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The germline regulates longevity and somatic repair in a sex-specific manner (RNA-Seq)

ABSTRACT: Classical evolutionary theories propose tradeoffs between reproduction, damage repair, and lifespan. However, the specific role of the germline in shaping vertebrate aging remains largely unknown. Here, we use the turquoise killifish (N. furzeri) to genetically arrest germline differentiation at discrete stages, and examine how different ‘flavors’ of infertility impact life-history. We first constructed a comprehensive single-cell gonadal atlas, providing cell-type-specific markers for downstream phenotypic analysis. Next, investigating our genetic models revealed that only germline ablation enhanced female damage repair, while arresting germline differentiation did not. Conversely, germline-ablated males were significantly long-lived, indicating that the mere presence of the germline can negatively affect lifespan. Transcriptomic analysis highlighted enrichment of pro-longevity pathways and genes, with functional conservation in germline-ablated C. elegans. Finally, germline depletion extended male healthspan through rejuvenated metabolic functions. Our results suggest that different germline manipulation paradigms can yield pronounced sexually dimorphic phenotypes, implying alternative mechanisms to classical evolutionary tradeoffs.

ORGANISM(S): Nothobranchius furzeri

PROVIDER: GSE248739 | GEO | 2024/03/06

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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The germline regulates longevity and somatic repair in a sex-specific manner (RNA-Seq)

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