Patterns of Aging Biomarkers, Mortality, and Damaging Mutations Illuminate the Beginning of Aging and Causes of Early-Life Mortality

• Published in: Cell reports (Cambridge) 2019-12, Vol.29 (13), p.4276-4284.e3
• Main Authors: Kinzina, Elvira D., Podolskiy, Dmitriy I., Dmitriev, Sergey E., Gladyshev, Vadim N.
• Format: Article
• Language: English
• Subjects: age-related; aging; cancer; clock; damage; incidence; lifespan; mortality; mutations; selection
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.091

An increase in the probability of death has been a defining feature of aging, yet human perinatal mortality starts high and decreases with age. Previous evolutionary models suggested that organismal aging begins after the onset of reproduction. However, we find that mortality and incidence of diseases associated with aging follow a U-shaped curve with the minimum before puberty, whereas quantitative biomarkers of aging, including somatic mutations and DNA methylation, do not, revealing that aging starts early but is masked by early-life mortality. Moreover, our genetic analyses point to the contribution of damaging mutations to early mortality. We propose that mortality patterns are governed, in part, by negative selection against damaging mutations in early life, manifesting after the corresponding genes are first expressed. Deconvolution of mortality patterns suggests that deleterious changes rather than mortality are the defining characteristic of aging and that aging begins in very early life. [Display omitted] •Mortality from age-related diseases is U-shaped with the nadir below reproductive age•Quantitative biomarkers of aging change continuously throughout life•Mutation burden causes early-life mortality and contributes to selection•Aging is best defined by damage rather than mortality and starts very early in life Kinzina et al. highlight the importance of adequate definition of aging and address long-standing questions on the onset of aging and causes of early-life mortality. They show that aging is better represented by the accumulation of deleterious changes rather than mortality and thus starts early in life.