Decoding Human Longevity: Genetic and Molecular Insights from Accelerated to Successful Ageing

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. This synthesis was conducted using a qualitative narrative review approach integrating human genetic data, mechanistic studies, and translational evidence across models of accelerated and successful ageing. Left: Longevity genes, molecular pathways, experimental models, and epigenetic clocks define the biology of ageing and guide interventions that reshape the ageing trajectory. Right: Protective alleles (leaves) from centenarians (vigorous tree) can be transferred to counteract premature ageing and age-related diseases (withered tree). • Ageing is a heterogeneous process shaped by genetic and environmental factors • Progeroid mutations and centenarian variants unveil genetic dichotomy of ageing • Extreme phenotypes reveal convergent pathways across ageing trajectories • Clinical translation remains limited by largely preclinical evidence