Differences in the rate that germline mutations accumulate in healthy young adults could help predict relative lifespan in both sexes and the remaining years of fertility in women, according to the results of research by scientists at the University of Utah (U of U) Health. Their study, believed to be the first of its kind, found that young adults who acquired fewer mutations over time lived about five years longer than those who acquired mutations more rapidly. The researchers suggest that the discovery could eventually lead to the development of interventions that may help to slow the aging process.
“If the results from this small study are validated by other independent research, it would have tremendous implications,” commented Lynn B. Jorde, PhD, chair of the department of human genetics at U of U Health and a co-author of the study, which is published in Scientific Reports. “It would mean that we could possibly find ways to fix ourselves and live longer and better lives.” Jorde and colleagues reported their findings in a paper titled, “Germline mutation rates in young adults predict longevity and reproductive lifespan.”
Scientists have long known that DNA damage occurs continually in the body. There are various mechanisms that typically repair this damage and prevent potentially harmful mutations, the authors explained. However, as we get older, these mechanisms become less efficient, and so more mutations accumulate. And, as the investigators pointed out, “…several classes of DNA damage are known to accumulate through adulthood in both sexes, though at higher rates in men.” Older parents, for instance, tend to pass on more genetic mutations through their germline (egg and sperm) to their children, than do younger parents.
The somatic theory of aging proposes that somatic mutations accumulating through life result in cell apoptosis, senescence, and tumorigenesis, or other cell pathologies, which lead to tissue dysfunction, chronic diseases, and death. There do remain a number of questions, however, the authors noted. One of these is how early in life might levels of mutation accumulation predict remaining longevity. Another question is whether levels of mutation accumulation early in life can predict reproductive lifespan. And also, do somatic and germline mutation accumulation rates rise after puberty? This would be predicted by the evolutionary biology principle that the force of natural selection to maintain robust health should begin to decline once the reproductive phase of life is attained, the investigators commented.
Headed by Richard Cawthon, MD, PhD, a U of U associate professor of human genetics, the researchers theorized that accumulated mutations could be a biomarker for rates of aging and potentially predict lifespan in younger individuals as well as fertility in women. To investigate this in more detail the team sequenced DNA from 61 men and 61 women who were grandparents in 41 three-generational families. The families were part of the Centre d’Etude du Polymorphisme Humain (CEPH) consortium, which was central to many key investigations that have contributed toward a modern understanding of human genetics.
Germline mutations are passed onto offspring, so the researchers analyzed blood DNA sequences in trios consisting of pairs of grandparents from the first generation and one of their children from the second generation. Mutations found in the child’s blood DNA that were not present in either parent’s blood DNA were inferred to have originated in the parents’ germlines. The researchers were then able to determine which parent each germline mutation came from, and, therefore, the number of such mutations each parent had accumulated in egg or sperm by the time of conception of the child.
With this knowledge, the researchers were able to compare each first-generation parent to others of the same sex, and estimate their rate of aging. “So, compared to a 32-year-old man with 75 mutations, we would expect a 40-year-old with the same number of mutations to be aging more slowly,” Cawthon explained. “We’d expect him to die at an older age than the age at which the 32-year-old dies.”
When the scientists analyzed their data they found that mutations began to occur at an accelerating rate during or soon after puberty, suggesting that aging begins in our teens. The study results also found that some young adults acquired mutations at up to three times the rate of others. “Our data suggest that germline mutation accumulation rates in young adults may be a measure of the rate of aging,” they wrote. “ … these data suggest that the rate of aging may vary 3-fold between young adults.”
After adjusting for age, the researchers determined that individuals with the slowest rates of mutation accumulation were likely to live about five years longer than those who accumulated mutations more rapidly. This is a difference comparable to the effects of smoking or lack of physical activity, according to Cawthon. Women with the highest mutation rates also had significantly fewer live births than other women and were more likely to be younger when they gave birth to their last child. This suggested that high rates of mutation affected their fertility.
“Here we have shown that lower sex- and parental-age-adjusted germline mutation rates in young adults are associated with lower all-cause mortality for both sexes, and more liveborn children and older age at last birth for the women,” the authors concluded. “Together, these observations support the hypothesis that aging begins at or soon after puberty, due to a decline in the force of natural selection to maintain robust health once the reproductive phase of life is attained.”
Added Cawthon, “The ability to determine when aging starts, how long women can stay fertile, and how long people can live is an exciting possibility. 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.”
The authors further suggested how the new knowledge might be used to benefit health. “Interventions in adults directed toward returning mutation accumulation rates to the negligible or very low levels that may be present prepubertally would be expected to have broad benefits, greatly lowering the risks for multiple aging-related diseases and dramatically extending the human healthspan,” they wrote. “Perhaps a relatively small number of genes that are master regulators of gene networks maintaining genome stability and homeostasis generally are downregulated at puberty, but can be reprogrammed or otherwise coaxed back to their prepubertal levels of activity by a combination of lifestyle, dietary, and/or pharmacological interventions.”