Scientists have discovered a handful of ultrarare mutations present in our cells from birth that likely shave years off a persons life. Each of these DNA variants, most likely inherited from our parents, can reduce life span by as much as 6 months, the researchers estimate. And different combinations can dictate how long people live before developing age-related diseases such as cancer, diabetes, and dementia.
A persons genes dont set a specific natural life spandiet and many other factors play large roles, toobut studies have shown that DNA variants can influence the aging process. Biologists chalk up less than one-third of that influence to the genes we inherit. The source of other age-influencing DNA variation is environmental: Sun damage, chemical exposure, and other insults that create thousands of random mutations. Each cells collection of these environmental mutations differs, and most dont greatly impact a persons life span.
Hunting for these rare mutations, which are found in less than one in every 10,000 people, required a group effort. Harvard University geneticist Vadim Gladyshev, a senior co-author in the new study, partnered with academic colleagues and a biotech company called Gero LLC to scour the UK Biobank, a public database containing the genotypes of about 500,000 volunteers.
Using more than 40,000 of these genotypes, the team looked for correlations between small changes in DNA and health conditions, a so-called genomewide association study. Specifically, the variants they were targeting knock out genes entirely, depriving all the cells in the body of certain proteins.
On average, each person is born with six ultrarare variants that can decrease life span and health span, the amount of time people live before developing serious diseases, the team reports this month in eLife. The more mutations, the more likely a person was to develop an age-related illness at a younger age or die. The exact combination matters, Gladyshev says, but in general, each mutation decreases life span by 6 months and health span by 2 months.
The results build on what is already known about aging: Family genes matter. But rather than studying the common mutations found in especially long-lived people, researchers can now target rarer variants present in everyone. Gladyshev hopes this information can be used in clinical trials to categorize participants by their mutations in addition to things like gender and actual age.
He admits the findings are potentially controversial, as they minimize the perceived contribution to aging of environmental somatic mutations acquired throughout life. Somatic mutations live in a larger universe of age-related changes influenced by lifestyle, he says, adding that changes to hormone and gene expression also come with age. They [all] contribute to the aging process, but on their own they do not cause it.
Jan Vijg, a geneticist at the Albert Einstein College of Medicine who studies the role of somatic mutations in aging, agrees, though he adds that somatic mutations can still cause diseases such as skin cancer that decrease life span.
Alexis Battle, a biomedical engineer at the Johns Hopkins University School of Medicine, points to an important caveat, however: The new research only looked at the exome, the 1% of the genome that actively builds the proteins that direct our cells. The rest is largely a black box, although growing evidence shows it can affect gene expression. Both Battle and Vijg agree that this DNA could be even more important in aging than the regions targeted by Gladyshev and his colleagues.
Going forward, Gladyshev would like to repeat his analysis on DNA from centenarians: those that live to be older than 100. Most of the previous research focused on what these people have that makes them long-lived, he says. But [we want to look at] the oppositeits what they dont have.
sciencemag.org, 24 April 2020