In 2013, Lopez-Otin and colleagues published a landmark paper in Cell identifying what are now known as the hallmarks of ageing: nine interconnected biological mechanisms that drive the deterioration of function with increasing chronological age. Understanding these mechanisms explains why the lifestyle interventions with the strongest evidence for longevity, exercise, dietary quality, sleep, and stress management, have such broad effects across multiple health conditions.
The Nine Hallmarks
- Genomic instability: accumulation of DNA damage from oxidative stress, radiation, and replication errors
- Telomere attrition: progressive shortening of the protective caps on chromosomes with each cell division
- Epigenetic alterations: changes in gene expression patterns that diverge increasingly from the optimal youthful state
- Loss of proteostasis: declining capacity to maintain correct protein folding and clear misfolded proteins
- Deregulated nutrient sensing: dysregulation of the mTOR, AMPK, sirtuins, and IGF-1 signalling pathways that coordinate cellular metabolism
- Mitochondrial dysfunction: accumulation of mitochondrial DNA mutations and declining oxidative phosphorylation efficiency
- Cellular senescence: accumulation of cells that have stopped dividing but resist apoptosis, producing a chronic inflammatory secretion called SASP
- Stem cell exhaustion: declining regenerative capacity from reduced stem cell numbers and function
- Altered intercellular communication: dysregulation of hormonal, neurological, and inflammatory signalling between tissues
The Lifestyle Interventions That Address Multiple Hallmarks
Exercise, particularly aerobic exercise and HIIT, addresses at least five of the nine hallmarks directly: it improves mitochondrial function, reduces senescent cell burden, supports stem cell function, reduces chronic inflammation, and improves nutrient sensing pathways through AMPK activation. This explains the extraordinary breadth of the evidence for exercise across almost every health condition associated with ageing.