSCs reversed cellular senescence and promoted cell differentiation [ 165 ]. …