The 12 Hallmarks of Ageing, Explained — and Which You Can Influence

In 2013, a team led by Carlos López-Otín published a paper that changed how researchers think about ageing. Rather than treating it as a single, inevitable slide, they broke it into nine distinct biological processes — the hallmarks of ageing. A decade later, in January 2023, the same team expanded the list to twelve, adding three mechanisms the field had come to recognise as fundamental: disabled macroautophagy, chronic inflammation, and dysbiosis.

The framework has become one of the most influential organising models in ageing biology. Almost every trending longevity topic — intermittent fasting, senolytics, the gut microbiome, rapamycin — traces back to one or more of these twelve processes. Understanding them is the first step toward knowing which claims deserve your attention, and which are noise.

What makes a "hallmark"

The authors set three criteria for a process to qualify:

1. It manifests during normal ageing.
2. Experimentally accelerating it speeds up ageing.
3. Intervening to slow or reverse it extends healthy lifespan — at least in animal models.

That third criterion is what makes the framework more than academic. It implies that ageing is not one thing going wrong, but many — and that some of those things may be individually addressable.

The twelve hallmarks

The hallmarks fall into three broad tiers, based on where they sit in the causal chain.

Primary hallmarks — the initial triggers

These are the upstream causes of cellular damage that accumulate with age:

Genomic instability. DNA damage from replication errors, oxidative stress, and environmental exposures builds up over a lifetime. Repair mechanisms gradually lose fidelity.

Telomere attrition. The protective caps on chromosome ends shorten with each cell division, eventually limiting a cell's ability to divide safely.

Epigenetic alterations. The chemical marks that tell genes when to switch on or off drift over time, disrupting gene-expression patterns. This drift is what epigenetic clocks measure.

Loss of proteostasis. The cell's protein quality-control systems — chaperones, autophagy, the proteasome — become less effective, allowing misfolded or damaged proteins to accumulate.

Disabled macroautophagy. Autophagy — the cell's recycling system — clears damaged components. Its decline with age means cellular waste builds up. This was elevated from a sub-process to a standalone hallmark in 2023.

Antagonistic hallmarks — responses that turn harmful

These processes are beneficial in youth but damaging when chronic or excessive:

Deregulated nutrient-sensing. The signalling pathways that detect food availability (insulin/IGF-1, mTOR, AMPK, sirtuins) shift toward growth-promoting mode even when growth is no longer needed.

Mitochondrial dysfunction. The cell's energy plants produce less ATP and more reactive oxygen species, contributing to inflammation and energy shortfalls.

Cellular senescence. Cells that stop dividing but refuse to die accumulate with age, secreting a cocktail of inflammatory signals — the senescence-associated secretory phenotype, or SASP — that damages neighbouring tissue.

Integrative hallmarks — the downstream consequences

These emerge from the upstream damage and affect the organism as a whole:

Stem cell exhaustion. The reservoirs of fresh cells that repair tissues shrink, reducing the body's regenerative capacity.

Altered intercellular communication. Cell-to-cell signalling — hormonal, neuronal, inflammatory — becomes noisier and less coordinated.

Chronic inflammation. Low-grade, sterile inflammation — termed "inflammaging" — is now understood as both a consequence of other hallmarks and a driver of further damage. It was added as a standalone hallmark in 2023.

Dysbiosis. Age-related shifts in the gut microbiome — reduced diversity, loss of beneficial species, overgrowth of pro-inflammatory taxa — feed back into systemic inflammation and metabolic disruption. Also new in 2023.

Which hallmarks can you actually influence?

The honest answer: several, to varying degrees. But no single intervention addresses all twelve simultaneously, and — as the 2023 review itself notes — interventions that mitigate individual hallmarks have largely been demonstrated in animal models rather than in human lifespan trials. The evidence is strongest for slowing the rate of accumulation, not for reversal.

Chronic inflammation — STRONG evidence for measurement; EMERGING for targeted intervention. Inflammaging is a significant risk factor for morbidity and mortality in older adults. High-sensitivity C-reactive protein (hs-CRP) is the most widely used blood marker for systemic low-grade inflammation, and meta-analyses link elevated hs-CRP to higher all-cause, cardiovascular, and cancer mortality in a dose-dependent manner. Lifestyle factors — exercise, diet quality, weight management — are associated with lower inflammatory markers, though the evidence for specific interventions reducing hs-CRP enough to change clinical outcomes is still developing.

Deregulated nutrient-sensing — STRONG evidence for the pathway; EMERGING for human interventions. The insulin/IGF-1 and mTOR signalling cascades are among the most conserved ageing mechanisms across species. The CALERIE trial — the first randomised controlled trial of caloric restriction in healthy, non-obese humans — showed that two years of moderate caloric restriction (averaging roughly 12%) improved cardiometabolic risk markers including fasting insulin, LDL cholesterol, and blood pressure. HbA1c, a standard measure of average blood glucose over approximately two to three months, offers an accessible window into how well your metabolic machinery is handling glucose over time.

Mitochondrial dysfunction and fitness — STRONG for exercise broadly. A narrative review mapping physical exercise against the hallmarks found a positive association with every one examined: from telomere maintenance and epigenetic regulation to mitochondrial biogenesis, autophagy activation, and reduced inflammation. The breadth of exercise's positive associations across ageing pathways is notable, and few single interventions can claim a comparable range of evidence.

Disabled macroautophagy — EMERGING. Both fasting and exercise are associated with autophagy activation in animal and cell models, though measuring autophagy flux in living humans remains technically difficult. Whether fasting protocols activate clinically meaningful autophagy in humans is plausible but not yet demonstrated in healthspan-outcome trials.

Dysbiosis — EMERGING. The gut microbiome shifts with age, and studies of centenarians show compositional differences compared with younger adults. Diet is a strong modulator of microbiome composition, but as the authors of a 2022 review noted, targeted restoration of age-related microbial changes in humans remains at an early stage, with no large trial yet demonstrating reversal of dysbiosis or lifespan extension.

Cellular senescence — HYPED-BUT-THIN for consumer products. Senescence is one of the best-characterised hallmarks, and senolytic compounds (dasatinib plus quercetin, fisetin) have cleared senescent cells and improved healthspan in mouse models. Early-phase human trials are under way, but consumer-grade senolytic supplements have not yet demonstrated clinical outcome benefits in peer-reviewed trials. There is currently no routine clinical assay for senescent-cell burden — the downstream signal is the inflammatory load these cells generate, which loops back to hs-CRP.

Genomic instability, telomere attrition, epigenetic alterations, stem cell exhaustion. These are real and measurable (particularly via epigenetic clocks), but direct consumer interventions are limited. Physical exercise has been associated with favourable effects on telomere maintenance and epigenetic regulation in observational and mechanistic studies, but these remain associations, not proven causal levers. The evidence for any single targeted intervention is MIXED.

How strong is the evidence overall?

The hallmarks framework itself is STRONG — it is a widely cited and influential organising model in ageing biology, grounded in decades of cross-species research. Its value is as a map, not a treatment protocol.

For specific interventions targeting individual hallmarks, the picture is more nuanced. Exercise has been reviewed as having positive effects across multiple hallmarks simultaneously, and caloric restriction has improved cardiometabolic markers in a human RCT. Targeted pharmacological interventions — rapamycin, senolytics, NAD+ precursors — have strong animal evidence but limited human outcome data, placing them in the EMERGING to HYPED-BUT-THIN range.

The honest gap: as the hallmarks authors acknowledge, most evidence for lifespan extension through targeting individual hallmarks comes from animal models. In humans, the best evidence to date shows improved biomarkers and risk factors — meaningful, but not the same as a demonstrated increase in lifespan.

How Omniwo helps you measure this

You cannot manage what you cannot measure — and several hallmarks have accessible blood proxies.

Omniwo's BioAge Test computes a blood-based biological age using an algorithm in the PhenoAge family (originally described by Levine et al.) from an at-home finger-prick kit, giving you a composite number rather than a single trendy molecule. Two of those core markers map directly onto hallmarks discussed above:

• hs-CRP — a widely used read-out of chronic inflammation (hallmark eleven). A single reading is a snapshot; tracking it over time provides more context than any one measurement.
• HbA1c — a standard measure of average blood glucose over approximately two to three months, offering a window into deregulated nutrient-sensing (hallmark six).

For the fitness-related hallmarks — mitochondrial dysfunction, altered intercellular communication — Omniwo reads resting heart rate and heart rate variability from its five live wearable integrations (Oura, WHOOP, Strava, Polar, Apple Health), letting you track the physiological signals that sit alongside your blood work.

What Omniwo does not measure: senescent-cell burden, NAD+ levels, telomere length, or gut microbiome composition. Where a hallmark has no in-panel proxy, the honest approach is to track its downstream effects — and that is what a composite BioAge trend, re-tested over months, is designed to do.

Omniwo's tests and content are for wellness and educational insight. They do not diagnose, treat, cure or prevent any disease, and do not replace advice from a qualified healthcare professional.

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This article is educational and not medical advice. See our medical disclaimer.