Theories of Ageing

Ageing is now accepted to be a multifactorial process; extended longevity is consistently associated with enhanced metabolic capacity and stress response.

Genetics matters — each species has a characteristic longevity — but heritability accounts for only about 35% or less of the variance in lifespan, while environmental factors account for more than 65%.

Genes specifically selected to promote ageing are unlikely to exist; ageing is not a programmed adaptive trait.

Kane groups all theories into three categories: (i) accumulation of damage to informational molecules, (ii) regulation of specific genes, and (iii) depletion of stem cells.

Somatic mutation theory: greater susceptibility to mutagenesis or defective DNA repair drives ageing. Support: species longevity correlates positively with DNA repair enzyme capacity. Against: the human spontaneous mutation rate is too low to account for the changes required, and there is no evidence of a general failure of repair systems — though limited maintenance may allow somatic damage to accumulate.

Error catastrophe theory (Orgel): errors in DNA, RNA and protein synthesis each amplify the others until an error catastrophe occurs; translation was thought the likeliest source. Against: increased translational errors have not been found in vivo or in vitro, and amino acid substitutions do not increase with age, although post-translational changes such as glycosylation may alter enzyme activity.

Free radical / oxidative damage theory (Harman): superoxide radicals, the major by-product of oxidative metabolism, react with DNA, RNA, proteins and lipids to cause cellular damage. Scavenging enzymes and vitamins C and E are protective.

Evidence against a simple free radical theory: there is no significant loss of scavenging enzymes with age, and vitamins C and E do not increase longevity in experimental animals.

Evidence for: overexpression of antioxidative enzymes retards age-related oxidative damage and extends maximum lifespan in transgenic fruit flies, and caloric restriction lowers oxidative stress and extends maximum lifespan in rodents.

Loss of molecular fidelity (Hayflick): genes do not drive ageing — the general loss of molecular fidelity does. Every molecule becomes subject to thermodynamic instability. This distinguishes ageing from disease, because ageing occurs in every multicellular animal that reaches a fixed size at reproductive maturity, occurs after reproductive maturity in all species, and has the same universal molecular aetiology.

Evolutionary theory (Darwin): current organisms result from an incrementally accumulative evolutionary process — "survival of the fittest" — organisms surviving longer had more opportunity to breed and propagate their design.

Gene regulation theory: specific genes regulate ageing. Genes extending lifespan have been found in yeast, nematodes and fruit flies, and they reinforce the importance of metabolic capacity and stress response. DNA microarray work found relatively few genes changed in ageing human fibroblasts, with downregulation of mitosis-control genes proposed as a general cause — but the pattern is not reproduced in other tissues, suggesting different mechanisms in different tissues.

Replicative senescence (Hayflick limit): cells in culture divide a fixed number of times and then enter replicative senescence. Human fibroblasts manage about 50 doublings (most cell types 60–70); replicative life in vitro correlates inversely with donor age. Replicative senescence is believed to have evolved to protect higher organisms from cancer.

Telomere theory: with each division a portion of the terminal chromosome (the telomere) is not replicated and shortens — about 50–100 base pairs are lost per replication. Telomerase adds bases back; transfection of its catalytic component into senescent cells extends telomeres and replicative lifespan and restores a young pattern of gene expression.

Telomere caveats: relevance in vivo remains unknown; studies of the oldest old show no relationship between telomere length and mortality, though healthy centenarians had significantly longer telomeres than unhealthy ones. Telomerase inhibitors are potential anticancer therapies. Stress-induced premature senescence shows that oxidative stress and oncogene activation can produce an identical senescent phenotype without telomere shortening.

Stem cell depletion: convergence of the above mechanisms reduces proliferative potential. Cells are of three types — continuously replicating (epidermal, gastrointestinal, haematopoietic), replicating on challenge (liver), and non-replicating (neurons, cardiac and skeletal muscle) — and in non-replicating tissues, cell loss produces a permanent deficit (for example, loss of dopaminergic neurons affecting gait and balance).

Neuroendocrine theory (Dilman): age-related hypothalamic functional decline from reduced sensitivity to feedback. Controversial, because pituitary secretion also depends on sex, body composition, stress, illness, comorbidity, medication, frailty, caloric intake, immune status, activity and cognition.

Immunological theory: thymic involution after puberty with falling thymosins, reduced IL-2 production and receptor expression, and diminished lymphocyte proliferative response — predisposing to infection, autoimmunity and cancer.

Network and remodelling theories (Franceschi): ageing is active remodelling, not simple decline, with inflammaging at its centre. The "seven pillars" of ageing and age-related disease are adaptation to stress, loss of proteostasis, stem cell exhaustion, metabolic derangement, macromolecular damage, epigenetic modification and inflammation.

Hormesis: stress is not necessarily deleterious — low-intensity stimulation activates maintenance and repair mechanisms and improves health, whereas stress exceeding the organism's adaptive capacity causes disease. This is the theoretical basis for exercise, caloric restriction and the Mediterranean diet.

Nine mechanisms are given as the fundaments of ageing in Pathy: genomic instability, telomere attrition, epigenetic modifications, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion and altered intercellular communication.

Caloric restriction and mutations in nutrient and growth signalling pathways extend lifespan by 30–50% in preclinical models; in humans, long-term caloric restriction and intermittent fasting produce favourable metabolic changes but are not feasible for most people and may have adverse effects.

Cautions from the textbook: the reductionist single-marker approach fails because a living system is homeodynamic, with tolerance, compensation and adaptation — illustrated by failed beta-amyloid trials in Alzheimer's disease and by the unproven benefit of lengthening telomeres. The "hormonal fountain of youth", from Brown-Séquard's testicular extract onward, has been a consistent disappointment.