Clinical and Fundamental Medicine · Oct 23, 2026

Molecular mechanisms of aging: signaling pathways, cellular senescence, and geroprotective approaches

By Tiasto V, Андреевна БМ

Aging is accompanied by interconnected changes in genomic stability, epigenetic regulation, proteostasis, mitochondrial function, and intercellular communication, leading to impaired cellular and tissue homeostasis. This review examines the molecular mechanisms of aging, with an emphasis on the signaling pathways of insulin/insulin-like growth factor 1 (IGF-1), mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and sirtuins, and on nicotinamide adenine dinucleotide (NAD⁺) metabolism. Cellular senescence is analyzed separately, including mechanisms of cell-cycle arrest, the development of the senescence-associated secretory phenotype (SASP), and the potential of senotherapy. Caloric restriction and selected pharmacological interventions affecting the regulatory mechanisms of aging are considered. The main unresolved challenges remain the validation of biomarkers of biological age, confirmation of the clinical significance of geroprotective interventions, and justification of their combined use. Addressing these challenges is necessary to establish the relationship between changes in molecular parameters and preservation of the functional status of the organism during aging. Aging is accompanied by interconnected changes in genomic stability, epigenetic regulation, proteostasis, mitochondrial function, and intercellular communication, leading to impaired cellular and tissue homeostasis. This review examines the molecular mechanisms of aging, with particular emphasis on the insulin/insulin-like growth factor 1 (IGF-1) signaling pathway, the mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), sirtuins, and nicotinamide adenine dinucleotide (NAD⁺) metabolism. Cellular senescence is considered separately, including the mechanisms of cell-cycle arrest, the development of the senescence-associated secretory phenotype (SASP), and the potential of senotherapeutic approaches. Caloric restriction and selected pharmacological interventions targeting regulatory mechanisms of aging are also discussed. Major unresolved challenges include the validation of biological age biomarkers, confirmation of the clinical relevance of geroprotective interventions, and the establishment of an evidence base for their combined use. Addressing these challenges is essential for determining the relationship between changes in molecular markers and the preservation of functional capacity during aging.

doi.org/10.24866/3033-5485/2026-3/31-46Open accessMechanisms