Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
Nat Commun. 2023 Aug 18;14(1):5021. doi: 10.1038/s41467-023-40618-x.
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.
蛋白质翻译（PT）在无脊椎动物、啮齿动物和人类中随年龄增长而下降。人们认为年轻时升高的 PT 对健康有益，而 PT 最终会随着衰老的被动副产物而下降。在果蝇中，我们发现成年早期 PT 的短暂升高对晚年的衰老轨迹和蛋白质稳态产生持久的负面影响。阻断生命早期的 PT 升高可显著延长寿命/健康跨度并预防与年龄相关的蛋白质聚集，而在长寿的果蝇品系中短暂诱导生命早期的 PT 激增则会消除它们的长寿/蛋白质稳态益处。生命早期的 PT 升高会引发蛋白质稳态功能障碍，沉默应激反应，并通过保幼激素-脂质转移蛋白轴和生殖系信号驱动与年龄相关的功能下降。我们的研究结果表明，PT 在成年早期后会被适应性抑制，从而减轻晚年的蛋白质稳态负担，减缓与年龄相关的功能下降，提高寿命。我们的工作为理解终生 PT 动态如何塑造未来的衰老轨迹提供了理论框架。
