Rare Mutations Work Together to Reduce Lifespan

The combined effects of rare, inherited mutations have a negative impact on healthspan and longevity, according to a study published this week in eLife. The combinations of these rare mutations determine how soon a person will develop diseases such as cancer, heart disease, and dementia.

Most research into the genetic variants linked to lifespan that researchers currently know about have been found in people who live extremely long lives. However, the variants responsible for survival of the rest of the population remain poorly understood.

“The role of ultra-rare damaging mutations that decrease lifespan and healthspan has been largely overlooked,” says co–senior author Vadim Gladyshev of Harvard Medical School. “They are different in different people, but in combination, they exhibit an unexpectedly large effect on lifespan.”

Until recently, these ultra-rare mutations have been difficult to study. “Only common gene variants could be probed in genetic studies due to a small number of participants,” explains co–first author Anastasia Shindyapina, also of Harvard. “However, large datasets that sequenced tens of thousands of people now allow us to assess the effects of DNA variation that appear in less than one out of 10,000 subjects.”

Some of the most damaging genetic variants are known as ultra-rare protein-truncating variants (PTVs). These variants tend to have a larger impact than more common genetic variants and can dramatically change the amount and function of important proteins in the body. Increased frequency of PTVs has been linked to complex diseases such as schizophrenia, epilepsy, and autism. For this study, the researchers investigated how the number of PTVs a person is born with vs. accumulates over time influences their lifespan.

The team analyzed genomic data from more than 40,000 people who were registered in the UK Biobank. They compared each individual’s “burden” of PTVs with both their lifespan and healthspan. A high PRV burden was correlated with a shorter lifespan and healthspan, and each additional ultra-rare PTV in a person’s genome accounted for a reduction in lifespan of six months and a reduction in healthspan of two months.

In addition to the genetic variants we are born with, we accumulate more as we age. The research predicted that the natural accumulation of PTVs increases proportionally with age, but their effects on lifespan and healthspan are likely to be minor compared with the effects of PTVs that we are born with.