Hallmarks of Aging
Hallmarks of Aging Explained
The 12 hallmarks of aging organize research, but they are not established causes of aging and few have direct human trial evidence.
If you’ve read about longevity science, supplements or anti-aging clinics lately, you’ve probably seen a diagram of the “hallmarks of aging.” It shows up in research talks and in product marketing alike. This Humanic Blue guide explains the hallmarks so you can tell the difference between a research framework and a sales pitch.
The useful distinction is framework versus explanation. The hallmarks of aging are a list of biological processes, first 9 and now 12, that researchers proposed as common features of aging across species. They include DNA damage, shortening chromosome tips, drifting gene regulation, failing cellular recycling, damaged mitochondria, lingering “senescent” cells and chronic inflammation. Researchers use the list to organize experiments and look for drugs. It isn’t an established account of what causes aging, and a prominent critique argues it shouldn’t be treated as one. In humans, hallmark-related interventions have changed disease outcomes or aging biomarkers in particular settings, but none has been shown to delay multiple age-related diseases or extend life.
Key Takeaways
- The hallmarks list grew from 9 in 2013 to 12 in 2023 and has become a major reference point in aging biology.
- Interventions targeting some hallmarks extend lifespan in animals; none has done so in humans.
- Critics argue the hallmarks describe features of aging rather than explain its causes.
Where did the hallmarks list come from?
In 2013, Carlos López-Otín of the University of Oviedo and colleagues published a review in Cell titled The hallmarks of aging. It proposed nine hallmarks, which the authors described as tentative, as features of aging shared across different organisms, with a particular focus on aging in mammals.
In 2023, the same team updated it to 12, adding disabled macroautophagy, chronic inflammation and dysbiosis. They set three conditions for a hallmark: it appears with age, speeding it up accelerates aging, and slowing it decelerates aging.
The template, according to a 2021 critique, came from the “hallmarks of cancer,” papers describing the traits that distinguish cancer cells.
The 12 hallmarks, and where human evidence stands
| Hallmark | Plain English | Human intervention evidence |
|---|---|---|
| Genomic instability | DNA damage builds up | No human aging-outcome trials identified in our review |
| Telomere attrition | Chromosome end-caps shorten | No human aging-outcome trials identified in our review |
| Epigenetic alterations | Gene switches drift | Calorie restriction slightly slowed one aging estimate based on chemical patterns on DNA (CALERIE) |
| Loss of proteostasis | Protein quality control falters | No human aging-outcome trials identified in our review |
| Disabled macroautophagy | Cellular recycling slows | Early; no outcome trials |
| Deregulated nutrient-sensing | Growth and fuel signals misfire | Rapamycin extends mouse lifespan; metformin’s TAME trial not yet launched |
| Mitochondrial dysfunction | Cellular power plants decline | Nicotinamide riboside (NR), a vitamin B3 form, raises blood levels of NAD+, a molecule cells use in energy metabolism; this does not establish better health or longer life |
| Cellular senescence | Damaged cells linger | Drugs that clear senescent cells (senolytics) have improved health and lifespan in mice; slowing human aging has not been shown |
| Stem cell exhaustion | Repair reserves run down | Stem-cell therapy investigational; not shown to slow aging |
| Altered intercellular communication | Signals between cells go awry | No human aging-outcome trials identified in our review |
| Chronic inflammation | Low-grade inflammation persists | Canakinumab cut repeat heart events but raised fatal infections (CANTOS) |
| Dysbiosis | Gut microbes shift | Early; no aging outcome trials |
Each row’s human evidence is covered in more depth elsewhere. Rapamycin and TAME are in What Is Geroscience?, NR in Longevity Supplements: What Has Evidence in Humans?, senolytics in What Are Senolytics, and Do They Work? and stem cells in Can Stem Cell Therapy Reverse Aging?
What happened when one hallmark was tested in people?
The inflammation row shows what happens when a hallmark meets a real trial.
In CANTOS, targeting an inflammatory pathway reduced repeat cardiovascular events at one dose in people who had already had a heart attack and had elevated inflammation. That tests a specific disease mechanism, not the whole hallmarks framework or human lifespan extension.
The trade-off mattered: fatal infections were more frequent with canakinumab, and overall mortality did not significantly differ. Novartis, which makes the drug, funded the trial.
CANTOS therefore found a benefit for a specific group of patients, alongside a serious harm, without establishing longer survival. A hallmark diagram alone cannot show those trade-offs.
What does CANTOS establish about a disease pathway rather than aging as a whole?
Why do some researchers question the hallmarks?
Not everyone thinks the hallmarks are the right foundation. In a 2021 paper titled “The hoverfly and the wasp,” João Pedro de Magalhães of the University of Liverpool and David Gems credited the list as “a useful shared overview for biogerontology during a time of transition in the field.”
But they drew a sharp line: “while the hallmarks of cancer provide a paradigmatic account of the causes of cancer with profound explanatory power, the hallmarks of aging do not.” Their worry was that the list “obscured the urgent need to define a genuine paradigm,” meaning an explanation of what actually drives aging.
In plain terms: the hallmarks describe what changes with age, but not necessarily why. The title appears to allude to mimicry: a hoverfly can look like a wasp without being one.
De Magalhães also reports commercial ties to the longevity industry. He’s chief scientific officer of Centaura, “a company that aims to prevent and reverse aging,” and an advisor to the Longevity Vision Fund and NOVOS, according to the paper’s disclosures. On the other side, two authors of the 2023 hallmarks update report ties to companies that sell telomere tests and develop senescence drugs.
What would distinguish a feature accompanying aging from a mechanism that drives it?
What’s Interesting
The hallmarks have become a marketing vocabulary. Supplements and clinics now claim to target “mitochondrial dysfunction” or “cellular senescence,” borrowing the framework’s credibility. But the framework’s own authors call its original version tentative, and its best-known critics say it doesn’t explain aging. The diagram is a map of research questions, not a menu of solutions.
What This Means in Practice
For the question of living longer and better, the hallmarks organize what researchers are testing. The framework does not establish which products improve human health.
- A hallmark claim and a health claim differ. Changing a laboratory marker does not establish that a product reduces disease or deaths.
- CANTOS found both benefit and harm. Targeting inflammation reduced repeat cardiovascular events in selected patients, increased fatal infections and did not establish longer survival.
- Human outcome research is a separate question, covered in What Are the Best Habits for Longevity?
A clinician can discuss any off-label drug and its risks. ClinicalTrials.gov lists registered aging trials.
Bottom Line
The hallmarks of aging are 12 cell-level processes that researchers use to organize aging biology, from DNA damage and short telomeres to lingering senescent cells and chronic inflammation. They’re a framework, not an established causal explanation, and critics argue they describe aging more than they explain it. Some hallmark-targeted treatments extend animal lifespan. In humans, the large outcome trial discussed here reduced repeat cardiovascular events in people with a previous heart attack and elevated inflammation, but increased fatal infections and did not establish longer survival. No hallmark-based treatment has been shown to extend human life.
A NOTE FROM LONGEVITY365
We read research, consult expert perspectives and work to make complicated health information easier to understand. What you’re reading here reflects how we’ve interpreted and organized that information. It is educational content—not personal medical advice, diagnosis or treatment guidance.
We’re not perfect, and neither is the available research. Evidence changes, new studies emerge and what’s appropriate for one person may not be appropriate for another.
Use this article as a starting point for your own research and conversations with qualified professionals. Always talk with your doctor or another trusted healthcare professional before making decisions that could affect your health, particularly if you take medications, are receiving treatment, have existing health conditions, are pregnant or have other circumstances that could affect what’s appropriate for you.
Reader Questions
A few questions to carry into the comments or your next conversation. Please leave out identifying or personal medical details.
- 01What did this article make clearer about the gap between an aging mechanism and a proven human outcome?
- 02Which claim would you want to see tested in people before it affected a real health decision?
- 03What question should readers keep asking when "Hallmarks of Aging Explained" shows up in longevity marketing?
Extra Insights & Sources
The evidence summaries and linked sources behind this article.
What We Know
- The hallmarks list has become “a major reference point for the biogerontology field,” in the critics’ words, and grew from 9 to 12. Established.
- Several hallmark-targeted interventions extend lifespan in animals. Supported (animal).
- The one large hallmark-targeted human outcome trial here, CANTOS, reduced repeat heart events but increased fatal infections and found no statistically significant difference in overall mortality. Supported.
What We Don’t Know
- Whether the hallmarks are causes of aging or features that accompany it. Contested.
- Whether targeting any hallmark can slow human aging or extend life. Unknown.
- Which hallmarks, if any, matter most in people. Unknown.
Detailed trial results
In CANTOS, published in the New England Journal of Medicine in 2017, 10,061 people who’d had a heart attack and had elevated hsCRP, an inflammation marker, were randomly assigned to canakinumab, an antibody that blocks an inflammatory signal called interleukin-1β, or placebo. At the 150-mg dose, the combined rate of heart attacks, strokes and cardiovascular deaths was lower than with placebo (hazard ratio, or HR, 0.85—about a 15% lower rate during follow-up). This combined result does not mean that each type of event fell separately.
The investigators also reported more fatal infections with canakinumab than with placebo and no statistically significant difference in deaths from any cause (HR 0.94). The estimate was slightly lower with treatment, but the trial did not establish a survival benefit. The trial was funded by Novartis, which makes the drug.
Source Materials
- López-Otín et al., Cell (2013) — Review that proposed nine hallmarks and the original organizing framework. It is a mechanistic synthesis, not a clinical trial or proof that the listed processes cause human aging.
- López-Otín et al., Cell (2023) — Updated review expanding the framework to 12 hallmarks and restating the three inclusion premises. Most intervention evidence underpinning those premises comes from experimental models; relevant author commercial interests are described in the article.
- Gems and de Magalhães, Ageing Research Reviews (2021) — Open-access conceptual critique distinguishing a useful descriptive framework from a paradigmatic causal account. It provides the principal counterargument used here and reports de Magalhães’s longevity-industry ties.
- Ridker et al., New England Journal of Medicine (2017) — Novartis-funded CANTOS randomized trial in 10,061 post-myocardial-infarction patients with elevated hsCRP. The 150-mg dose reduced the prespecified cardiovascular composite, increased fatal infections and did not significantly reduce all-cause mortality. It tests IL-1β inhibition in secondary cardiovascular prevention, not the hallmarks framework or human aging itself.
- Evidence-status entries for rapamycin, metformin/TAME, nicotinamide riboside, senolytics and stem cells are concise route-outs to the linked Longevity365 evidence reviews, where their primary sources, populations and limits are documented. They are not counted here as direct human validation of the hallmarks framework.
Featured image: Image by Stockphoty via Envato Elements.
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