Anti-Ageing Interventions

Geroscience hypothesis: the accumulation of diseases and loss of function with ageing is driven by common biological mechanisms. Targeting these should delay multiple diseases simultaneously and extend healthspan.

Interventions that slow ageing are likely to delay the onset of cancer, diabetes, cardiovascular disease and neurodegenerative disease together — the fundamental argument for anti-ageing medicine.

Pathy's lists the therapeutic opportunities as senolytics, inflammasome inhibitors, mesenchymal stem cells, calorie-restriction mimetics and autophagy inducers — plus lifestyle interventions (physical activity, diet).

Habitual physical activity increases average life expectancy by about two years.

Many changes attributed to biological ageing can be prevented by chronic physical activity, particularly the body-composition changes: decreased muscle mass, decreased bone mass and strength, increased adipose tissue and central fat deposition.

Exercise prevents and/or treats obesity, cardiovascular disease, type 2 diabetes, hypertension, osteoarthritis, osteoporosis, stroke, peripheral vascular disease, renal failure, dementia and depression.

Strong evidence that exercise improves muscle strength, muscle mass, bone density, falls incidence and mobility across the whole health and frailty spectrum.

High-intensity resistance training is the optimal prescription for sarcopenia, also improves balance, and improves aerobic capacity as much as moderate-intensity aerobic training — one prescription targeting both major deficits.

Aerobic exercise does NOT improve strength or balance and is insufficient as an isolated prescription. Falls-prevention programmes based on walking are inferior to strength-and-balance programmes and have been associated with increased fracture rates in those at risk.

Explosive resistance training ("power training") is central, because muscle power declines far more steeply than strength with age (fast-twitch fibre atrophy plus altered neural recruitment).

Multicomponent exercise (resistance + balance + gait retraining) improves all the hallmarks of frailty. The VIVIFRAIL programme provides individualised prescription "passports" based on SPPB and gait speed.

Sequence in the very frail follows the physiology of mobility: strength/power to stand up → balance to stay upright → endurance to walk.

High-intensity strength training works even in nonagenarians (Fiatarone, 1990) and in acutely hospitalised and institutionalised older adults.

Physical activity may ameliorate immunosenescence and thereby reduce age-related multimorbidity.

Caloric restriction increases lifespan by up to 50% in mammals, acting through reduced IGF-1, sirtuins and TOR — but is not practical in humans, hence the search for CR mimetics.

Mediterranean diet promotes epigenetic rejuvenation (NU-AGE study).

Antioxidant vitamins have failed: there is no significant loss of scavenging enzymes with ageing, and vitamins C and E do not increase longevity in experimental animals. Broad-spectrum vitamin supplementation is nonetheless considered reasonable for most older people.

Vitamin D 800–2000 IU daily reduces fracture risk and prevents falls. Salt restriction and weight loss (TONE trial) effectively lower blood pressure in older people.

Growth hormone: GH falls with age causing muscle loss, but GH replacement did NOT restore muscle strength despite increasing muscle mass, and was associated with increased cardiovascular mortality risk, glucose intolerance and diabetes. Paradoxically, reduced GH signalling correlates with increased longevity in rodents.

DHEA: levels fall with age, but replacement had no beneficial effect on memory or muscle strength — only a slight effect on libido, mainly in women.

Oestrogen: KEEPS showed control of postmenopausal symptoms without a serious increase in cardiovascular mortality or VTE, but HRT is not recommended after age 60. WHI showed observational benefits were exaggerated and risks of heart disease, stroke and cancer.

Testosterone: free testosterone falls with age (raised SHBG, raised fat mass) and correlates with muscle mass, strength, frailty, sexual function and cognition. Replacement improves symptoms and reverses lower urinary tract symptoms. Trials show benefit in grip strength, Functional Independence Measure, and post-operative ability to stand, with effects confined to men aged 75 and over and the frail. Evidence is not conclusive but justifies further study.

Key exam line: growth hormone and testosterone cannot be recommended for older men with normal or low-normal hormone levels.

Senolytics — selective elimination of senescent cells attenuates age-related deterioration of several organs and extends lifespan in mice. Rapamycin extends lifespan in mice even when begun late (barrier: immunosuppression). Metformin acts on nutrient sensing, mitochondrial dysfunction, DNA damage and inflammation. Anti-IL-1beta (canakinumab) reduced the incidence of age-related diseases in humans.

Stem cells and epigenetic reprogramming: transplanting muscle-derived stem cells from young mice extended health- and lifespan in progeroid mice even where donor cells were undetectable, suggesting benefit via secreted factors. However, embryonic and pluripotent stem cells are NOT a reversal of ageing — they form tumours. Epigenetic reprogramming carries a malignancy risk; the goal is to reset the ageing clock while leaving the differentiated state untouched.

CALERIE — first randomised human evidence that an intervention slows ageing. 220 adults randomised to 25% caloric restriction versus ad libitum diet for two years showed slowing of the pace of ageing by DunedinPACE, without significant change in PhenoAge or GrimAge; roughly 3% slowing, associated with 15% lower risk of death. (Nature Aging 2023)

Senolytics reach human trials. SToMP-AD and STAMINA tested 12 weeks of intermittent oral dasatinib plus quercetin in older adults with or at risk of Alzheimer's disease; in STAMINA, reductions in plasma TNF-alpha correlated with MoCA improvement (r = −0.65, p = 0.02). Safety, feasibility, CNS penetrance and biological activity were established, and a Phase 2 RCT is now underway.

Metformin as a geroprotector — a major setback. In a 21-year DPP follow-up, metformin did not significantly reduce multimorbidity risk; 85% of participants developed two or more chronic conditions (82% lifestyle, 85% metformin, 87% placebo). Intensive lifestyle intervention was associated with lower long-term multimorbidity burden. TAME remains the pending definitive test. (JAMA 2026)

Partial epigenetic reprogramming moves toward the clinic. In vivo reprogramming through transient Yamanaka factor expression shows promise for restoring regenerative competence across retina, skeletal muscle, heart, liver, brain and intestine, but carries critical safety concerns — teratoma formation, organ failure and loss of cell identity — mitigated by cyclic induction and targeted delivery. A protocol of 2 days on and 5 days off per week has allowed safe long-term reprogramming; in neuron-restricted models cyclic induction improves hippocampal activity, restores youthful heterochromatin and enhances memory, whereas continuous expression is ineffective or deleterious. A platform using Oct4, Sox2, Klf4 (OSK), omitting the c-Myc oncogene, has its lead programme ER-100 in development for optic neuropathies including glaucoma and NAION, with plans to enter the clinic in Q1 2026. (Aging Cell 2025)

The field now has validation standards. The Biomarkers of Aging Consortium published recommendations on validating biomarkers of ageing, noting systematic validation is required before use as surrogate endpoints in gerotherapeutic trials. (Nature Medicine 2024)