Combined effect of rare mutations has negative impact on health and longevity

In a study published recently in the eLife journal, researchers have reported that the combined effects of rare and damaging mutations that occur at birth itself have adverse effects on healthspan and longevity.

Genetic Mutation Concept

Image Credit: Double Brain/

This discovery indicates that an additional inherited damaging mutation could reduce the life span by six months, and the combinations of these rare, damaging mutations determine how soon an individual is likely to develop diseases like dementia, heart disease, and cancer.

Researchers have now suggested that a majority of the genetic variants associated with lifespan have been identified in people who have a long lifespan, such as centenarians who live to 100 or above. The genetic variants that are responsible for the survival of the remaining population have not been clearly understood.

Scientists have now proposed that the remaining variance that accounts for the lifespan could be due to the combination of very rare but extremely damaging mutations existing in the genome of every individual.

The role of ultra-rare damaging mutations that decrease lifespan and health span has been largely overlooked. They are different in different people, but in combination, they exhibit an unexpectedly large effect on lifespan.”

Vadim Gladyshev, Study Co-Senior Author and Professor, Brigham and Women’s Hospital and Harvard Medical School

Until recently, only common gene variants could be probed in genetic studies due to a small number of participants,” explained Anastasia Shindyapina, the study’s co-first author and postdoctoral researcher at Brigham and Women’s Hospital, Harvard Medical School.

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.”

Today, one of the most damaging genetic variants is believed to be ultra-rare protein-truncating variants (PTVs). These variants are likely to have a bigger impact when compared to that of the more common genetic variants, and can radically change the function and amount of crucial proteins in the body.

Greater frequency of PTVs has been associated with complex diseases, like autism, epilepsy, and schizophrenia. In this research, Shindyapina, together with Aleksandr Zenin, the study’s co-first author and researcher at Gero, Singapore, and their collaborators embarked to find out how the number of PTVs that is present at birth influences the individual’s lifespan.

The researchers also wanted to find out whether the buildup of additional PTVs throughout life can have an impact on the length of survival and overall health, in general.

The researchers studied genomic data that was acquired from over 40,000 people registered in the UK Biobank and who, on an average basis, were in their mid-50s. They subsequently compared the individual “burden” of PTVs (the overall number of PTVs for each person’s genome) to their lifespan as well as their “healthspan,” which is the time required to develop complex medical conditions such as heart disease, cancer, dementia, stroke, and chronic obstructive pulmonary disease.

The researchers also discovered that individuals who had a higher burden of ultra-rare PTVs had a shorter health span and thus a shorter lifespan.

Every additional ultra-rare PTV in the genome of an individual was responsible for reducing the health span by two months and reducing the lifespan by six months.

Apart from the genetic variants that every individual is born with, more variants get accumulated as people age. The study predicted that the natural buildup of PTVs boosts proportionally with age but their impacts would probably be less when compared to the impacts of PTVs present in individuals at birth.

This implies that the genetic variation we accumulate throughout life only accounts for a small fraction of the increased risk of disease and death that we all face as we grow older, if our theoretical calculations are correct.”

Andrei Tarkhov, Study Author and PhD Student, Skolkovo Institute of Science and Technology

Tarkhov is also a researcher at Gero.

Our finding that accumulated mutations during a lifetime do not accelerate disease or death contradicts previous hypotheses. Together our results illustrate the surprising role of rare mutations previously inaccessible for genetic studies in the aging process. They also demonstrate the power of whole exome and genome sequencing to uncover the genetic architecture of complex diseases in the interest of developing future therapeutics.

Peter Fedichev, Study Co-Senior Author and Principal Investigator, Gero

Journal reference:

Shindyapina A. V., et al. (2020) Germline burden of rare damaging variants negatively affects human health span and lifespan. eLife.


The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
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