Thread by @mkaeberlein

For those who want to get beyond the pop-sci diet guru analysis, here’s a little deeper dive on this recent time restricted feeding paper in @nature

nature.com/articles/s4158…

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Strongly encourage you to *read the paper* and reach your own conclusions. As always, I welcome feedback if you think I got something wrong, but here’s what I took away:

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In fruit flies:

Time restricted feeding (TRF, 12h:12h) did not reproducibly extend lifespan

Intermittent fasting (24h:24-48h) ***shortened lifespan***

A TRF protocol (iTRF, 20h:28h) that induced autophagy at just the right time extended lifespan by ~15%

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The pop-sci diet gurus will tell you this paper supports the idea that time restricted feeding (TRF) and intermittent fasting (IF) slow aging without needing to eat less. No. If you accept this paper at face value, IF shortens lifespan and TRF usually does nothing…

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… unless you shift the day/night cycle just right so that TRF induces autophagy during the night. I’ve discussed before why we should not recommend dietary interventions from lab animals to the general public:

https://twitter.com/mkaeberlein/status/1439638604293160963

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This is another good example of the risk of extrapolating from dietary interventions with poorly understood mechanisms of action. You get it wrong, and there’s a good chance there’s no benefit or it’s harmful

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The diet regimen that increased lifespan reproducibly was something they called iTRF, which is a cyclic 20 hour fasting followed by 28 hour feeding protocol that the authors found by “trial and error” (direct quote - again read the paper).

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Oddly, iTRF only extended lifespan between d10 and d40. “maintaining this diet through old age did not extend lifespan” (direct quote – again read the paper)

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Ok, so IMO the cool nuggets here are (esp #3):

(1)iTRF caused circadian regulation of autophagy during the dark
(2)TRF during the day failed to increase lifespan
(3)circadian induction of autophagy during the dark is sufficient to increase lifespan

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But, keep in mind the effect size was only ~15%. Not sure how excited I can get about a 15% lifespan extension in fruit flies. (They called it “robust” in the abstract 🤦‍♂️) Still, the biology here is cool

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My interpretation is that, at least in fruit flies, a small part of the effect of caloric restriction is likely due to induction of autophagy during the dark cycle, which is regulated by the circadian machinery

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When you due this through true CR, you (apparently) don’t have to worry about the circadian cycle and you get a big benefit. But if you want the (small) benefit from TRF, you better get the timing just right or you get zilch

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Next question is whether this is true in mammals. If so, it suggests some interesting experiments. For example, would rapamycin in the evening be more effective than rapamycin in the morning?

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So, if you want to do TRF based on this paper - you do you. Just be sure to boost your autophagy only during the human equivalent of the fly dark cycle and only during the human equivalent of d10-d40 of fly adulthood

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