It remains an open question as to whether anything discovered about the roots of individual variation in life expectancy within a species will give rise to usefully effective interventions to treat aging. Some researchers hold up the passage of late life aging in centenarians as a goal to aim for - but centenarians, while having evaded death for longer than most, are nonetheless greatly impacted by degenerative aging and exhibit significant dysfunction and mortality rates. We must aim higher, to create therapies that produce results that do not happen naturally in old people, such as comprehensive clearance of senescent cells in aged tissues, replacement of damaged mitochondria with functional mitochondria, and so forth. Actual repair of dysfunction, not just slowing it down a little.
Ageing is an inevitable, yet highly heterogeneous process shaped by genetic, epigenetic, and environmental influences. While most individuals experience progressive functional decline, a minority exhibits accelerated degeneration due to rare pathogenic mutations, whereas others achieve exceptional healthy longevity. This continuum - from progeroid syndromes to centenarians - provides a unique framework to examine how deleterious and protective genetic variants differentially modulate conserved biological pathways. Genetic models of accelerated ageing reveal mechanisms driving premature functional deterioration, whereas studies of exceptionally long-lived individuals highlight variants associated with resilience, stress adaptation, and preserved homeostasis. Together, these extremes define a genetic dichotomy that informs, but does not deterministically predict, ageing trajectories.
This review critically highlights current evidence on genetic factors and molecular mechanisms that regulate human ageing across this spectrum. Beyond established hallmarks such as cellular senescence and chronic inflammation, we discuss emerging pathways implicated in successful ageing, including hypoxic adaptation, transcriptional and chromatin regulation, autophagy, and metabolic reprogramming. We further evaluate epigenetic clocks as quantitative tools for assessing biological ageing, emphasising their strengths, limitations, and context dependence. Throughout, we distinguish between genetic associations, mechanistic findings, and preclinical evidence, explicitly addressing gaps, biases, and translational uncertainty.
Link: https://doi.org/10.1016/j.arr.2026.103176
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