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Increased alcohol dehydrogenase 1 activity promotes longevity
Abbas Ghaddar1, Vinod K Mony1, Swarup Mishra2
1Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, VA 22903, USA.
Abstract:
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.
Insights
Scientists identified a key downstream effector, alcohol dehydrogenase (ADH-1), that drives longevity across species. Overexpressing ADH-1 extends healthspan and lifespan by reducing aging-promoting glycerol levels.
Area of Science:
- Aging research
- Molecular biology
- Genetics
Background:
- Most longevity-promoting molecules are upstream regulators, obscuring fundamental aging mechanisms.
- Transcription factor EB (TFEB)/HLH-30 is crucial for longevity interventions and extends lifespan when overexpressed.
Purpose of the Study:
- To identify downstream effectors of TFEB/HLH-30 that are necessary and sufficient for promoting longevity.
- To elucidate fundamental anti-aging mechanisms by focusing on downstream effectors.
Main Methods:
- Investigated effectors downstream of TFEB/HLH-30 in C. elegans.
- Assessed the role of alcohol dehydrogenase (ADH-1) and its mediated anti-aging response (AMAR).
- Examined ADH-1's effect on glycerol levels and longevity in C. elegans, yeast, and conserved across species.
Main Results:
- Identified the alcohol-dehydrogenase-mediated anti-aging response (AMAR) as essential for longevity induced by HLH-30 overexpression, caloric restriction, mTOR inhibition, and insulin-signaling deficiency.
- Sole overexpression of ADH-1 is sufficient to activate AMAR, extend healthspan and lifespan, and reduce glycerol levels.
- ADH-1 overexpression promotes longevity in yeast, and its orthologs are induced in calorically restricted mice and humans.
Conclusions:
- ADH-1 acts as a conserved downstream effector driving longevity across phyla.
- Reducing glycerol, an aging-promoting alcohol, via ADH-1 is a fundamental anti-aging mechanism.
- The AMAR pathway highlights a key effector for extending healthspan and lifespan.
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