Summary: New research shows that people who carry a higher load of ultra-rare protein‑truncating variants (PTVs) tend to have shorter healthspans and lifespans. On average, each extra ultra‑rare PTV in an individual’s genome corresponded to roughly six months less life and about two months less healthy life.
Source: eLife
Overview
Researchers report that rare, highly damaging genetic mutations present from birth can collectively shorten both the period of life spent in good health and total lifespan, according to a study published in eLife. The study indicates that each additional inherited ultra‑rare protein‑truncating variant has a measurable, negative effect on when a person develops major age‑related illnesses and on overall survival.
Most genetic variants associated with longer life discovered so far come from studies of very long‑lived individuals, such as centenarians. However, the genetic contributors that explain differences in lifespan across the broader population remain largely unresolved. The new study proposes that part of this unexplained variation comes from combinations of extremely rare but highly damaging mutations that differ between individuals yet, in aggregate, exert a substantial influence on health and longevity.
“The role of ultra‑rare damaging mutations that decrease lifespan and healthspan has been largely overlooked,” says co‑senior author Vadim Gladyshev, Professor at Brigham and Women’s Hospital and Harvard Medical School. “They vary from person to person, but in combination they show an unexpectedly large effect on lifespan.”
Co‑first author Anastasia Shindyapina, a postdoctoral researcher at Brigham and Women’s Hospital, Harvard Medical School, notes that until recently studies were limited to more common variants because of sample size constraints. “Large sequencing datasets now allow us to study DNA changes that appear in fewer than one in 10,000 people,” she explains.
What are ultra‑rare PTVs and why they matter
Ultra‑rare protein‑truncating variants (PTVs) are among the most damaging types of genetic changes. They tend to have a larger functional impact than more common variants because they can dramatically alter the amount or function of important proteins. Higher frequencies of PTVs have been previously linked to complex disorders such as schizophrenia, epilepsy and autism. The current study examined how the number of PTVs a person inherits affects the timing of disease onset and overall lifespan, and whether PTVs that accumulate during life play a meaningful role in aging.
The investigators analyzed exome and genome data from over 40,000 individuals in the UK Biobank, with an average age in the mid‑fifties. For each person, they calculated a PTV burden (the total count of ultra‑rare PTVs) and compared that burden to both lifespan and healthspan, defined here as the time before the first occurrence of major age‑related diseases such as cancer, heart disease, chronic obstructive pulmonary disease, stroke and dementia.
Key findings
The study found a clear association between higher ultra‑rare PTV burden and reduced healthspan and lifespan. Quantitatively, each additional ultra‑rare PTV correlated with about a six‑month reduction in lifespan and approximately a two‑month reduction in healthspan. Individuals who lived longer tended to carry both fewer ultra‑rare PTVs and less damaging forms of these variants.
Inherited vs. accumulated mutations
The authors also considered mutation accumulation over a lifetime. Their modeling suggests that while somatic accumulation of PTVs does increase with age, the contribution of these acquired mutations to overall mortality and morbidity acceleration is likely small compared with the effect of inherited PTVs. “This implies that genetic variation accumulated during life accounts for only a small fraction of the increased disease and death risk we experience as we age, if our theoretical estimates are correct,” says co‑author Andrei Tarkhov, a researcher at Gero and PhD student at Skolkovo Institute of Science and Technology.
Co‑senior author Peter Fedichev, Principal Investigator at Gero, adds: “Our finding that mutations accumulated during a lifetime do not substantially accelerate disease or death challenges some prior assumptions. Together, these results highlight the unexpected importance of very rare inherited mutations in aging and underscore the value of whole‑exome and whole‑genome sequencing for uncovering genetic architecture behind complex age‑related diseases.”
About the study and citation
Original Research: “Germline burden of rare damaging variants negatively affects human healthspan and lifespan.” Anastasia V Shindyapina, Aleksandr A Zenin, Andrei E Tarkhov, Didac Santesmasses, Peter O Fedichev, Vadim N Gladyshev. eLife. DOI: 10.7554/eLife.53449.
About this neuroscience research article
Source: eLife
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Abstract (summary)
Heritability of human lifespan is estimated at 23–33% from twin studies. Genome‑wide association studies have linked some alleles to lifespan traits, but they account for only a small fraction of heritability. This study reports that the burden of the rarest protein‑truncating variants is negatively associated with healthspan and lifespan across two large cohorts, explaining portions of their variability. Longer‑lived people tend to carry fewer and less damaging ultra‑rare PTVs. The somatic accumulation of PTVs over a lifetime appears to explain only a small share of mortality and morbidity acceleration and is unlikely to be the primary causal driver of aging. Overall, rare damaging mutations—both inherited and accumulated—contribute to aging, and combining ultra‑rare variant burden with common allele data helps better account for apparent heritability of human lifespan.
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