Abstract
Ageing may be due to mutation accumulation across the lifespan, leading to tissue dysfunction, disease, and death. We tested whether germline autosomal mutation rates in young adults predict their remaining survival, and, for women, their reproductive lifespans. Age-adjusted mutation rates (AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d’Etude du Polymorphisme Humain) families were determined. Age at death, cause of death, all-site cancer incidence, and reproductive histories were provided by the Utah Population Database, Utah Cancer Registry, and Utah Genetic Reference Project. Higher AAMRs were significantly associated with higher all-cause mortality in both sexes combined. Subjects in the top quartile of AAMRs experienced more than twice the mortality of bottom quartile subjects (hazard ratio [HR], 2.07; 95% confidence interval [CI], 1.21–3.56; p = 0.008; median survival difference = 4.7 years). Fertility analyses were restricted to women whose age at last birth (ALB) was ≥ 30 years, the age when fertility begins to decline. Women with higher AAMRs had significantly fewer live births and a younger ALB. Adult germline mutation accumulation rates are established in adolescence, and later menarche in women is associated with delayed mutation accumulation. We conclude that germline mutation rates in healthy young adults may provide a measure of both reproductive and systemic ageing. Puberty may induce the establishment of adult mutation accumulation rates, just when DNA repair systems begin their lifelong decline.
Highlights
(AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d’Etude du Polymorphisme Humain) families were determined
Several monogenic progeroid syndromes are characterized by DNA repair deficiencies, increased somatic mutation rates, early onset of ageing-related phenotypes, and shortened lifespans[2], strongly supporting the somatic mutation theory of ageing
In healthy individuals DNA damage is continuous[3], and while most of it is repaired, several classes of DNA damage are known to accumulate through adulthood in both sexes[4,5,6,7], though at higher rates in men[8]
Summary
(AAMRs) in 61 women and 61 men from the Utah CEPH (Centre d’Etude du Polymorphisme Humain) families were determined. Recent studies[9,10,11] have reported that somatic mutations in blood nuclear DNA can be detected and quantified in most healthy middle-aged and older individuals, and that higher somatic mutation levels predict higher all-cause mortality, providing further support for the somatic mutation theory of ageing. As yet, it is unknown whether mutation accumulation in germline and/or somatic tissues during normal ageing is an important limiter of reproductive lifespan in women. Older ages at natural menopause are associated with longer lifespans[22]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
