Early-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling

Authors: HARPER, KIM - University Of Alabama At Birmingham; PARKER, DANITA - University Of Alabama At Birmingham; HARDIMAN, MADISON - University Of Alabama At Birmingham; MUNKACSY, ERIN - University Of Texas At San Antonio; JIANG, NISI - University Of Texas At San Antonio; ROGERS, ARIC - Mdi Biological Laboratory; BAI, YIDONG - University Of Texas At San Antonio; Brent, Colin; MOBLEY, JAMES - University Of Alabama At Birmingham; AUSTAD, STEVEN - University Of Alabama At Birmingham; PICKERING, ANDREW - University Of Alabama At Birmingham

Submitted to: Nature Communications
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/1/2023
Publication Date: 8/18/2023
Citation: Harper, K., Parker, D., Hardiman, M., Munkacsy, E., Jiang, N., Rogers, A.N., Bai, Y., Brent, C.S., Mobley, J., Austad, S., Pickering, A. 2023. Early-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling. Nature Communications. 14: Article 5021. https://doi.org/10.1038/s41467-023-40618-x.
DOI: https://doi.org/10.1038/s41467-023-40618-x

Interpretive Summary: Protein translation (PT) declines with age in invertebrates, rodents, and humans. This decline in PT has been assumed to be a passive byproduct of aging. However, inhibition of PT has repeatedly been shown to retard aging, extend lifespan, and lessening the severity of age-related diseases. This unresolved “protein synthesis paradox” has imposed a barrier to fully understand how PT regulates aging. Accordingly, we modified PT at various life stages in Drosophila. We find that a short spike in PT during early-adulthood has a long-lasting negative impact on aging and health in later-life. Blocking this PT spike improved fly health and lifespan, whereas inducing the early-life PT spike in long-lived fly strains reduces their longevity. During the early-life PT rise, an increase in juvenile hormone drives aging by causing proteins to aggregate. Our findings suggest that PT is adaptively suppressed after early-adulthood to retard aging. Our work resolves the paradox and provides a novel theoretical framework for understanding how lifetime PT dynamics regulate the onset of aging.

Technical Abstract: Protein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related functional decline via juvenile hormone-lipid transfer protein axis and germline signaling. Our findings suggest that PT is adaptively suppressed after early-adulthood, alleviating later-life proteostatic burden, slowing down age-related functional decline, and improving lifespan. Our work provides a theoretical framework for understanding how lifetime PT dynamics shape future aging trajectories.