Tier 4 — mechanistic

Hallmarks of aging: An expanding universe

López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G
Cell 2023 Volume 186, issue 2, pages 243–278

Bibliography

PubMed
PMID 36599349
DOI
10.1016/j.cell.2022.11.001
Funding
C. López-Otín was supported by the European Research Council (ERC Advanced Grant DeAge), Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, and La Caixa Foundation (HR17-00221); IUOPA by Fundación Bancaria Caja de Ahorros de Asturias. M.A. Blasco was funded by AEI/MCI project RETOS SAF2017-82623-R with ERDF cofunding, Comunidad de Madrid COVIDPREclinicalMODels-CM, and ERC Horizon 2020 grant 882385 (SHELTERINS); CNIO support included Instituto de Salud Carlos III. L. Partridge was supported by Horizon 2020 grant 741989, the Max Planck Society and BBSRC. M. Serrano was funded by IRB core support, La Caixa Foundation, the Milky Way Research Foundation and Catalonia 2017 SGR 282. G. Kroemer listed multiple French and EU public/philanthropic cancer-research funders and programs. The authors stated that none of the funders had a role in study design, data collection/analysis, publication decision or manuscript preparation.
Competing interests
M.A. Blasco is founder and shareholder of Life Length, SL. M. Serrano is shareholder/advisor of Rejuveron Senescence Therapeutics and Altos Labs and shareholder of Senolytic Therapeutics and Life Biosciences. G. Kroemer disclosed multiple industry research contracts, consulting, board roles, scientific cofounder roles and patents related to aging, cancer, cystic fibrosis and metabolic disorders; family-member industry relationships were also disclosed. Carlos López-Otín and Linda Partridge were not listed with competing interests in the PubMed declaration.

Study snapshot

DesignNarrative conceptual review updating and expanding the 2013 framework.
ModelCross-species synthesis with emphasis on mammalian ageing.
SampleNot applicable — review article.
InterventionNone. Expands the original nine hallmarks to twelve by adding disabled macroautophagy, chronic inflammation and dysbiosis.
DurationNot applicable.
EndpointsExpansion of the hallmark set from nine to twelve; Hierarchical relationships between primary, antagonistic and integrative hallmarks; Therapeutic implications

What the study showed, in plain terms

Ten years after the original, the same five authors revisited their framework and expanded it from nine hallmarks to twelve. The three additions were disabled macroautophagy — the cell's recycling machinery failing — chronic inflammation, and dysbiosis, meaning disruption of the microbial communities the body depends on.

When a supplement label promises to target all twelve hallmarks of aging, this is the paper being referenced. It is worth knowing exactly what that claim does and does not import. The paper organises the twelve into primary hallmarks that cause damage, antagonistic hallmarks that are compensatory responses which turn harmful, and integrative hallmarks that produce the visible decline. It maps mechanisms and it discusses candidate interventions.

What it does not do is measure any of the twelve in people taking a commercial powder. A formula can contain an ingredient with a published link to each of the twelve categories and still have no evidence that the finished product moves any of them in a human. Mapping is cheap; measurement is not.

Key findings

  • The hallmark set is expanded from nine to twelve, adding disabled macroautophagy, chronic inflammation and dysbiosis.
  • Hallmarks are grouped as primary (causes of damage), antagonistic (compensatory responses that become deleterious) and integrative (culprits of the phenotype).
  • The hallmarks are described as deeply interconnected rather than independent, so they do not function as twelve separate scoreable targets.
  • The paper is explicitly a research agenda for identifying and testing interventions, not a validation of any existing intervention.

What this study can and cannot tell us

A conceptual review with no primary data. It cannot support any efficacy claim for any product, ingredient or dose.

The twelve-hallmark framing is the single most-quoted citation in longevity supplement marketing. The correct reading of a targets all twelve hallmarks claim is that a brand has mapped its ingredient list onto this taxonomy. That mapping is an editorial exercise performed by the brand, is not audited by anyone, and says nothing about dose, bioavailability, formula version or human outcome.

Because hallmarks are interconnected, counting how many a formula touches is not a meaningful measure of formula quality. A product hitting three hallmarks at doses matched to human trials is a stronger proposition than one hitting twelve at doses no human study has used.

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