Circadian autophagy drives iTRF-mediated longevity

Matt Ulgherait, Adil M. Midoun, Scarlet J. Park, Jared A. Gatto, Samantha J. Tener, Julia Siewert, Naomi Klickstein, Julie C. Canman, William W. Ja and Mimi Shirasu-Hiza ()
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Matt Ulgherait: Columbia University Vagelos College of Physicians and Surgeons
Adil M. Midoun: PSL Research University
Scarlet J. Park: The Scripps Research Institute
Jared A. Gatto: Columbia University Vagelos College of Physicians and Surgeons
Samantha J. Tener: Columbia University Vagelos College of Physicians and Surgeons
Julia Siewert: Columbia University Vagelos College of Physicians and Surgeons
Naomi Klickstein: Columbia University
Julie C. Canman: Columbia University Vagelos College of Physicians and Surgeons
William W. Ja: The Scripps Research Institute
Mimi Shirasu-Hiza: Columbia University Vagelos College of Physicians and Surgeons

Nature, 2021, vol. 598, issue 7880, 353-358

Abstract: Abstract Time-restricted feeding (TRF) has recently gained interest as a potential anti-ageing treatment for organisms from Drosophila to humans1–5. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03934-0

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