Читать книгу Pathy's Principles and Practice of Geriatric Medicine - Группа авторов - Страница 45

Major metabolic changes during ageing are insulin resistance, body composition modifications (increase in visceral fat mass and decrease in skeletal muscle mass), and decline in both sex steroids and hormones of the somatotrophic axis. This axis comprises the growth hormone and insulin‐like growth factor (IGF‐1), which shares a downstream intracellular pathway with insulin, thereby signalling nutrient abundance and anabolism. Interestingly, genetically driven reductions in the functions of GH, IGF‐1 receptors, insulin receptors, and their intracellular effectors (including mammalian target of rapamycin, mTOR) are associated with longevity in humans and model organisms.^41,42 More comprehensively, insulin/IGF‐1 axis activity decreases during ageing, whereas its constitutive impairment extends longevity. This paradox may be understood if we consider intense trophic and anabolic activity as an accelerator of ageing, and the downregulation of insulin/IGF‐1 and mTOR pathways as defensive responses against systemic damage during ageing, aimed at reducing cell growth and metabolism.^15,43

Furthermore, both dietary restriction and drugs that mimic it (e.g. rapamycin) were shown to increase lifespan in animal models (including mice) through the effect on the insulin/IGF‐1 pathway, emphasising the role of deregulated nutrient‐sensing in the biology of ageing.^44,45 Of note, mTOR inhibitors are currently approved and used as immunosuppressive drugs for recipients of organ transplants. Nevertheless, given their side effects, their net effect on human ageing remains to be determined. Metformin is also seen as a potential anti‐ageing drug due to its positive effect on deregulated nutrient sensing and mitochondrial dysfunction, DNA damage, and inflammation.⁴⁶