The hallmarks of aging is a scientific framework, first proposed in a widely cited 2013 paper and updated in 2023. It organises biological ageing into a set of distinct but interconnected cellular and molecular mechanisms, rather than treating it as one undifferentiated process. This framework underlies much of modern longevity science, providing shared vocabulary and shared targets across what were previously studied as separate, unrelated age-related diseases.
- First proposed in a widely cited 2013 paper, refined and expanded since.
- Organizes aging into distinct, interconnected cellular and molecular mechanisms.
- Reframed research toward shared mechanisms underlying multiple age-related diseases.
- Mitochondrial dysfunction and chronic inflammation are two hallmarks with trackable proxies.
Why the hallmarks reframing matters
Before this framework gained traction, ageing research and age-related disease research proceeded separately. Cardiovascular disease, cancer, neurodegeneration and metabolic disease were each studied in isolation, as though they were unrelated conditions that happened to correlate with advancing age.
The hallmarks framework proposed instead that a set of distinct, identifiable mechanisms at the cellular and molecular level drive multiple age-related diseases at once.
The implication is the reason it caught on. An intervention targeting one shared hallmark might plausibly help with several conditions, rather than needing a separate intervention per disease.
Two hallmarks that show up in tracked markers
Of the several hallmarks identified in the framework, two show up with reasonably trackable real-world proxies covered elsewhere in this encyclopedia. Mitochondrial dysfunction, the gradual decline in cellular energy-production efficiency, has a trainable countermeasure in aerobic exercise, covered in the mitochondrial function entry. Chronic low-grade inflammation, often called "inflammaging," has trackable blood proxies like hs-CRP, covered in its own dedicated entry. Neither of these tracked proxies directly measures the cellular hallmark itself, current consumer-accessible testing doesn't reach that level, but both are reasonable, evidence-supported indirect windows into these underlying processes.
The twelve hallmarks of aging
If you see a source confidently citing a number of hallmarks other than twelve, check its date before trusting the rest of it. The count changed in 2023 and a lot of content has not caught up.
The 2013 paper set out nine, and grouped them into three tiers describing where each sits in the causal chain. The 2023 update in Cell added three more, bringing the total to twelve, and placed them within that existing scheme rather than reorganising it. That grouping is the useful part: it separates the damage itself from the body's responses to it, and both from the system-wide consequences that follow.
Primary hallmarks: the root damage
These are unambiguously harmful. They accumulate over time and everything below is downstream of them.
- Genomic instability. DNA accumulates damage from metabolism, radiation and ordinary replication errors. Repair systems handle most of it, but not all, and the unrepaired fraction builds up across decades.
- Telomere attrition. The protective caps on chromosome ends shorten each time a cell divides. Once they are too short the cell stops dividing, which limits the tissue's capacity to renew itself.
- Epigenetic alterations. The chemical marks that tell a gene when to switch on or off drift with age, so cells gradually lose the correct instructions for what they are supposed to be doing. This is the layer epigenetic clocks attempt to read.
- Loss of proteostasis. Proteins must be folded correctly and broken down when damaged. When that quality control fails, misfolded proteins accumulate, a mechanism implicated in several neurodegenerative diseases.
- Disabled macroautophagy. Added in 2023. Autophagy is the cell's recycling system for clearing damaged components. When it slows, waste accumulates inside cells that would previously have been cleared.
Antagonistic hallmarks: responses that turn harmful
These begin as protective responses to the damage above. At low levels they help; sustained, they cause problems of their own, which is what makes them antagonistic.
- Deregulated nutrient sensing. The pathways that read energy availability, including insulin signalling and mTOR, become less accurate. This is the hallmark most directly connected to insulin resistance, and the one rapamycin and metformin are studied against.
- Mitochondrial dysfunction. The structures producing cellular energy become less efficient and leak more reactive byproducts. Of the twelve, this is the one with the best-evidenced intervention touching it, through Zone 2 training, and most practically measure, through VO2 Max.
- Cellular senescence. Damaged cells stop dividing but don’t die. Halting division prevents damaged cells replicating, which is protective, but senescent cells secrete inflammatory signals that irritate surrounding tissue. Clearing them is the premise behind senolytics.
Integrative hallmarks: system-wide consequences
These emerge when the damage and the responses to it accumulate beyond what tissues can compensate for. They are what aging looks like from the outside.
- Stem cell exhaustion. The reserve populations that replace worn-out cells decline in number and capability, so tissues repair more slowly and less completely. This underlies much of what is visible in sarcopenia and slower wound healing.
- Altered intercellular communication. The hormonal and chemical signalling between cells and tissues becomes noisier and less coordinated, so systems that should act together drift out of step.
- Chronic inflammation. Added in 2023, though studied for years under the name inflammaging. A persistent low-grade immune activation with no infection to resolve, measurable through hs-CRP.
- Dysbiosis. Added in 2023. The composition of the gut microbiome shifts with age in ways associated with inflammation and reduced metabolic resilience.
The authors set criteria intended to keep this list disciplined: a hallmark should worsen with age, accelerating it should speed aging, and targeting it should slow aging. In practice the first two are far better satisfied than the third, which is the substance of the criticism that the framework describes aging more convincingly than it explains it.
Selected hallmarks and their relevance
| Hallmark | Tier | Trackable consumer proxy |
|---|---|---|
| Genomic instability | Primary | None |
| Telomere attrition | Primary | None |
| Epigenetic alterations | Primary | None |
| Loss of proteostasis | Primary | None |
| Disabled macroautophagy | Primary | None |
| Deregulated nutrient sensing | Antagonistic | None |
| Mitochondrial dysfunction | Antagonistic | VO2 Max, Zone 2 response |
| Cellular senescence | Antagonistic | None |
| Stem cell exhaustion | Integrative | None |
| Altered intercellular communication | Integrative | None |
| Chronic inflammation | Integrative | hs-CRP |
| Dysbiosis | Integrative | None |
Two of twelve. That ratio is the honest summary of what this framework currently offers an individual, and it is why the page treats it as useful for orientation rather than as a shopping list.
From framework to something measurable
Coverage name-drops the hallmarks of aging without connecting the framework to anything measurable or actionable for one person.
Two of them you can track directly. Mitochondrial function shows up in aerobic capacity, and chronic inflammation shows up in hs-CRP.
The rest are useful for understanding why interventions work, and not currently things you can measure at home. That is worth saying plainly rather than implying otherwise.
It tracks real proxies for two hallmarks of aging, not just the concept.
Sources
Key references for the claims on this page. Where a figure is attributed to a specific study or body, it is named here.
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–1217. The original nine-hallmark framework and the primary, antagonistic and integrative tiers. DOI
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–278. The update to twelve, adding disabled macroautophagy, chronic inflammation and dysbiosis. DOI · PMID 36599349
- Gems D, de Magalhães JP. The hoverfly and the wasp: a critique of the hallmarks of aging as a paradigm. Ageing Research Reviews. 2021;70:101407. The critique of the framework as descriptive rather than explanatory. DOI
Frequently asked
What are the hallmarks of aging?
A framework organizing biological aging into distinct, interconnected cellular mechanisms, first proposed in 2013.
Why does this framework matter?
It reframed research toward shared mechanisms driving multiple age-related diseases simultaneously.
How many hallmarks are there?
Nine were proposed in the original 2013 Cell paper by Lopez-Otin and colleagues. The 2023 update in the same journal expanded the list to twelve, adding disabled macroautophagy, chronic inflammation, and dysbiosis. If you see a source confidently citing a different number, check its date before trusting the rest of it.
Are the hallmarks causes of aging or symptoms of it?
That distinction is the framework's most debated point. The authors set three criteria intended to separate the two: a hallmark should worsen with age, accelerating it should speed ageing, and targeting it should slow ageing.
The first two are far better satisfied than the third, and applied hallmark by hallmark the third is met to very different degrees. Cellular senescence has senolytic intervention data. Deregulated nutrient sensing has rapamycin and metformin trials. Telomere attrition and altered intercellular communication have very little in the way of interventions that slow ageing by targeting them.
That is a map of where the evidence is thickest rather than a verdict on the framework, and it says nothing about how well any of those interventions work.
Gems and de Magalhães put the criticism formally in 2021. Their argument is that the hallmarks of cancer, the explicit template for this framework, provide a paradigmatic account of causes with real explanatory power, and the hallmarks of ageing do not. Their specific objections are the implicit assumption that damage is the main primary cause of ageing, the neglect of ageing-related disease, and the implicit assumption that "ageing as a whole" exists as a single manipulable thing.
Worth noting how they frame it. Both authors say explicitly that the 2013 paper is an excellent overview of the field and that they recommend it to students. It is a critique of the paper's status as a paradigm, not a dismissal of its value, which is the same position this page takes.
The 2013 paper is the most highly cited article in ageing research. That is why a framework its critics regard as descriptive rather than explanatory became the field's organising vocabulary anyway.
Can I target a specific hallmark directly?
Not with any precision, and anything sold on that premise is running ahead of the evidence. What exists are interventions that touch several hallmarks indirectly at once. Exercise is the clearest example, affecting mitochondrial function and chronic inflammation together without being designed around either.
Which hallmarks connect to measurable markers?
Two, most directly. Mitochondrial dysfunction is reflected in cardiorespiratory fitness, which is why VO2 Max carries the weight it does. Chronic inflammation shows up in hs-CRP within Systemic Health. The remaining hallmarks are real but currently sit beyond what any consumer tool can honestly measure.
Is the framework universally accepted?
It is very widely used as an organising structure, which isn’t the same as being settled science. The main criticism is that it describes what changes with age more convincingly than it explains why. It remains useful for orientation while being a poor basis for buying anything.