Theories of Ageing

Ageing is a failure to maintain homeostasis under physiological stress. It is a progressive process associated with dysfunction.

No single theory explains ageing. Each older person is unique, and the elderly population is heterogeneous — a 65-year-old may be immobile while a 90-year-old is fully independent.

Evolutionary theories explain WHY we age; biological/molecular theories explain HOW we age. Only the latter is directly relevant to clinical geriatrics.

The Gompertz curve shows the incidence of death rises exponentially from reproductive maturity to maximum lifespan. Ageing is therefore the primary intrinsic factor of death.

The naked mole-rat is "non-Gompertzian" — its death rate does not rise with age, proving the curve reflects intrinsic ageing rather than external hazards alone.

After age 80 the death rate rises more slowly — the "late-life mortality plateau." Medical intervention produces rectangularization (compression) of mortality (Fries).

Wear and tear theory — the body simply wears out with repeated use.

Free oxygen radical theory (Harman, 1956) — reactive oxygen species (ROS) damage macromolecules. Pathy's notes this theory has been reshaped, because increased ROS may prolong lifespan in model organisms, and mitochondrial dysfunction can accelerate ageing without ROS.

Mitochondrial DNA theory — mtDNA is damaged with age; reduced biogenesis and poor autophagic quality control.

Somatic DNA damage theory — genomic instability from imbalance between DNA damage and repair. Werner syndrome (DNA helicase mutation) is the classical progeroid example.

Cross-linking theory and caloric restriction theory are also grouped under error theories.

Neuroendocrine theory — the hypothalamic-pituitary-adrenal (HPA) axis is the most important regulator of ageing.

Immunological theory — thymic atrophy reduces mature T-lymphocyte production; humoral immunity falls, antibody production drops, and infection risk rises.

Cellular senescence / Hayflick limit — human fibroblasts stop dividing after ~50 divisions. Telomeres shorten with each division until division stops. This protects against uncontrolled growth at the expense of ageing.

Cell death theory — apoptosis (programmed cell death) is responsible for tissue remodelling and homeostasis.

Medawar's mutation accumulation theory — natural selection cannot remove deleterious genes acting only in late life (the "selection shadow"), so harmful effects accumulate towards the end of life.

Williams' antagonistic pleiotropy theory — a gene with a small early benefit but a large late harm is still selected for, because early fitness matters more.

Kirkwood's disposable soma theory — limited energy must be divided between reproduction/function and repair/maintenance. The soma is maintained only until the germline is passed on.

Nine hallmarks in three groups: Primary (causes of damage): genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis Antagonistic (responses to damage): deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence Integrative (culprits of the phenotype): stem cell exhaustion, altered intercellular communication 20. Pathy's Table 1.1 lists eight components of biological ageing: genomic instability, epigenetic changes, mitochondrial dysfunction, loss of proteostasis, metabolic dysfunction, cell senescence, stem cell exhaustion, and immunosenescence.

Key mechanisms: SASP (senescence-associated secretory phenotype), inflammageing, insulin/IGF-1 and mTOR downregulation, and epigenetic (DNA methylation) clocks which predict age with error <5 years.

Telomere length is NOT currently accepted as a biological age marker despite its association with mortality — longitudinal changes are erratic.

Geroscience hypothesis — multimorbidity and functional loss in old age are driven by common biological mechanisms. Frailty and intrinsic capacity serve as clinical metrics of biological ageing.

Therapeutic opportunities listed in Pathy's: senolytics, inflammasome inhibitors, mesenchymal stem cells, calorie-restriction mimetics (rapamycin, metformin), autophagy inducers, plus exercise and diet.

Twelve Hallmarks of Ageing. Lopez-Otin and colleagues expanded the framework to twelve hallmarks: the original nine plus disabled macroautophagy, chronic inflammation and dysbiosis. These are interconnected and link to the proposed "hallmarks of health" (spatial compartmentalisation, maintenance of homeostasis, adequate stress responses). A process qualifies as a hallmark only if it appears with age, accelerates ageing when accentuated, and slows ageing when therapeutically targeted. (Cell 2023)

Challenge to the damage paradigm — hyperfunction theory. Blagosklonny's hyperfunction theory reframes ageing as the late-life continuation of growth-promoting pathways that become pathological once selective pressure declines. De Magalhaes' developmental theory describes ageing as a mismatch between developmental programmes optimised for early life and their persistence into later life. Continued mTOR signalling after growth is complete is itself considered hyperfunctional. These are "quasi-programs" — run-on of developmental programmes. (Ageing Res Rev 2022; Aging 2022)

Organ-specific and multi-omic ageing clocks. Plasma proteomic signatures of organ ageing track health and disease; brain and immune system ageing predict healthspan and longevity; organ-specific signatures predict 20-year risk of age-related disease in Whitehall II. Brain-imaging measures such as DunedinPACNI estimate pace of ageing from a single MRI. First-generation clocks (Horvath, Hannum) predict chronological age; second-generation (PhenoAge, GrimAge) predict mortality; third-generation (DunedinPACE) measure rate of ageing. (Nature 2023; Lancet Digit Health 2025; Nat Aging 2025)

Senolytics move into human trials. Two open-label Phase 1 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 improvement in MoCA (r = −0.65, p = 0.02). Safety, feasibility, CNS penetrance and biological activity were confirmed; a Phase 2 RCT is now underway. (eBioMedicine 2025)

Metformin as a geroprotector — a setback. In a 21-year follow-up of the Diabetes Prevention Program, 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. Lifestyle currently outperforms any pharmacological geroprotector. TAME remains the pending definitive trial. (JAMA 2026)