Why Do Some People Live Past 100? What Centenarian DNA Is Revealing About the Genetics of Longevity

Longevity genetics has a replication problem that almost no popular account mentions. Over three decades, dozens of genes have been announced as the key to exceptional lifespan. Only a handful have survived attempts to find them again in a different population.

The clinical footprint is correspondingly small. On 2 October 2026 ClinicalTrials.gov listed 13 registered studies involving centenarians and 100 involving longevity genetics, against 20,774 returned by a search for targeted cancer therapy. The people who live past a hundred are among the most discussed and least trialled subjects in medicine.

None of that makes the science empty. It means the honest question is not which gene lets someone reach 105, but why so few candidate answers have held up — and what the ones that did are actually telling us.

In 2023, scientists at the University of Rochester did something that sounds more like science fiction than biology. They took a single gene from a naked mole rat — an animal reported to live up to 41 years that rarely develops cancer and seems to age in slow motion compared to every other rodent on Earth — and introduced it into ordinary laboratory mice. The mice lived longer. They got sick less often. Their guts stayed healthier. Their tumours were fewer and smaller.

One gene. Moved from one species to another. And something fundamental about how the recipient animal aged actually changed.

The result, published in Nature, was proof of a principle longevity researchers had long suspected: the genetic mechanisms behind exceptional lifespan are not locked inside the animals that evolved them. At least in some cases they can be transferred, which makes the question of harnessing them for human benefit less theoretical.

The genetic study of centenarians, people who reach 100, and supercentenarians, who reach 110, has accelerated as whole-genome sequencing has become cheap. What it is finding is that longevity is neither simply the absence of bad luck nor simply the reward of a healthy lifestyle. It has a genetic architecture, and it is beginning, slowly, to be understood.

What Makes a Centenarian Genetically Different?

The first question anyone asks when confronted with someone who has reached 100 years old is almost always the wrong one. What did they eat? Did they exercise? Did they drink? The answers are rarely consistent enough to explain the phenomenon. There are centenarians who smoked for decades. There are centenarians who ate red meat daily and drank wine every evening. There are centenarians who never exercised in any formal sense. The lifestyle factors that predict healthy aging in a population do not reliably explain exceptional longevity at the individual level.

What does predict it, with reasonable consistency, is family history. Twin studies have long suggested that roughly 20 to 30 per cent of the variation in human lifespan is genetic, a figure challenged in 2026 for reasons set out below, and the familial signal grows stronger for those who live past 90 or 100.

The New England Centenarian Study at Boston University Medical Center, one of the longest-running centenarian research programmes in the world, has identified genetic signatures in centenarians that differ systematically from the general population. Centenarians do not simply lack the gene variants associated with disease — they appear to carry specific protective variants that actively buffer against the damage that accumulates with age. The distinction matters: it is not just the absence of vulnerability but the presence of protection.

A 2025 study in Human Genomics illustrates both the promise and the problem. Researchers compared the genomes of three centenarians and 18 supercentenarians and found 754,520 genetic variants shared by all 21, highlighting pathways such as extracellular-matrix remodelling, signal transduction and protein metabolism. But the study had no comparison group of ordinary agers, and many variants shared by 21 people are shared by nearly everyone; the authors themselves call the findings preliminary and ask for larger studies with proper controls.

The molecule of heredity at the centre of all this is explored in depth in our foundational guide to what DNA is and how it works.

The Longevity Gene Found in People Who Live Past 100

Among the most compelling recent discoveries in centenarian genetics is a gene called LAV-BPIFB4 — the Longevity Associated Variant of the BPIFB4 gene. This variant is found at significantly higher frequencies in centenarians and supercentenarians than in the general population, and its effects on biology appear to be broadly protective in ways that are only beginning to be understood.

In a study published on 29 September 2025 in Signal Transduction and Targeted Therapy — a Nature portfolio journal — researchers Yan Qiu, Monica Cattaneo, Anna Maciag, Annibale A. Puca, and Paolo Madeddu, working across the Bristol Heart Institute at the University of Bristol and IRCCS MultiMedica in Italy, demonstrated that a single injection of LAV-BPIFB4 into animal models of progeria significantly improved cardiac function.

According to the peer-reviewed paper, mice received a single intraperitoneal injection of LAV-BPIFB4 delivered via an adeno-associated viral vector, which enhanced cardiac BPIFB4 protein expression 2.5-fold and significantly reduced age-related decline in left ventricular diastolic function. Histological analysis confirmed decreased perivascular fibrosis, an increased number of coronary arterioles, and a measurable reduction in cardiac cells expressing p16 and p21 — the standard molecular markers of cellular senescence.

Progeria is caused by a mutation that produces a toxic protein called progerin, which disrupts the structure of the cell nucleus and drives accelerated aging. The longevity gene did not eliminate progerin. It did not correct the underlying mutation. What it appeared to do was make cells more resilient to progerin’s toxic effects — fortifying the cell against damage rather than removing its source. According to the researchers, this suggests that the gene helps cells withstand the effects of aging insults rather than prevent them from occurring — a distinction that has significant implications for how longevity therapies might be designed.

This connects directly to the biology we explored in our article on telomeres and cellular aging: the accumulation of senescent cells — cells that have stopped dividing but refuse to die, releasing inflammatory signals that damage surrounding tissue — is one of the central mechanisms of aging. LAV-BPIFB4 reduces the burden of these senescent cells in heart tissue, complementing the senolytic drug approach of clearing them directly, explored in our coverage of senolytics and the clearing of ageing cells.

The Naked Mole Rat: Nature’s Most Instructive Anomaly

To understand why the University of Rochester’s gene transfer experiment matters so much, you need to understand just how extraordinary the naked mole rat actually is.

Naked mole rats are mouse-sized rodents native to East Africa. They are, by conventional mammalian standards, bizarre. They are nearly hairless. They are eusocial — like ants or bees, living in colonies with a single breeding queen and a caste of non-reproducing workers. They are poor at regulating their own body temperature, which drifts with their surroundings far more than in other mammals. And they are, by a very large margin, the longest-lived rodents known to science.

A typical mouse lives for two to three years. Naked mole rats commonly live past 30 years in captivity, with some reported to reach 41 — nearly ten times the expected lifespan of a comparable rodent. More importantly, they do not age in the way other mammals do. Their risk of death does not increase with age. A 30-year-old naked mole rat is not measurably more likely to die than a 5-year-old one — a property called negligible senescence that appears to be unique among mammals. Cancer is rare in them. They show few signs of cardiovascular disease, neurodegeneration, or arthritis.

Vera Gorbunova and Andrei Seluanov at the University of Rochester have spent decades studying what makes naked mole rats so resistant to aging and disease. One of their key findings has been the role of high molecular weight hyaluronic acid — HMW-HA — a large, protective molecule that naked mole rats produce in unusually high quantities. HMW-HA appears to protect cells from cancer-causing changes, regulate immune function, and reduce the chronic inflammation that drives much of aging’s damage. Naked mole rats produce a particularly large and stable form of HMW-HA, encoded by a specific version of the gene HAS2 — hyaluronan synthase 2.

The study, led by Zhihui Zhang with co-authors including Steve Horvath, creator of the Horvath epigenetic clock, was published in Nature in August 2023 as “Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice.” Mice carrying the naked mole-rat gene had more hyaluronan in many tissues, less spontaneous and chemically induced cancer, longer lives and better health in old age.

The mice’s gene expression patterns — their transcriptome signature — shifted measurably toward that of longer-lived species. The most significant change the researchers observed was attenuated inflammation across multiple tissues, achieved through several distinct pathways: a direct immunoregulatory effect on immune cells, protection from oxidative stress, and improved gut barrier integrity during ageing.

This 2023 paper built directly on earlier foundational work by the same Rochester laboratory. A 2020 study published in Nature Communications first demonstrated that the very-high-molecular-mass hyaluronan produced by naked mole rats has superior cytoprotective properties compared to the hyaluronan produced by mice and humans — protecting cells from stress-induced cell-cycle arrest and death through the CD44 receptor pathway. That discovery established the molecular foundation that made the subsequent gene-transfer experiment possible.

The gain in median lifespan was 4.4 per cent, which on an 80-year human life would be roughly three and a half years if the effect scaled, a big if. The mice were more resistant to spontaneous tumours and chemically induced skin cancer, their guts stayed healthier with age, and their age-related inflammation was lower.

“Our study provides a proof of principle that unique longevity mechanisms that evolved in long-lived mammalian species can be exported to improve the lifespans of other mammals.”
— Vera Gorbunova, Doris Johns Cherry Professor of Biology and Medicine, University of Rochester. University of Rochester / Nature, August 2023.

The team’s stated next goal is to transfer this benefit to humans — either by slowing the degradation of HMW-HA or by enhancing its synthesis. They have already identified candidate molecules and are testing them in pre-clinical trials.

The Immune System as the Hidden Architecture of Longevity

Several centenarian studies point to the immune system. That might seem counterintuitive, since we tend to think of ageing as something that happens to cells and organs, but an immune system that stays balanced may be part of what lets some people avoid the diseases of old age.

A whole-genome study of Chinese centenarians published in 2020 found immune-related pathways among the most enriched in their genomes, with certain HLA types, variants of the immune system’s recognition machinery, more common than in the general population.

If that signal holds, the advantage could work in several ways at once: more effective clearance of senescent cells, better control of chronic infections, and variants that keep the inflammatory response from becoming the chronic low-grade state, sometimes called inflammaging, that underlies much heart disease, neurodegeneration and cancer. These are hypotheses, not established findings.

Epigenetic Age: Younger Than the Calendar

The clearest molecular signature so far comes from epigenetic aging. The epigenetic clock estimates biological age from DNA methylation patterns, and a 2015 study of Italian families found that people aged 105 to 109 were about 8.6 years younger by this measure than their calendar age, while their children were 5.1 years younger than age-matched controls. What genetic factors keep methylation patterns so faithful is one of the most active questions in the field.

The Replication Problem Nobody Mentions

Read enough coverage of longevity genetics and you will meet a long parade of decisive-sounding discoveries. Read the follow-up literature and most of them quietly disappear. This is the central methodological fact of the field, and it is worth understanding before any individual gene story.

The difficulty is structural. Centenarians are, by definition, rare, which makes cohorts small. A small cohort produces statistical associations easily and reliable ones rarely. When another team looks for the same variant in a different population — a Japanese cohort rather than a Sardinian one, say — the effect frequently vanishes. Very few candidate longevity genes have replicated consistently across ancestries, and those that have tend to be involved in broad processes such as lipid handling, the APOE gene, or insulin signalling, FOXO3, rather than anything specific to extreme old age.

There is a second confound that inflates apparent genetic effects: families share more than DNA. They share diet, altitude, income, healthcare access, and often the same village for generations. Twin and family studies converge on genetics explaining roughly a quarter of the variation in human lifespan, which leaves the substantial majority to environment, behaviour and chance.

The thin clinical record reflects this uncertainty. It is not a conspiracy against ageing research; it is what happens when the endpoint is a lifespan, the cohort is scarce, and no intervention follows directly from a finding.

What survives all this scepticism is genuinely interesting, and it is not a gene for long life. It is the observation that centenarians do not merely live longer with the same diseases — many of them compress illness into a short period at the very end, staying functional for decades beyond the point where their peers are not. Whatever the genetics of that turns out to be, the target it suggests is healthy years rather than total years, which is a more achievable goal and a more useful one.

How Much of Longevity Is Actually in Your Genes?

This is the question that people really want answered, and it deserves a direct and honest response: the answer is complicated, and anyone who gives you a simple number is oversimplifying.

Population studies have traditionally put genetic factors at roughly 20 to 30 percent of the variation in human lifespan overall — an estimate that a 2026 reanalysis argues is measuring the wrong thing. Environmental factors — diet, exercise, smoking, stress, socioeconomic status, access to healthcare — account for most of the rest. This is why lifestyle matters, and why the advice to eat well, exercise, sleep, and not smoke is genuinely evidence-based even in the context of longevity genetics research.

But the genetic contribution appears stronger at the extremes. For people who live past 90, then 100, then 110, the familial signal grows, and the lifestyle factors that predict whether someone dies at 65 or 75 say less about whether someone reaches 105.

Gains in life expectancy in wealthy nations have slowed in recent decades. The easy gains, from cutting child mortality, controlling infectious disease and making surgery safer, have largely been realised, and what remains means engaging with the biology of ageing itself. That is one reason centenarian genetics has attracted more attention, and why it connects to the broader effort to reverse the biology of aging rather than merely slow it.

How a 2026 Study Revised the Heritability Figure

The 20 to 30 percent estimate quoted above has been the standard answer for decades, and it is worth explaining why it is now contested, because the argument is a good example of how a number can be accurate and misleading at the same time.

In January 2026 a team led by Ben Shenhar and Uri Alon at the Weizmann Institute, working with colleagues at the Karolinska Institutet and Leiden University Medical Center, published a reanalysis in Science. Their starting point was the puzzle that lifespan looked oddly unheritable. Twin studies put it at 20 to 25 percent, and some large pedigree studies had pushed the figure as low as 6 percent — far below the heritability of most other complex human traits, and below what is measured for lifespan in other species. If ageing is a biological process, that was a strange result.

Their explanation is that the estimates were contaminated by the wrong kind of death. Statisticians distinguish intrinsic mortality, which follows from ageing and the body’s own failure modes, from extrinsic mortality — accidents, violence, infectious disease. Extrinsic deaths are, for these purposes, essentially random with respect to a person’s genes. A cyclist killed by a lorry at thirty had whatever longevity genes they had; the lorry did not consult them. Because historical populations carried a great deal of extrinsic mortality, every measurement of lifespan heritability was diluted by deaths that genes were never going to influence.

Correcting for this using mathematical modelling and twin cohorts — including, unusually, twins raised apart, which separates shared genes from shared households — the team put the heritability of intrinsic lifespan above 50 percent. That is roughly double the conventional figure, and it places human lifespan in line with other complex traits and with what is seen in other animals.

Being precise about what this does and does not say matters more here than usual, because the headline version circulating since publication is wrong in a specific way. It does not mean your lifespan is fifty percent fixed at conception. It means that among deaths caused by ageing rather than by accident or infection, more than half the variation tracks genetic differences. Those are different claims. The older 20 to 30 percent figure remains the right answer to the question “how much of all variation in how long people actually live is genetic?” The new figure answers “how much of the variation in ageing itself is genetic?” Both are useful; confusing them is how a reasonable paper becomes an unreasonable headline.

It should also be read as one study proposing a new correction, not a settled consensus. It will be tested, and reanalyses that double a long-standing number deserve exactly the scepticism this article applies to everything else. But the direction of the argument is relevant to the rest of this piece: if the heritable component of ageing is genuinely that large, then searching for the gene variants that centenarians carry is a better-motivated project than the older figures implied.

What the Genetics of Cancer Tells Us About Living Long

One of the most revealing aspects of centenarian biology is what it reveals about cancer — and the relationship between cancer resistance and longevity is more complex than it initially appears.

Cancer deaths become less common at the very oldest ages, and many centenarians do not die of it. Why is not settled. Leading hypotheses include more effective immune surveillance of pre-cancerous cells and better DNA repair; the hyaluronan story from naked mole rats is suggestive, but it has not been shown to apply to human centenarians.

This connects to a point from our article on the genetics of cancer: telomerase, the enzyme that maintains telomere length, is reactivated in 85 to 90 per cent of cancers, letting them divide without limit. How long-lived people keep tissue renewal going while holding that enzyme in check is one of the questions centenarian research may help answer.

What This Research Could Actually Lead To

The practical implications of longevity genetics research are beginning to materialise into therapeutic programmes, though the timeline from discovery to clinical application remains long.

The University of Bristol team working on LAV-BPIFB4 has framed their result as opening a gene-therapy route to mitigating cardiovascular aging. The initial application — treating progeria — would benefit only a tiny number of children with this rare condition. But the researchers are explicit that the gene’s effects on normal cardiac aging could eventually be relevant to the far larger population of people experiencing age-related heart disease. Clinical trials in humans are a future ambition rather than a current reality, but the mechanistic understanding now exists to design them.

The University of Rochester team’s work on HMW-HA is already at a more advanced stage of translation. They have identified small molecules that slow the degradation of hyaluronic acid and are testing them in pre-clinical trials. The goal, stated explicitly by Gorbunova, is to develop drugs that maintain HMW-HA levels in aging human tissue — effectively mimicking one of the naked mole rat’s core longevity adaptations without requiring gene therapy.

More broadly, centenarian genome studies are building a catalogue of candidate longevity variants. If they replicate, they could point to drug targets: pathways a medicine might push in people who did not inherit the protective versions.

The Question Underneath the Science

Beneath all of this sits a question journal papers rarely address: what does it mean to understand the genetics of longevity?

Every centenarian alive today was born before the discovery of DNA’s structure. They grew up without antibiotics for most of their childhood, lived through wars and famines and upheavals that shortened countless other lives, and arrived at extreme old age carrying genetic protection they never knew they had. Their longevity is not the result of longevity research — it is the subject of it. They did not choose their genes.

The generation that might choose them — or at least influence them through precision medicine, gene therapy, or targeted drugs — is being born now. What the research described in this article represents is the early mapping of a territory that medicine has never previously had the tools to explore. The genetics of longevity is not the genetics of immortality. It is the genetics of resilience — of cells that repair themselves a little more faithfully, immune systems that stay active a little longer, hearts that handle stress a little more gracefully.

Whether that resilience can be extended to more people, through medicine that borrows from centenarians and naked mole rats what nature has not seen fit to give everyone, is the question that will define the next generation of genetics research. It is the same deep question of where we came from and what our DNA records about us, explored from another angle in our article on what DNA reveals about true human origins.

Frequently Asked Questions

Sources

Primary peer-reviewed research:

1. Zhang, Z., Tian, X., Lu, J.Y. et al. (2023). Increased hyaluronan by naked mole-rat Has2 improves healthspan in mice. Nature 621, 196–205. DOI: 10.1038/s41586-023-06463-0
2. Qiu, Y., Cattaneo, M., Maciag, A., Puca, A.A., Madeddu, P. (2025). A longevity-associated variant of the human BPIFB4 gene prevents diastolic dysfunction in progeria mice. Signal Transduction and Targeted Therapy 10. DOI: 10.1038/s41392-025-02416-3
3. Takasugi, M., Firsanov, D., Tombline, G. et al. (2020). Naked mole-rat very-high-molecular-mass hyaluronan exhibits superior cytoprotective properties. Nature Communications 11, 2376. DOI: 10.1038/s41467-020-16050-w
4. Genetic Signatures of Exceptional Longevity: Coding Region SNPs in Centenarians and Supercentenarians. PMC / National Library of Medicine (2025–2026). PMC12506250
5. Shen, S., Li, C., Xiao, L. et al. (2020). Whole-genome sequencing of Chinese centenarians reveals important genetic variants in aging. Human Genomics. DOI: 10.1186/s40246-020-00271-7

Science journalism and institutional coverage:

6. ScienceDaily (May 2026) — Scientists Successfully Transfer Longevity Gene and Extend Lifespan
7. SciTechDaily (October 2025) — Supercentenarian Longevity Gene Used to Slow Rapid Aging Disease
8. ScienceDaily / University of Bristol (November 2025) — A Gene from 100-Year-Olds Could Help Kids Who Age Too Fast
9. JMIR Research Protocols (March 2025) — Determinants of Extreme Longevity in Supercentenarians: A Scoping Review
10. ClinicalTrials.gov — registered centenarian and longevity-genetics studies (queried 22 August and 2 October 2026)
11. Deelen, J. et al. (2019) — A meta-analysis of genome-wide association studies identifies multiple longevity genes. Nature Communications 10:3669.
12. Willcox, B.J. et al. (2008) — FOXO3A genotype is strongly associated with human longevity. PNAS 105(37):13987-92.
13. Horvath, S. et al. (2015) — Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging 7(12):1159-70.