Knowledge cluster
The hallmarks of aging
Twelve biological processes that occur during ageing and that research has drawn together into a shared framework. This cluster explains each one, places the evidence in context and states where the model reaches its limits.
Where the model comes from
In 2013 a group led by Carlos López-Otín published a paper in the journal Cell titled The Hallmarks of Aging. It condensed the then-scattered field of ageing research into nine categories. The template was an essay from cancer research that had created order the same way. Ten years later the authors expanded their list to twelve, adding disabled macroautophagy, chronic inflammation and dysbiosis.
To count as a hallmark, a process was supposed to meet three conditions: it occurs during normal ageing, experimentally amplifying it accelerates features of ageing, and attenuating it slows them. In practice not all twelve meet all three conditions equally well, which the authors themselves concede.
The value of the model lies in the ordering, not in the explanation. It makes an unwieldy field discussable and shows how individual processes connect. What it does not do: it does not say which process contributes how much to ageing, and it provides no guidance for diagnostics or treatment.
What this model is not
The hallmarks are a description, not a proof. They were derived from existing literature and organise what stands out. For most of the twelve it is unresolved whether the process drives ageing or is predominantly a consequence of it. In a widely noted critique, Gems and de Magalhães pointed out that such a catalogue remains descriptive and risks conflating observation with explanation.
The categories are also not independent. Senescent cells drive chronic inflammation, dysbiosis likewise feeds inflammation, nutrient sensing regulates autophagy, and the stem cell niche is influenced by all of it. The division into twelve is a reasoned choice, not a fact of nature. The grouping into primary, antagonistic and integrative processes also comes from the 2013 version; for the three additions from 2023 the assignment is less clear.
The model is not suitable for medical decisions. No validated test determines your hallmarks, and no score summarises them. For several of the twelve there is no method at all that could be applied in a living person. Where providers nevertheless derive measurements and treatments from them, the impression arises of a precision the evidence does not support.
And yet the model remains scientifically compelling. It has given research a shared language, and individual hallmarks have led to robust clinical results, such as targeted anti-inflammation after myocardial infarction or the stabilisation of a misfolding-prone protein in amyloidosis. That is precisely the distinction this cluster tries to sustain: fascinating as a framework, cautious in application.
What is measurable at all
A common misunderstanding is that the twelve processes can be determined individually. For the majority there is no method applicable in preventive care. This overview therefore separates by measurability before going into the individual pages.
Adjacent markers available
No method in preventive care
- Telomere attrition
- Loss of proteostasis
- Disabled macroautophagy
- Cellular senescence
- Stem cell exhaustion
The twelve at a glance
The grouping comes from the 2013 version. For the three hallmarks added in 2023 the assignment is less clear-cut and should be read here as an approximation.
Primary causes
Damage that accumulates over time. In the 2013 taxonomy these are considered triggers rather than responses.
Telomere attrition
Chromosome ends shorten with every division. Longer is not automatically better.
Detail page to followLoss of proteostasis
Proteins must be folded exactly right to work. The quality control for this declines with age.
Detail page to followDisabled macroautophagy
Cells break down their own components and reuse them. This recycling loses capacity with age.
Detail page to followAntagonistic responses
The body’s counter-responses to that damage. Protective at low intensity, harmful when chronically overactive.
Cellular senescence
Cells stop dividing permanently but do not die. From this in-between state they reshape their surroundings.
Detail page to followIntegrative consequences
Consequences that emerge once the counter-responses no longer suffice. They shape the clinical picture of ageing.
Stem cell exhaustion
Tissue reserves for renewal shrink and slow down. The cells themselves are not always the problem.
Detail page to followDysbiosis of the microbiome
Gut flora shifts with age. What counts as a healthy microbiome cannot yet be defined.
Detail page to followFrequently asked questions about the model
What are the hallmarks of aging?→
The hallmarks of aging are twelve biological processes that occur during ageing and that a research group led by Carlos López-Otín drew together into a shared framework. The first version from 2013 contained nine categories; a 2023 expansion brought it to twelve. To count as a hallmark, a process should occur during normal ageing, experimentally amplifying it should accelerate features of ageing, and attenuating it should slow them. The framework organises a widely scattered research field and makes connections discussable. It is explicitly an ordering model and not a diagnostic tool: it does not say which process contributes how much to ageing.
Do the twelve hallmarks fully explain ageing?→
No, and that is not an aside but the core of any serious assessment. The hallmarks were derived from existing literature and describe what stands out. For most of them it is open whether the process drives ageing or is predominantly a consequence of it. The categories also overlap considerably: senescent cells drive inflammation, dysbiosis likewise feeds inflammation, nutrient sensing regulates autophagy. In a well-known critique, Gems and de Magalhães showed that such a catalogue remains descriptive and readily conflates observation with explanation. The model is a useful framework, not a closed theory of ageing.
Can your hallmarks be measured?→
Not as an overall picture, and for the majority of the twelve not at all. The most accessible are epigenetic alterations via methylation analyses, chronic inflammation via values such as high-sensitivity CRP and interleukin-6, and nutrient sensing via insulin, HbA1c and IGF-1. For telomere attrition no routine test can be interpreted meaningfully, for cellular senescence no validated blood test exists, and for autophagy there is no method in a living person at all. There is no score summarising the twelve. Anyone offering a hallmark measurement or an age derived from one exceeds what the methods deliver.
Why were three hallmarks added in 2023?→
Because the evidence changed considerably over ten years. Disabled macroautophagy sat under proteostasis in 2013 but proved distinct enough to stand on its own, partly because it is closely tied to nutrient sensing. Chronic inflammation had long been described since Franceschi’s work on inflammaging but was only listed as its own category in 2023. Dysbiosis was added because microbiome research grew strongly over this period. For these three additions, assignment to the primary, antagonistic and integrative groups is less clear than for the original nine.
Foundational literature
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The Hallmarks of Aging. Cell. 2013;153(6):1194–1217.
- López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. Hallmarks of aging: An expanding universe. Cell. 2023;186(2):243–278.
- 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.
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.