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Family Study Finds Germline Mutation Rates Predict Longevity, Fertility

NEW YORK – People who accumulate mutations within their cells more slowly live longer than those who amass mutations quickly and have extended fertility, a new study has found. 

Researchers from the University of Utah analyzed mutation rates among more than 120 individuals from the Utah Centre d'Etude du Polymorphisme Humain families. The somatic theory of aging suggests that somatic mutations arise and accumulate throughout people's lives and lead to apoptosis, cellular senescence, and tumor development, which then contribute to disease and death. In their study, the researchers looked at germline mutation rates, which served as a proxy for the typically higher somatic mutation rates.

By comparing mutation rates to mortality rates and other data, the researchers found that how often mutations appear could predict both lifespan and, among women, fertility. Puberty appears to be a key timeframe for establishing mutation rates, the researchers reported in their Scientific Reports paper on Friday.

"If the results from this small study are validated by other independent research, it would have tremendous implications," senior author Lynn Jorde from the University of Utah said in a statement. "It would mean that we could possibly find ways to fix ourselves and live longer and better lives."

The researchers determined germline mutations rates — which they say are influenced by the same mechanisms as somatic mutation rates — for 61 men and 61 women from the CEPH Utah population by determining the number of de novo mutations in their children that could be attributed to a change from either the maternal or paternal germline. 

Using age at death and cause of death data, the researchers examined whether these mutation rates affect lifespan. Among all adults, they found that a one standard deviation increase in age-adjusted mutation rate was associated with increased mortality. Those in the quartile with the lowest mutation rates lived approximately 4.7 years longer than those in the top quartile with the highest mutation rates.

This difference in lifespan is comparable to the effect of smoking or not being physically active, the researchers noted.

Among women in the study, those with the highest mutation rates had fewer children than those with lower mutation rates. Additionally, women with high mutation rates tended to be younger when they gave birth to their last child. Together, the findings suggest mutation rates could affect female fertility.

The researchers also began to trace back when these mutation rates are set, noting that they appear to vary between fetal and adult tissue, for instance. In their analysis based on mutation rate and parental age, they estimated that mutation rates are established in women around 18 years of age and in men at around 14 years of age. This suggests that puberty could have a causal role in determining adult mutation rates, they noted.

Bolstering this idea, they found that older age at menarche among the women in their cohort was associated with a lower mutation rate.

"The ability to determine when aging starts, how long women can stay fertile, and how long people can live is an exciting possibility," first author Richard Cawthon from Utah said in a statement. "If we can get to a point where we better understand what sort of developmental biology affecting mutation rates is happening during puberty, then we should be able to develop medical interventions to restore DNA repair and other homeostatic mechanisms back to what they were before puberty. If we could do that, it's possible people could live and stay healthy much longer." 

He and his colleagues cautioned, though, that their study was small and said that investigations in larger cohorts are needed.

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