Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, VA 22903, USA.
Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, VA 22903, USA; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA 22903, USA.
Curr Biol. 2023 Mar 27;33(6):1036-1046.e6. doi: 10.1016/j.cub.2023.01.059. Epub 2023 Feb 17.
Several molecules can extend healthspan and lifespan across organisms. However, most are upstream signaling hubs or transcription factors orchestrating complex anti-aging programs. Therefore, these molecules point to but do not reveal the fundamental mechanisms driving longevity. Instead, downstream effectors that are necessary and sufficient to promote longevity across conditions or organisms may reveal the fundamental anti-aging drivers. Toward this goal, we searched for effectors acting downstream of the transcription factor EB (TFEB), known as HLH-30 in C. elegans, because TFEB/HLH-30 is necessary across anti-aging interventions and its overexpression is sufficient to extend C. elegans lifespan and reduce biomarkers of aging in mammals including humans. As a result, we present an alcohol-dehydrogenase-mediated anti-aging response (AMAR) that is essential for C. elegans longevity driven by HLH-30 overexpression, caloric restriction, mTOR inhibition, and insulin-signaling deficiency. The sole overexpression of ADH-1 is sufficient to activate AMAR, which extends healthspan and lifespan by reducing the levels of glycerol-an age-associated and aging-promoting alcohol. Adh1 overexpression is also sufficient to promote longevity in yeast, and adh-1 orthologs are induced in calorically restricted mice and humans, hinting at ADH-1 acting as an anti-aging effector across phyla.
有几种分子可以延长生物的健康寿命和寿命。然而，大多数是上游信号枢纽或转录因子，协调复杂的抗衰老程序。因此，这些分子指出了但没有揭示驱动长寿的基本机制。相反，在不同条件或生物体中促进长寿所必需和充分的下游效应物可能揭示基本的抗衰老驱动因素。为此，我们寻找了转录因子 EB（TFEB）下游的效应物，在秀丽隐杆线虫中称为 HLH-30，因为 TFEB/HLH-30 在抗衰老干预中是必需的，其过表达足以延长秀丽隐杆线虫的寿命并减少哺乳动物（包括人类）的衰老生物标志物。结果，我们提出了一种由 HLH-30 过表达、热量限制、mTOR 抑制和胰岛素信号缺陷驱动的线虫长寿所必需的酒精脱氢酶介导的抗衰老反应（AMAR）。ADH-1 的单一过表达足以激活 AMAR，通过降低甘油水平来延长健康寿命和寿命——甘油是一种与年龄相关的促进衰老的酒精。Adh1 过表达也足以促进酵母的长寿，并且在热量限制的小鼠和人类中诱导了 adh-1 同源物，暗示 ADH-1 在跨门进化中作为一种抗衰老效应物发挥作用。
