Caloric restriction (CR) activates autophagy. Intermittent fasting (IF) is basically kind-of-like the opposite of CR. I’m not knocking IF. The animal studies of autophagy, based on “chronic nutrition depletion,” more accurately reflect CR which results in decreased body weight or metabolic rate. IF generally includes refeeds, resulting in weight maintenance. Also, in the few human studies on it, weight loss (CR) but not fasting (IF) has been shown to induce autophagy.
If you’re actually losing weight over the long-term with an IF protocol, and thus are CR by definition, then I suspect you may be autophaging, too (yeah yeah, I know, that’s not really how autophagy works, but you get the picture).
Disclaimer: I’m relatively autophagy-agnostic; not really confident racing to maximize it is a great thing based on Human Studies.
Exhibit A: autophagy in skeletal muscle
Tl;dr: “a little exercise is a better than a lot of fasting”
A1) Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle (Moller et al., 2015)
The protocol: participants either fasted for 36 hours or received a glucose infusion before and during exercise (cycling at 50% max for an hour).
“In the present study, we demonstrate that short-term aerobic exercise activates autophagic signaling through ULK1 in human skeletal muscle, independently of nutrient background.”
They really should’ve stressed that the deck was stacked to show fasting activated autophagy… 36 hours of fasting is pretty long but it had no effect.
A2) Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation (Schwalm et al., 2015)
Protocol: shorter fast (overnight), but longer exercise – 2 hours at 55% or 70% max.
“In summary, the most effective strategy to activate autophagy in human skeletal muscle seems to rely on exercise intensity more than diet.”
Higher intensity = more autophagy, but again: no effect of fasting.
A3) more support for long-term CR (as opposed to IF) (Yang et al., 2016)
30% CR for 3-15 years!
“The CR individuals consumed a diet with a high nutrient-to-energy ratio, which supplied more than 100% of the recommended daily intake for all essential nutrients. All processed foods, rich in refined carbohydrates, free sugars, and partially hydrogenated oils, were strictly avoided by the CR practitioners.” A+!
“We found that CR significantly upregulated many autophagy genes, including ULK1, ATG101, beclin-1, APG12, microtubule-associated protein 1 light chain 3 (LC3), GAPRAP/GATE-16, and autophagin-1. Consistent with some of these gene expression changes, we found that beclin-1 and LC3 protein expression levels were significantly higher in the skeletal muscle of the CR volunteers than in the WD control subjects.”
Exhibit B: autophagy in adipose tissue (where elevated autophagy is theoretically no bueno)
Defective regulation of adipose tissue autophagy in obesity (Nunez et al., 2013)
Protocol: obese humans before and 1 year after bariatric surgery.
“human obesity was associated with increased autophagy, and body mass reduction led to an attenuation of autophagy in the adipose tissue.”
*Of note, bariatric surgery-induced weight loss is more similar to CR than IF; these patients eat frequent, small meals. In fact, IF may even be detrimental to autophagy in this #context. You may experience a slight increase in autophagy during early IF (not supported by evidence, but let’s just say theoretically for now), but when you compensate for the caloric deficit via refeeding, any theoretical benefits may be reversed. Again, I’m not knocking IF.
However, to be clear, I still don’t think the calorie bombs experienced by people eating 1 meal per day or restricting food intake to a small window are very healthy. There is some evidence showing all your calories in the morning are beneficial… but this was compared to all your calories in the evening, not 3 regularly-spaced meals (eg, see studies by Jacobs & Hirsch).
I don’t advocate grazing (eg, 6 meals per day) because chronic calorie influx or IF because re-feed calorie bombs (among other things)… I mean, neither method seems particularly friendly to any tissues or organs involved in metabolism and nutrient partitioning… regardless of whether you’re keto, LCHF, #carbthefuckup, or whatever.
Exhibit C: autophagy in liver
No nutritional studies on liver autophagy in humans; however, it might be regulated similar to muscle as it seems to move similarly in both tissues in diseases states (eg, Vanhorebeek et al., 2011 & Vescovo et al., 2012).
Exhibit D: autophagy in brain
No human studies on this, although CR has inconsistent effects on autophagy in mouse brain (eg, Mizushima et al., 2014, Alirezaei et al., 2010, & Kaushik et al., 2012). And exercise activates autophagy in mice similar to humans, at least according to this study (He et al., 2012), so it may activate autophagy in human brain as well… although I wouldn’t assume anything about autophagy in human brain at this point.
Conclusion: studies showing beneficial effects of autophagy are primarily animal studies. Human studies are correlative at this point. That said, if you want moar autophagy, best bet is CR and/or exercise. Maybe not so much with IF. Please don’t hate me for this.