Abstract
Medawar's mutation accumulation hypothesis explains aging by the declining force of natural selection with age: Slightly deleterious germline mutations expressed in old age can drift to fixation and thereby lead to aging‐related phenotypes. Although widely cited, empirical evidence for this hypothesis has remained limited. Here, we test one of its predictions that genes relatively highly expressed in old adults should be under weaker purifying selection than genes relatively highly expressed in young adults. Combining 66 transcriptome datasets (including 16 tissues from five mammalian species) with sequence conservation estimates across mammals, here we report that the overall conservation level of expressed genes is lower at old age compared to young adulthood. This age‐related decrease in transcriptome conservation (ADICT) is systematically observed in diverse mammalian tissues, including the brain, liver, lung, and artery, but not in others, most notably in the muscle and heart. Where observed, ADICT is driven partly by poorly conserved genes being up‐regulated during aging. In general, the more often a gene is found up‐regulated with age among tissues and species, the lower its evolutionary conservation. Poorly conserved and up‐regulated genes have overlapping functional properties that include responses to age‐associated tissue damage, such as apoptosis and inflammation. Meanwhile, these genes do not appear to be under positive selection. Hence, genes contributing to old age phenotypes are found to harbor an excess of slightly deleterious alleles, at least in certain tissues. This supports the notion that genetic drift shapes aging in multicellular organisms, consistent with Medawar's mutation accumulation hypothesis.
Highlights
To date, more than 300 hypotheses have been postulated to explain senescence, that is, age‐related loss of function and in‐ crease in mortality rates (Medvedev, 1990)
We studied the mutational load in multiple tissues, considering the possibil‐ ity that age‐dependent germline mutational load may vary among tissues, depending on tissue‐specific developmental patterns, mi‐ totic capacity, damage accumulation, and consequences for organ‐ ism‐level fitness
Across all datasets we studied, the frequency a gene was up‐regulated during aging in‐ versely predicted its evolutionary conservation
Summary
More than 300 hypotheses have been postulated to explain senescence, that is, age‐related loss of function and in‐ crease in mortality rates (Medvedev, 1990). To test whether one or both of these scenarios underlie ADICT, we compared the mean conservation metric among (a) genes up‐reg‐ ulated with age (ρEA > 0.1, q < 0.1) and (b) genes down‐regulated with age (ρEA < −0.1, q < 0.1), using (c) genes that show no age‐ related changes in expression level as a control We repeated this analysis across the 25 brain, liver, lung, and artery datasets showing the ADICT signature at q < 0.10, and using −ω0* as the conservation metric. If age‐related up‐regulation is a general indicator of poor sequence conservation for a gene, the more tissues or the more species in which a gene shows age‐related up‐regulation, the less conserved it might be To test this idea, we selected genes shared across the 25 ADICT datasets (in brain, liver, lung, and artery) and counted how many times each gene was up‐regulated with age. This again revealed a heterogeneous trend toward ADICT across tissues, with consistent ADICT trends in brain, liver, and lung (Figures S5 and S6)
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