The Hallmarks of Ageing, Explained Simply

Ageing feels like one thing. Biologically it is not. Since 2013 researchers have described it as a set of distinct, measurable processes — the hallmarks of ageing — accumulating over decades.

Context sits in our longevity supplements guide and the anti aging supplements range; for the compound most discussed against these mechanisms, see NMN benefits, side effects and dosage, the NMN supplements collection and NMN Pro 1000.

This guide explains all twelve hallmarks in plain English, shows how they connect, and separates what the evidence genuinely supports from what is still speculative.

What are the hallmarks of ageing?

The hallmarks are a framework organising the biology of ageing into a defined list of processes. It was introduced by Carlos López-Otín, Maria Blasco, Linda Partridge, Manuel Serrano and Guido Kroemer in Cell in 2013, deliberately modelled on the earlier "hallmarks of cancer" framework [1].

The point was practical rather than philosophical. If ageing is one vague process, there is nothing to target. If it is a defined set of processes, each becomes a potential intervention point.

The three criteria a hallmark must meet

1. It must appear with age. The change has to show up progressively during normal ageing.
2. Worsening it must accelerate ageing. Experimentally amplifying the process should make the organism age faster.
3. Improving it must slow ageing. Correcting the process should decelerate, halt or partly reverse age-related decline [1].

That third criterion is the demanding one, and it is why several plausible-sounding candidates have never made the list.

From nine hallmarks to twelve

The 2013 paper proposed nine [1]. A decade later the same team published an update, noting that close to 300,000 papers on the topic had appeared in the intervening ten years — roughly as many as in the entire preceding century [2].

The 2023 revision added three: disabled macroautophagy, chronic inflammation and dysbiosis. Inflammation and autophagy had previously been folded into other categories; the microbiome was largely absent in 2013 because the science was not yet mature [2].

How the hallmarks are grouped

A useful way to picture it: primary hallmarks are the damage, antagonistic hallmarks are the body's increasingly desperate repair response, and integrative hallmarks are what you see in the mirror and feel in your knees.

The primary hallmarks: where damage starts

1. Genomic instability

In plain English

Your DNA is copied trillions of times across a lifetime and constantly assaulted by UV light, radiation, tobacco smoke, alcohol metabolites and ordinary metabolic by-products. Repair systems catch most errors, not all, and their efficiency declines with age. Mutations accumulate in a cell-by-cell mosaic [2].

Progeroid syndromes — rare genetic conditions in which DNA repair is defective and children age prematurely — are the strongest evidence that genomic instability drives ageing rather than merely accompanying it [1].

What may help

Not smoking, moderating alcohol, sun protection and avoiding unnecessary radiation remain the highest-leverage actions. Nutritionally, adequate folate, B12 and NAD⁺ availability support DNA repair enzymes — NAD⁺ is a required substrate for the PARP repair enzymes, which is one reason NAD⁺ decline is discussed so heavily here. See our NAD supplement guide.

2. Telomere attrition

In plain English

Telomeres are repetitive DNA caps at chromosome ends, often compared to the plastic tips on shoelaces. Each cell division loses a small section, because DNA polymerase cannot copy the very end of a linear strand. When telomeres become critically short, the cell stops dividing permanently or dies [1,2].

What may help

Telomere length is heavily influenced by genetics and cumulative oxidative and inflammatory load. Regular aerobic exercise, adequate sleep and lower chronic stress are consistently associated with slower attrition. Be cautious about products claiming to lengthen telomeres — evidence is thin and the theoretical cancer risk of artificially activating telomerase is real. See longevity supplements that don't work.

3. Epigenetic alterations

In plain English

Epigenetics is the layer of chemical tags — principally DNA methylation and histone modification — deciding which genes are switched on in which cell. A liver cell and a neuron carry identical DNA but read it very differently.

With age this pattern drifts. Genes that should be quiet become active, genes that should be active go quiet, and cellular identity blurs [2]. That drift is measurable and forms the basis of the epigenetic clocks used to estimate biological age.

What may help

Methylation depends on dietary methyl donors, which is why methylation support attracts attention — see TMG in the UK and TMG vs methylfolate. The strongest human data on slowing epigenetic ageing comes from the CALERIE trial, discussed below [4]. On measurement, see what biological age actually means and how to lower your biological age.

4. Loss of proteostasis

In plain English

Proteins must fold into precise three-dimensional shapes to work. Cells run an elaborate quality-control system — chaperones assisting folding, disposal systems destroying proteins that fold incorrectly. With age that system is overwhelmed and misfolded proteins clump together [2].

Not an abstract concern: amyloid plaques in Alzheimer's disease, alpha-synuclein in Parkinson's disease and transthyretin in cardiac amyloidosis are all proteostasis failures.

What may help

Heat stress, exercise and periods without food all upregulate chaperone activity and protein clearance. Adequate protein intake matters too, particularly after 50, when muscle protein synthesis becomes less responsive.

5. Disabled macroautophagy

In plain English

Autophagy is the cell's recycling programme: damaged organelles, protein aggregates and debris are wrapped in a membrane, delivered to the lysosome and broken into reusable parts. Macroautophagy is the bulk version, promoted to a full hallmark in 2023 [2]. Autophagic capacity declines with age, so debris accumulates faster than it is cleared.

What may help

Fasting periods, exercise and reduced mTOR signalling are the best-established triggers. Spermidine has the most direct mechanistic link, and urolithin A targets mitophagy specifically. See autophagy explained, spermidine in the UK and urolithin A in the UK.

The antagonistic hallmarks: helpful, until they aren't

6. Deregulated nutrient sensing

In plain English

Four signalling networks tell your cells whether food is abundant or scarce: insulin/IGF-1, mTOR, AMPK and the sirtuins. Abundance signals drive growth; scarcity signals drive maintenance and repair [1,2].

Modern life keeps the growth switches permanently on. Chronically elevated insulin and mTOR signalling shifts cells away from repair, and it is one of the most consistent mechanisms by which caloric restriction extends lifespan in laboratory animals.

What may help

Resistance training and aerobic exercise improve insulin sensitivity more reliably than any supplement [9]. Time-restricted eating and lower refined carbohydrate intake also help. Compounds studied here include berberine, metformin and rapamycin — see berberine vs metformin, metformin for longevity and rapamycin and longevity. Metformin and rapamycin are prescription-only medicines and are not licensed for anti-ageing use.

7. Mitochondrial dysfunction

In plain English

Mitochondria generate most of the ATP your cells run on. With age they become fewer, structurally distorted and less efficient, leaking more reactive oxygen species while producing less energy [2]. Because muscle, heart and brain are the most mitochondria-dense, that is where it is felt first: less stamina, slower recovery, mental fatigue.

What may help

Zone 2 aerobic training is the single most effective mitochondrial intervention available — it increases both mitochondrial number and quality. See zone 2 training and longevity. On the supplement side: CoQ10 vs ubiquinol, PQQ vs CoQ10, our Mitopure review, urolithin A vs NMN and creatine for longevity.

8. Cellular senescence

In plain English

When a cell sustains damage it cannot repair, it can shut down permanently rather than risk becoming cancerous. That is senescence, and it is protective in the short term. The problem is that senescent cells do not sit quietly — they secrete inflammatory signals known as the senescence-associated secretory phenotype, which damages neighbouring healthy tissue [2].

Because immune clearance becomes less efficient with age, they accumulate: a small number of cells with a disproportionate effect. This is the "zombie cell" idea.

What may help

Exercise and immune health support natural clearance. Senolytic compounds are an active research area, with fisetin and quercetin the most discussed nutraceuticals, though human evidence remains early-stage — see fisetin vs quercetin.

The integrative hallmarks: when the system fails

9. Stem cell exhaustion

In plain English

Adult stem cells replace worn-out cells in skin, blood, gut lining, muscle and elsewhere. Their numbers and function fall with age, partly through the primary hallmarks above and partly because the surrounding tissue environment becomes less supportive [2]. Practical consequences: slower wound healing, thinning skin, reduced muscle repair, weaker immune responses, reduced bone density.

What may help

Resistance training directly stimulates muscle satellite cells. Sufficient protein, vitamin D and sleep all support regeneration. For skin, see supplements for skin ageing and astaxanthin vs collagen.

10. Altered intercellular communication

In plain English

Cells talk constantly — through hormones, cytokines, neurotransmitters and extracellular vesicles. Ageing degrades the signal-to-noise ratio. Hormonal axes shift, inflammatory signalling rises, and neurohormonal control becomes less precise [2].

What may help

Sleep regularity, resistance training and, where clinically appropriate, medically supervised hormone therapy. Shift workers face particular challenges — see supplements for shift workers. For women in hormonal transition, see NMN and menopause and longevity supplements for women over 40.

11. Chronic inflammation

In plain English

"Inflammageing" describes low-grade, persistent inflammation developing with age in the absence of infection. It is driven by senescent cells, gut permeability, visceral fat, accumulated debris and a less well-regulated immune system [2].

It is a shared upstream contributor to cardiovascular disease, type 2 diabetes, neurodegeneration and frailty, which is why it earned hallmark status in 2023.

What may help

Reducing visceral fat, treating sleep apnoea, maintaining oral health, eating more fibre and oily fish, and regular moderate exercise. Excessive training without recovery has the opposite effect — see supplements for endurance athletes.

12. Dysbiosis

In plain English

The gut microbiome shifts with age: diversity falls, beneficial short-chain-fatty-acid producers decline, and the intestinal barrier becomes more permeable. Bacterial fragments crossing that barrier feed systemic inflammation, directly linking this hallmark to the previous one [2].

What may help

Dietary fibre diversity is the best-supported lever — a wide range of plant foods rather than a single supplement. See Akkermansia muciniphila in the UK, butyrate supplements and glutamine vs collagen for gut health. Population-level dietary evidence is discussed in Blue Zones and longevity.

How the twelve connect

The hallmarks are not a checklist of independent problems. They form a network, which is why single-target interventions tend to underwhelm [2].

Epigenetic alterations sit near the centre of the network, which is why so much longevity research now focuses on them [2,10].

What actually moves the needle

The honest hierarchy of evidence, from strongest to weakest.

Tier 1: strong human evidence

• Resistance and aerobic exercise. Touches at least eight hallmarks simultaneously. NHS guidance is strengthening activity on at least two days weekly plus 150 minutes of moderate activity [9].
• Not smoking. Accelerates genomic instability, telomere attrition and inflammation more than any other modifiable factor.
• Sleep of adequate duration and regularity. Underpins proteostasis, immune regulation and hormonal signalling.
• Dietary quality and adequate protein. Fibre diversity for the microbiome; sufficient protein for muscle and stem cell function.
• Maintaining healthy body composition. Visceral fat is metabolically inflammatory tissue.

Tier 2: plausible mechanisms, developing evidence

Credible biological rationale and some human data, but nothing approaching Tier 1 certainty. An addition to lifestyle, never a replacement [10].

If you are assembling a routine, see how to build a longevity stack, how to start longevity supplements and what a stack costs in the UK. Quality matters enormously — check third-party tested supplements, how to read a certificate of analysis and supplement fillers before buying.

Tier 3: experimental, not recommended outside research

Partial epigenetic reprogramming, senolytic drug protocols, off-label rapamycin and plasma exchange all sit here. Some may prove transformative. None currently has the human safety and efficacy data to justify routine use, and self-experimentation with prescription medicines carries genuine risk.

Measuring your biological age

Chronological age counts birthdays. Biological age attempts to measure how worn your systems actually are — and the gap between the two is what this framework is really about.

That gap is not abstract in the UK. Healthy life expectancy at birth is now 60.7 years for men and 60.9 for women — meaning men spend 77% and women 73% of life in "good" general health. Both figures fell in the latest period, by 1.8 and 2.5 years respectively, the lowest since the ONS series began [6] — part of a sustained decline [11]. Set against total life expectancy of 79.1 and 83.0 years [7], that is roughly 18 and 22 years lived in poorer health. Closing that gap, not extending lifespan, is the real target [8].

Available measures include DNA methylation clocks (Horvath, PhenoAge, GrimAge, DunedinPACE), inflammatory and metabolic blood panels, grip strength, VO₂ max and gait speed. Standard bloods are worth more than most people assume — an HbA1c test, cholesterol test or a single panel such as the Full Body MOT Health Check or Welzo Well-Human advanced blood test.

Common myths

Myth: fixing one hallmark reverses ageing

The hallmarks are interconnected [2]. Improving mitochondrial function while chronic inflammation and poor sleep remain unaddressed produces limited benefit. There is no single lever.

Myth: the framework is settled science

It is a useful organising model, not a law of nature. The authors themselves describe the boundaries between hallmarks as diffuse and the classification as necessarily somewhat arbitrary [2]. The 2022 Copenhagen symposium proposed fourteen hallmarks including two — altered mechanical properties and splicing dysregulation — that the twelve-hallmark model does not contain [3]. Expect further revision.

Myth: supplements can replace lifestyle

No supplement matches the breadth of exercise [9]. Supplements fill specific gaps — a point we make repeatedly in is NMN a scam? and does resveratrol actually work?

Myth: it is too late to start

Several hallmarks respond to intervention at any age. Muscle mass and mitochondrial density improve with training in people in their seventies and eighties. Starting earlier is better; starting late still helps. See longevity supplements for men over 50 and longevity supplements in your 30s.

Frequently asked questions

What are the 12 hallmarks of ageing?

Genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation and dysbiosis. Defined by López-Otín and colleagues in Cell in 2023, updating the original nine published in 2013 [1,2].

Why did the hallmarks go from 9 to 12?

A decade of research justified promoting three processes to full hallmark status: disabled macroautophagy, chronic inflammation and dysbiosis. Autophagy and inflammation had previously been treated as components of other hallmarks, while microbiome science was not sufficiently developed in 2013 [2].

Is the twelve-hallmark model universally agreed?

No. A 2022 symposium in Copenhagen produced a separate proposal published in Aging, adding five hallmarks to the original nine — including altered mechanical properties and splicing dysregulation, neither of which appears in the twelve-hallmark model [3]. It is an influential working framework, not a fixed list.

Which hallmark of ageing is the most important?

There is no scientific consensus. Epigenetic alterations attract the most attention because they sit centrally in the network and appear at least partly reversible in animal models [2]. In practical terms, the hallmarks most responsive to daily behaviour — nutrient sensing, mitochondrial function and chronic inflammation — matter most for the average person.

Can the hallmarks of ageing be reversed?

Some can be partially improved. Mitochondrial density increases with training, inflammation falls with weight loss and better sleep, and epigenetic ageing slowed measurably in the CALERIE caloric restriction trial — by 2–3% on one clock out of three [4]. Full reversal of ageing has been demonstrated only in laboratory animals under specific experimental conditions and is not available or proven in humans.

What is the difference between the hallmarks of ageing and biological age?

The hallmarks describe the mechanisms. Biological age attempts to measure the cumulative result of those mechanisms in a single number. One is the cause, the other the readout.

Do NMN and NAD⁺ supplements target the hallmarks of ageing?

NAD⁺ is required by DNA repair enzymes (PARPs) and sirtuins, connecting it to genomic instability, epigenetic regulation and mitochondrial function. Human trials show NMN and NR reliably raise blood NAD⁺, but evidence that this translates into slower ageing in humans is still developing. Our NMN guide reviews the current data.

At what age do the hallmarks of ageing start?

Earlier than most people assume. Mitochondrial density and muscle mass begin declining measurably from the late twenties and thirties, long before symptoms appear [2]. This is why prevention beats correction.

What lifestyle changes affect the most hallmarks at once?

Exercise, by a clear margin — it influences mitochondrial function, nutrient sensing, senescence, stem cells, inflammation and intercellular communication simultaneously. NHS guidance is 150 minutes of moderate activity weekly plus strengthening work on two or more days [9]. Sleep quality and dietary quality follow closely.

How long does it take to see changes from targeting the hallmarks?

Subjective changes in energy and sleep may appear in weeks. Body composition and fitness markers shift over three to six months. Epigenetic and biological age measures typically need twelve months or more to show reliable movement — and should be read as trends rather than single results [4]. See how long supplements take to work.

References

1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–1217. https://pubmed.ncbi.nlm.nih.gov/23746838/
2. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: an expanding universe. Cell. 2023;186(2):243–278. https://www.cell.com/cell/fulltext/S0092-8674(22)01377-0
3. Schmauck-Medina T, Molière A, Lautrup S, et al. New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary. Aging (Albany NY). 2022;14(16):6829–6839. https://www.aging-us.com/article/204248/
4. Waziry R, Ryan CP, Corcoran DL, et al. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging. 2023;3(3):248–257. https://www.nature.com/articles/s43587-022-00357-y
5. National Institute on Aging (NIH). Cutting calories may slow the pace of aging in healthy adults. https://www.nia.nih.gov/news/cutting-calories-may-slow-pace-aging-healthy-adults
6. Office for National Statistics. Healthy life expectancy, UK: between 2011 to 2013 and 2022 to 2024. https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/healthandlifeexpectancies/bulletins/healthstatelifeexpectanciesuk/between2011to2013and2022to2024
7. Office for National Statistics. National life tables — life expectancy in the UK: 2022 to 2024. https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/lifeexpectancies
8. World Health Organization. Ageing and health fact sheet. https://www.who.int/news-room/fact-sheets/detail/ageing-and-health
9. NHS. Physical activity guidelines for adults aged 19 to 64. https://www.nhs.uk/live-well/exercise/exercise-guidelines/physical-activity-guidelines-for-adults-aged-19-to-64/
10. Targeting the hallmarks of aging: mechanisms and therapeutic opportunities. Frontiers in Cardiovascular Medicine. 2025;12:1631578. https://pmc.ncbi.nlm.nih.gov/articles/PMC12259695/
11. Centre for Ageing Better. Healthy life expectancy continues to decline. https://ageing-better.org.uk/news/healthy-life-expectancy-continues-decline

All product photography in this article is owned by Welzo and served from the Welzo media library. Research positions correct at the time of publication.