Tier 4 — mechanistic

The Hallmarks of Aging

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G
Cell 2013 Volume 153, issue 6, pages 1194–1217

Bibliography

PubMed
PMID 23746838
PubMed Central
PMC3836174
DOI
10.1016/j.cell.2013.05.039
Funding
Funding statement not carried in the Europe PMC author-manuscript front matter reviewed. The authors acknowledge institutional affiliations at Universidad de Oviedo, CNIO, Max Planck Institute for Biology of Ageing, University College London and INSERM.
Competing interests
No competing-interests declaration is present in the author-manuscript front matter reviewed.

Study snapshot

DesignNarrative conceptual review proposing a categorisation framework.
ModelCross-species synthesis with emphasis on mammalian ageing.
SampleNot applicable — review article.
InterventionNone. The paper defines criteria a candidate hallmark must meet: it manifests during normal ageing, its experimental aggravation accelerates ageing, and its experimental amelioration retards ageing.
DurationNot applicable.
EndpointsDefinition of nine candidate hallmarks of aging; Criteria for hallmark classification; Interconnectedness between hallmarks

What the study showed, in plain terms

This is the paper that gave the longevity industry its vocabulary. Written in 2013 by five of the field's most cited researchers, it proposed that ageing — despite looking like a single process from the outside — can be broken into nine distinct cellular and molecular mechanisms: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.

The authors were deliberately strict about what earns the label. A hallmark had to satisfy three tests: it must appear during normal ageing, making it worse must accelerate ageing, and fixing it must slow ageing down. They were candid that not all nine met the third and hardest test, and they said so explicitly.

That distinction matters enormously when reading supplement marketing. A product that says it targets the hallmarks of aging is referencing this framework. The framework is a map of mechanisms, not a certification scheme and not a clinical endpoint. Nothing in this paper establishes that any commercial formula changes any hallmark in a living person.

Key findings

  • Nine candidate hallmarks of ageing are proposed: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication.
  • Three inclusion criteria are set: manifestation during normal ageing, acceleration of ageing on experimental aggravation, retardation of ageing on experimental amelioration.
  • The authors state directly that the third criterion is the hardest to satisfy and that not all nine hallmarks are fully supported by interventions that succeed in ameliorating ageing.
  • Hallmarks are described as extensively interconnected, so amelioration of one may impinge on others — which cuts against reading a hallmark count as an additive score.
  • The stated goal of the framework is to identify pharmaceutical targets, not to grade consumer products.

What this study can and cannot tell us

This is a conceptual review, so it generates no primary data and no effect estimates. It sits at the bottom of any evidence hierarchy that ranks by study design, while sitting at the very top of the field by influence — a combination that is routinely exploited in marketing copy.

The nine-hallmark list was superseded in 2023 by the same authors, who expanded it to twelve. Any product page claiming to target all twelve hallmarks is referencing the 2023 revision, not this paper. Citing the 2013 nine-hallmark version alongside a twelve-hallmark claim is a version error.

Most of the supporting evidence discussed is from model organisms and cell systems. Mapping an ingredient onto a hallmark on this basis establishes a rationale for testing it, not a demonstrated human outcome.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability