The Genetic Clues of Early Death

April 15, 2025 
By Rebecca Handler 
Illustration by Jennie Ellison, created with Leonardo AI and Canva

We all wonder, at some point, how much time we have left. Some of us focus on eating better, avoiding stress, getting enough sleep, and taking our vitamins. But what if something deep within – something we can’t see, feel, or control – is silently influencing our lifespan?

In one of the largest studies of its kind, Stanford Medicine researchers, including Junyoung Park, PhD, Andrés Peña-Tauber, Lia Talozzi, PhD, Michael D. Greicius, MD, and Yann Le Guen, PhD, analyzed genetic data from nearly 400,000 people to uncover the subtle impact of rare genetic mutations that may be responsible for shortening lifespans, even in those who seem perfectly healthy.

The Value of Looking Backward

The study’s foundation is the UK Biobank, a sprawling, long-term research effort that, since the early 2000s, has collected health and genetic data from half a million people. The individuals who participated, mostly aged between 40 and 69, agreed to have their genetic material sequenced and their health records tracked for decades.

Over the years, researchers gathered genetic data, monitored participants' health, and, crucially, recorded their age at death. This allowed scientists to directly link genetic variants to lifespan – an insight few datasets can provide.

“Previous studies suggest that genetics plays a modest (10–25%) role in lifespan compared to environmental factors,” explains Yann Le Guen, PhD, a quantitative geneticist in Stanford’s Department of Medicine and co-author of the study. “Identifying variants linked to earlier death or prolonged survival can reveal key biological pathways, improve genetic testing for overall health, and support precision medicine.”

What really sets this study apart is that it focused not just on common genetic variants but on mutations found in less than 1% of the population. Many of these rare variants have powerful effects, especially when they appear in genes responsible for things like DNA repair or immune regulation.

The researchers also examined somatic mutations – DNA changes that occur over a person’s lifetime, particularly in blood-forming cells. These mutations aren’t inherited and don’t exist throughout the entire body. However, the researchers discovered that their presence may have significant consequences.

Finding Patterns in 400,000 DNA Samples

One of the most surprising findings wasn’t just how many genetic variants were linked to shorter lifespan — it was where those variants appeared. Many were found in genes already known to play a role in cancer, including BRCA1, BRCA2, TP53, PTEN, and TET2. These genes normally act like the body’s quality control team: they repair DNA damage and stop cells from growing out of control.

“When we looked at the results, we were surprised to see so many cancer-related genes,” said Le Guen. “We thought we’d find more connections to heart disease or brain conditions.”

Instead, the strongest signs of early death were tied to the same genes that, when disrupted, can also lead to cancer.

But this doesn’t mean everyone with these mutations had cancer at the time their blood was drawn for the UK Biobank study (between 2006 and 2010) — in fact, most did not. However, the researchers found that individuals carrying these rare, pathogenic gene variants were much more likely to eventually develop cancer. In fact, cancer was the most common cause of death among these individuals, based on linked health records and diagnostic codes. This suggests that when these protective genes stop working properly, they may silently influence the body in ways that gradually increase the risk of cancer.

The Blood Knows Things Before We Do

One of the most fascinating aspects of the study is its emphasis on clonal hematopoiesis – a term that may soon gain more recognition in public health. As we age, our blood-forming stem cells acquire mutations, most of which are harmless. However, in some cases, a single mutated cell multiplies more rapidly than the rest, eventually dominating the blood supply in a process called clonal expansion.

It’s not cancer – yet. But it’s something like a prequel.

“Clonal hematopoiesis increases with age and is linked to a higher risk of blood cancers,” Le Guen said, referencing a landmark Stanford study from 2014. “Our study shows that standard whole-exome sequencing can detect these somatic mutations, which are associated with earlier death and cancer risk – even in people without a diagnosis.”

This study adds another layer: people with certain clonal mutations – especially in genes like TET2, DNMT3A, ASXL1, and SRSF2 – were significantly more likely to die younger than those without them, even if they hadn’t yet developed any disease.

“Standard genetic testing can detect these mutations,” said Le Guen. “They’re not just abstract markers – they’re associated with real differences in lifespan.”

The researchers also discovered new potential risk genes, including CKMT1B, which they linked for the first time to a rare form of throat cancer. It’s this kind of insight that could eventually help shape who gets screened for what, and when – not necessarily based on family history or symptoms, but on the subtle signals already embedded in the genome.

This finding raises a tantalizing possibility: Could a routine genetic test one day reveal hidden biological risks years that may contribute to earlier mortality?

A Window Into the Future or a New Kind of Uncertainty?

The idea of using genetic screening not just to diagnose disease, but to forecast risk of early death, veers into ethically murky territory. What do you do with that knowledge? What if there’s no effective means of intervention? How do you balance preparedness with peace of mind?

Le Guen is aware of the tension, but sees the study’s findings as an opportunity, not a sentence.

“While it's understandable to feel concerned about carrying a high-risk mutation, early detection is key to effective treatment,” he shares. “Knowing one's genetic risk can lead to more personalized and frequent screenings, enabling closer clinical follow-up, earlier cancer detection, and often significantly improved survival.”

In other words, information doesn’t have to mean inevitability. It can mean vigilance, better monitoring, and – if possible –preventative care.

A Broader View of Mortality

Of course, genes are not destiny. Lifespan is shaped by a constellation of social, environmental, and behavioral factors. But part of what makes genetic data so powerful is its constancy. Unlike lifestyle factors, which are hard to track over decades, your DNA stays the same from birth – except, as this study shows, when it doesn’t.

Somatic mutations – the genetic edits that occur in your cells over time – add a layer of dynamic risk that evolves as we age. These mutations may eventually help explain why some people’s health appears to “turn” in midlife, or why sudden illness strikes without warning.

In that sense, this isn’t just a study about death. It’s a study about how quietly our bodies can change, and how early those changes might begin to matter.

The researchers caution that their findings are based on individuals of European ancestry, due to limitations in the UK Biobank’s diversity. They plan to extend their analysis to broader datasets, like the U.S.-based AllOfUs program, which includes participants from many different backgrounds.

But even with that caveat, the implications are clear: we are learning to read risk in our genomes, not just for disease, but for the arc of our lives.

What we do with that knowledge – how we protect, use, and interpret it – will shape not just medicine, but how we understand the boundary between health and illness, chance and fate.