Circadian autophagy drives iTRF-mediated longevity

Time-restricted feeding (TRF) has recently gained interest as a potential anti-ageing treatment for organisms from Drosophila to humans 1 – 5 . TRF restricts food intake to specific hours of the day. Because TRF controls the timing of feeding, rather than nutrient or caloric content, TRF has been...

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Published in:	Nature (London) Vol. 598; no. 7880; pp. 353 - 358
Main Authors:	Ulgherait, Matt, Midoun, Adil M., Park, Scarlet J., Gatto, Jared A., Tener, Samantha J., Siewert, Julia, Klickstein, Naomi, Canman, Julie C., Ja, William W., Shirasu-Hiza, Mimi
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 14-10-2021 Nature Publishing Group
Subjects:	14/1 14/19 14/35 38/89 631/443/319 631/443/7 64/24 82/1 82/29 82/51 82/80 Aging Aging - genetics Aging - radiation effects Animals Autophagy Autophagy (Cytology) Autophagy - genetics Autophagy - physiology Biomarkers Circadian Clocks - radiation effects Circadian rhythm Circadian Rhythm - genetics Circadian Rhythm - physiology Circadian Rhythm - radiation effects Circadian rhythms Climbing Darkness Diet Drosophila Drosophila melanogaster - genetics Drosophila melanogaster - physiology Drosophila melanogaster - radiation effects Feeding Behavior - physiology Feeding Behavior - radiation effects Female Food Food intake Fruit flies Gene expression Health aspects Humanities and Social Sciences Insects Insulin Life span Longevity Longevity - genetics Longevity - physiology Longevity - radiation effects Male Markers Methods Microorganisms Molecular modelling multidisciplinary Muscles Nutrient content Phagocytosis Physiological aspects Proteins Science Science (multidisciplinary) Time Factors Transcription United States
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Summary:	Time-restricted feeding (TRF) has recently gained interest as a potential anti-ageing treatment for organisms from Drosophila to humans 1 – 5 . TRF restricts food intake to specific hours of the day. Because TRF controls the timing of feeding, rather than nutrient or caloric content, TRF has been hypothesized to depend on circadian-regulated functions; the underlying molecular mechanisms of its effects remain unclear. Here, to exploit the genetic tools and well-characterized ageing markers of Drosophila , we developed an intermittent TRF (iTRF) dietary regimen that robustly extended fly lifespan and delayed the onset of ageing markers in the muscles and gut. We found that iTRF enhanced circadian-regulated transcription and that iTRF-mediated lifespan extension required both circadian regulation and autophagy, a conserved longevity pathway. Night-specific induction of autophagy was both necessary and sufficient to extend lifespan on an ad libitum diet and also prevented further iTRF-mediated lifespan extension. By contrast, day-specific induction of autophagy did not extend lifespan. Thus, these results identify circadian-regulated autophagy as a critical contributor to iTRF-mediated health benefits in Drosophila . Because both circadian regulation and autophagy are highly conserved processes in human ageing, this work highlights the possibility that behavioural or pharmaceutical interventions that stimulate circadian-regulated autophagy might provide people with similar health benefits, such as delayed ageing and lifespan extension. Circadian-regulated autophagy contributes to the health benefits of intermittent time-restricted feeding in Drosophila .
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: MU and MSH conceived of the experiments. Experiments were performed and analyzed by: MU (all); AMM (lifespan experiments); SJP, WWJ (feeding analysis); JG (western blots and lifespan experiments); SJT (qRT-PCR and lifespan experiments); JS (lifespan experiments); NK (biochemical and imaging experiments, western blots). MU, JCC, and MSH made intellectual contributions, designed the figures, and wrote the manuscript.
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-021-03934-0