Molecular senescence, neuroendocrine metaflammation, and skeletal muscle insulin resistance in type-4 diabetes: from mitochondrial dysfunction to precision therapeutics.

With the global population aged 65 years and older projected to exceed 1.5 billion by 2050, sarcopenia-driven insulin resistance is emerging as an urgent yet still under-recognised contributor to the diabetes burden in older adults, underscoring the timeliness of a focused molecular synthesis of this entity for guiding both diagnostic recognition and therapeutic prioritisation. Molecularly different, age-driven insulin resistance promotes skeletal muscle ageing, mitochondrial bioenergetic collapse, and prolonged neuroendocrine metaflammation in type-4 diabetes (T4DM). In ageing myocytes, poor IRS-1/PI3K/Akt signalling, GLUT4 trafficking anomalies, AMPK suppression, ROS-mediated mtDNA instability, and decreased OXPHOS capacity induce T4DM. Senescent muscle cells generate IL-6, TNF-α, and MCP-1 when p16INK4a/p21 checkpoints activate, forming a self-reinforcing inflammatory cycle. Myostatin overactivation, irisin decrease, and FGF21 imbalance influence glucose homeostasis. Metabolism declines due to hypothalamic insulin resistance, microglial inflammation, gut dysbiosis-driven TLR4/NF-κB signalling, and epigenetic remodelling via miR-29, miR-34a, and l Using precision biomarkers like GDF-15, β2-microglobulin, and p16INK4a with multi-omics phenotyping may change diagnosis. Senolytics, NAD⁺ replenishment, SIRT1 activators, mitophagy inducers, anti-myostatin medicines, and exosome-based therapies shift metabolic care towards senescence. T4DM's molecular architecture and precision geriatric endocrinology translational targets are reviewed here.