On ageing and age-specific effects of spontaneous mutations

Evolutionary theories of ageing assume causal mutations either have beneficial early-life effects which gradually become deleterious with advancing age (antagonistic pleiotropy: AP) or mutations that only have deleterious effects at old age (mutation accumulation: MA). Mechanistically, ageing is predicted to result from damage accumulating in the soma. While this scenario is compatible with AP, it is not immediately obvious how damage would accumulate under MA. In a modified version of the MA theory, it has been suggested that mutations with weakly deleterious effects at young age can also contribute to ageing, if they generate damage that gradually accumulates with age. Mutations with increasing deleterious effects have recently gained support from theoretical work and studies of large-effect mutations. Here we address if spontaneous mutations also have negative effects that increase with age. We accumulate mutations with early-life effects in Drosophila melanogaster across 27 generations and compare their relative effects on fecundity early and late in life. Our mutation accumulation lines on average have substantially lower early-life fecundity compared to controls. These effects were further maintained throughout life, but they did not increase with age. Our results thus suggest that most spontaneous mutations do not contribute to damage accumulation and ageing.

衰老的进化理论假定，具有因果关联的突变可分为两类：一类是对生命早期具有有益效应、随年龄增长逐渐转为有害的突变（拮抗多效性（antagonistic pleiotropy, AP）），另一类是仅在高龄时产生有害效应的突变（突变积累（mutation accumulation, MA））。从机制层面来看，衰老被认为源于体细胞内损伤的累积。该理论框架虽与AP理论兼容，但却难以直接阐释突变积累理论下损伤是如何发生累积的。在突变积累理论的修正版本中，有研究提出：若突变所引发的损伤会随年龄逐步累积，那么那些在生命早期仅表现出轻微有害效应的突变，同样可推动衰老进程。近年来，具有有害效应随年龄增强的突变，已获得理论研究与大效应突变相关研究的支持。本研究旨在探究自发突变是否同样存在随年龄增长而加剧的负面效应。我们在27代传代过程中，于黑腹果蝇（Drosophila melanogaster）中累积了具有生命早期效应的突变，并比较其对生命早、晚期繁殖力的相对影响。相较于对照组，本研究中的突变积累品系的早期繁殖力平均显著降低。这类效应在整个生命周期中均持续存在，但并未随年龄增长而进一步增强。综上，本研究结果表明，绝大多数自发突变并不会促进损伤累积与衰老进程。