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Post-transcriptional characterization of the vertebrate aging brain sheds light on the origin of protein-transcript decoupling

ABSTRACT: Aging is associated with impaired proteostasis and reduced correlation between protein and mRNA levels. The mechanisms underlying such age-dependent alterations remain unclear. Here, we used the short-lived killifish Nothobranchius furzeri to define how aging affects the transcriptome, translatome and proteome of the vertebrate brain. Integrating these analyses with protein subcellular localization, solubility, and posttranslational modifications data we uncover that basic proteins, including ribosomal and RNA-binding proteins, progressively decrease with age. In contrast, abundant and long-lived proteins, including components of the mitochondrial respiratory chain, increase or remain stable despite a decrease in their mRNA levels. Chronic proteasome inhibition can induce some aging signatures in vivo, but it does not recapitulate the age-related protein-transcript decoupling. Instead, we find increased ribosome pausing in the aging brain reprograms the translation landscape accounting for age-dependent proteome alterations independent of transcription. These changes in protein biogenesis likely reduce availability of key protein complexes in older brains.

ORGANISM(S): Nothobranchius furzeri

PROVIDER: GSE236685 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:In many vertebrate species, age at maturity is proportional to organismal lifespan. A number of theories have attempted to provide a conceptual framework for this fascinating apparent co-evolution. The ‘disposable soma’ theory predicts that costly resources that are invested in germline preservation come at the expense of repairing age-related somatic damage. On the other hand, classical experiments in C. elegans have reported that germline ablation promotes longevity via endocrine signals mediated by the somatic gonad. However, how these seemingly opposing mechanisms may affect vertebrate aging is largely unknown. Here, we use the naturally short-lived turquoise killifish (N. furzeri) to demonstrate that germline ablation can enhance damage repair and promote vertebrate longevity. This was achieved by producing a detailed single-cell atlas of the killifish ovary and testis, and generating a panel of genetic perturbations to manipulate the killifish reproductive state. Specifically, we either block costly stages of germline differentiation by mutating gonadotropins and their receptors, or alternatively, ablate the germline altogether by mutating the dnd1 gene (dead end). Interestingly, only germline ablation enhances somatic repair, particularly in females, by improving tail regeneration following genotoxic stress. To investigate the observed sexual dimorphism, we directly compare several somatic cell types from WT and dnd1 fish. We identify a surprising male-specific upregulation of pro-longevity pathways, including protein homeostasis and stress resistance. Accordingly, only germline-depleted males experience a significant extension in maximal lifespan. Together, dissecting distinct paradigms of germline manipulations, reveals a functional link between the reproductive state, damage repair, and longevity. The sex-specific effect further supports the concept that phenotypes are independent of resource allocation, and instead, could be the result of a possible endocrine effect. Our findings may therefore have exciting implications for uncoupling the reproductive state from vertebrate aging.

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Post-transcriptional characterization of the vertebrate aging brain sheds light on the origin of protein-transcript decoupling

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