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Individuals With Polymerase Defects Have Increased Somatic Mutations, But Not Increased Aging

NEW YORK — The small mutations that accumulate in someone's genome during their lifetime are likely not the full cause of features associated with aging.

Much of aging had been thought to stem from the accumulation of genetic mutations as cells divide throughout someone's lifetime, as these mutations could disrupt the typical functions of genes and cells and contribute to aging-related diseases.

But by studying the genomes of individuals with germline mutations within the DNA polymerase genes POLE and POLD1 — which affect cells' ability to proofread during DNA replication — researchers from the Wellcome Sanger Institute and elsewhere found that these individuals did indeed have an increased mutational burden but did not show signs of premature aging. They did, though, have an increased risk of developing cancer.

"We were amazed to see that normal and seemingly healthy cells could tolerate so many mutations," co-first author Phil Robinson from the Wellcome Sanger Institute said in a statement. "This research has given us an insight into the potential reasons for their increased risk of cancer and also offers an immensely valuable window into the process of aging."

The study appeared Thursday in Nature Genetics.

The researchers collected normal intestinal crypt cell samples from 14 individuals with certain POLE or POLD1 mutations, which they compared to 109 normal intestinal crypts from individuals without those mutations. They focused on these cells as an intestinal crypt is a clone derived from a single ancestral crypt stem cell from about 10 years prior, allowing the researchers to then gauge differences in mutational burdens and mutational rates.

Single-base substitutions among the individuals with POLE or POLD1 mutations correlated with age and were more numerous than for healthy individuals. For example, individuals with a POLE L424V mutation had an average 331 SBS per year, individuals with a POLD1 S478N mutation had 152 SBS per year, and those with POLD1 D316N or L474P mutations had 58 SBS per year, while a healthy individual had an SBS rate of 49 per year.

At the same time, small insertion and deletion mutation rates with intestinal crypt cells were also higher among individuals with POLE or POLD1 mutations.

Meanwhile, the researchers also sampled endometrial glands, as well as blood and sperm to find an increased mutational burden across cell and tissue types.

These results suggested to the researchers that individuals with germline POLE or POLD1 mutations have higher "mutational ages." But while the consequences of these mutations appear to be an increased risk of colorectal cancer, endometrial cancer, and a few other cancer types, they do not appear to give rise to other hallmark diseases of aging. Additionally, individuals with germline POLE or POLD1 mutations can survive into the later ranges of the human lifespan, the researchers noted.

Based on these natural-experiment findings, the researchers concluded that there is unlikely to be a simple somatic mutation theory of aging.

"Our research shows that a higher mutational burden does not appear to result in early onset signs and features that we typically associate with aging," Robinson added. "While other types of mutations could potentially play a role, it suggests that there is a more complex process behind aging than the accumulation of mutations alone."