Germline Mutation Rate as an Insight into the Pace of Aging

DNA sequencing over generations can be used to determine individual rates of germline mutation, as mutations present in the child but not the parent must have occurred in the parent germline. Stochastic nuclear DNA damage takes place over the course of aging, and evidence suggests that this correlates with the pace at which a person is aging. While nuclear DNA damage determines cancer risk, the degree to which it contributes to other forms of age-related degeneration is an open question. Only damage occurring in stem cells or progenitor cells, and that can thus spread through tissue in daughter somatic cells, seems likely to have a meaningful effect. Interventions such as calorie restriction, known to slow aging and extend life in laboratory species, do slow the onset of such unrepaired damage to nuclear DNA. All of this makes the research noted here quite interesting.

Scientists have long known that DNA damage constantly occurs in the body. Typically, various mechanisms repair this damage and prevent potentially harmful mutations. As we get older, these mechanisms become less efficient and more mutations accumulate. Older parents, for instance, tend to pass on more genetic mutations through their germline (egg and sperm) to their children than younger parents.

Researchers theorized that these mutations could be a biomarker for rates of aging and potentially predict lifespan in younger individuals as well as fertility in women. The researchers 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.

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. That's because germline mutations are passed on to their offspring. Mutations found in the child's blood DNA that were not present in either parent's blood DNA were then 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.

Knowing that allowed the researchers to compare each first-generation parent to others of the same sex and estimate their rate of aging. "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. We'd expect him to die at an older age than the age at which the 32-year-old dies." The scientists found that mutations began to occur at an accelerating rate during or soon after puberty, suggesting that aging begins in our teens. Some young adults acquired mutations at up to three times the rate of others. 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.

Link: https://healthcare.utah.edu/publicaffairs/news/2020/06/06-aging.php

Comments

"The scientists found that mutations began to occur at an accelerating rate during or soon after puberty, suggesting that aging begins in our teens."

To me, it suggests that the rate of mutation is higher when the rate of cell division is higher (in this case, due to gonad development). It could also be due to a rapidly changing hormonal environment.

Posted by: Antonio at June 26th, 2020 9:13 AM

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