Lower germline mutation rates in young adults predict longer lives and longer reproductive lifespans

BACKGROUND Genome sequencing of large three-generation families allows identification of de novo mutations (DNMs) in the middle-generation and their attribution to the specific grandparental germlines in which they arose. We hypothesized that germline DNM accumulation during aging may limit the duration of childbearing in women, and if accompanied by mutation accumulation in somatic tissues, reflect aging rates generally in both sexes. Here we test whether germ cell DNMs present in the grandparent generation when they were young adults predict two clinically important outcomes in those same individuals: survival in both sexes, and age-related fertility decline in women. METHODS Germline DNM counts were determined in 122 grandparents from 33 three-generation Utah families and converted to DNM rates by normalizing each subject9s DNM counts to the callable fraction of their genome. Age at death, cause of death, cancer incidence, and reproductive histories were provided by the Utah Population Database and the Utah Cancer Registry. Fertility analyses were restricted to the 53 grandmothers whose age at last birth (ALB) was at least 30 years, the approximate age when the decline in female fertility ending with menopause begins. RESULTS After adjusting for birth year, sex and parental age effects in Cox proportional hazard regression models, a one standard deviation increase in DNM rates was significantly associated with higher all-cause mortality in both sexes combined (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.12-3.46; p=0.019). Women in the top 75% of DNM rates had higher all-cause mortality than women in the bottom 25% (HR, 2.14; 95% CI, 1.03-4.46; p=0.043); and men in the top 25% of DNM rates had higher all-cause mortality than men in the bottom 25% (HR, 4.37; 95% CI, 1.54-12.44; p=0.006). Among women with ALB ≥ 30 years, those in the top 50% of DNM rates had significantly fewer live births than those in the bottom 25% (p=0.026), and higher DNM rates were significantly associated (p=0.036) with a younger ALB (< 25th percentile, 34.8 years). CONCLUSIONS Germline mutation accumulation rates in healthy young adults may provide a measure of both reproductive and systemic aging. The data further suggest that inter-individual differences in mutation accumulation rates are established around puberty, just when DNA repair genes9 expression levels are known to begin their lifelong decline.