The original nine hallmarks (2013)
1. Genomic instability
DNA damage accumulates throughout life from both endogenous sources (replication errors, reactive oxygen species) and exogenous ones (UV radiation, environmental mutagens). DNA repair systems become less efficient with age, and unrepaired damage drives cellular dysfunction, senescence, and cancer. Interventions that support DNA repair: adequate sleep (glymphatic clearance), NAD+ precursors (NMN/NR support PARP enzymes central to base excision repair), and minimising exogenous DNA-damaging exposures.
2. Telomere attrition
Telomeres — protective caps at chromosome ends — shorten with each cell division. When telomeres reach a critical length, cells enter senescence or apoptosis. Telomere length is a commonly used (though imperfect) biological age proxy. Key modulators: telomerase activity (reduced by chronic stress and smoking; maintained by aerobic exercise), oxidative stress, and inflammation. A 2023 meta-analysis confirmed exercise is associated with significantly longer leukocyte telomere length across populations.
3. Epigenetic alterations
The epigenome — chromatin modifications, DNA methylation patterns, and histone modifications — drifts progressively from youthful patterns with age. This epigenetic 'noise' disrupts gene expression regulation. Epigenetic clocks (PhenoAge, GrimAge, DunedinPACE) measure these changes and provide the most validated biological age estimates currently available. Interventions with demonstrated epigenetic age slowing: caloric restriction, aerobic exercise, MBSR, and quality sleep.
4. Loss of proteostasis
Proteostasis — the maintenance of a functional proteome through chaperone-mediated folding, the ubiquitin-proteasome system, and autophagy — declines with age. Misfolded proteins aggregate (amyloid-beta, tau, alpha-synuclein) and cellular waste accumulates. Autophagy — the cellular self-cleaning process — is the primary proteostasis maintenance mechanism and is inhibited by continuous eating (mTOR activation) and enhanced by fasting, caloric restriction, and sleep.
5. Deregulated nutrient sensing
Four nutrient-sensing pathways — mTOR, AMPK, insulin/IGF-1, and sirtuins — are central regulators of lifespan in every model organism studied. Chronic over-nutrition (particularly excess glucose and branched-chain amino acids) keeps mTOR constitutively active, suppressing autophagy and accelerating ageing. AMPK activation (via exercise, caloric restriction, and metformin) has opposing effects. NAD+-dependent sirtuins, activated by NAD+ precursors and fasting, regulate stress responses, mitochondrial biogenesis, and DNA repair.
The mTOR-AMPK-sirtuin triad governs nutrient sensing and ageing across virtually all model organisms. Chronic over-nutrition suppresses AMPK and sirtuins while activating mTOR — the molecular signature of accelerated ageing. Exercise, fasting, and caloric restriction do the opposite.
6. Mitochondrial dysfunction
Mitochondria are the primary site of ATP production and a major source of reactive oxygen species (ROS). Mitochondrial function declines with age through accumulated mtDNA mutations, reduced mitophagy (clearance of dysfunctional mitochondria), and declining membrane potential. Reduced mitochondrial capacity manifests as fatigue, reduced exercise tolerance, and metabolic decline. Interventions: Zone 2 cardio is the most potent mitochondrial biogenesis stimulus; urolithin A (from pomegranate polyphenols) has Phase 2 trial evidence for improving mitophagy in older adults.
7. Cellular senescence
Senescent cells — cells that have permanently exited the cell cycle — accumulate with age and secrete pro-inflammatory factors (the SASP). In small numbers, senescence is beneficial (tumour suppression, wound healing); in chronic accumulation, it drives tissue dysfunction and systemic inflammation. Senolytics (dasatinib, quercetin, navitoclax) are being studied to reduce senescent burden; evidence in healthy humans is preliminary but the mechanistic case is strong.
8. Stem cell exhaustion
Stem cell populations in most tissues — haematopoietic, muscle, intestinal, neural — decline in number and function with age. This impairs tissue regeneration and repair capacity. Exercise increases circulating stem cell populations in multiple tissues; sleep and growth hormone secretion support stem cell function overnight.
9. Altered intercellular communication
Ageing disrupts intercellular signalling through altered inflammatory cytokine levels, changes in extracellular matrix composition, and degradation of neurohormonal signalling. Young blood parabiosis experiments in mice — connecting the circulation of young and old animals — revealed that circulating factors in young blood rejuvenate multiple aged tissues, pointing to specific plasma proteins as key communicators.
The five new hallmarks (2023 update)
The 2023 revision added: (10) Disabled macroautophagy (emphasising autophagy as a primary ageing mechanism rather than a component of proteostasis); (11) Chronic inflammation ('inflammaging' — now recognised as sufficiently central to ageing to merit its own hallmark); (12) Dysbiosis (microbiome disruption linked to metabolic, immune, and neurological ageing); (13) Altered mechanical properties (changes in tissue stiffness and extracellular matrix that drive organising signals); and (14) Loss of circadian rhythm integrity (consistent with mounting evidence that circadian disruption is a primary driver, not just a correlate, of ageing).
What this means for daily choices
The hallmarks framework reveals that most of the lifestyle interventions discussed throughout this site act on multiple hallmarks simultaneously. Sleep addresses glymphatic clearance (genomic stability), epigenetic ageing, circadian rhythm integrity, and growth hormone-driven stem cell function. Zone 2 exercise addresses mitochondrial function, telomere maintenance, senescence, and nutrient sensing via AMPK. Caloric restriction or TRE addresses mTOR/AMPK balance, epigenetic ageing, autophagy, and chronic inflammation. This is why the foundation comes first — it is the most broadly acting intervention set available.
References
- Lopez-Otin, C., et al. (2013). The hallmarks of aging. Cell, 153(6).
- Lopez-Otin, C., et al. (2023). Hallmarks of aging: an expanding universe. Cell, 186(2).
- Lazarus, J., et al. (2023). Telomere length and exercise: meta-analysis. Sports Medicine.
- Kraus, W. E., et al. (2022). Caloric restriction and epigenetic ageing: CALERIE reanalysis. Aging Cell.
- Singh, A., et al. (2022). Urolithin A supplementation and mitophagy in older adults: Phase 2 trial. Cell Reports Medicine.
- Conboy, I. M., et al. (2005). Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature, 433.