Intermittent fasting and Cellular Autophagy

Various dietary strategies have been described as having health benefits. These include the Mediterranean Diet, Dietary Approaches to Stop Hypertension (DASH), calorie restriction diets, and fasting. Several fasting regimens have become popular due to their purported positive effects on health. Fasting for 24 hours once or twice per week, the “5:2 diet,” wherein caloric intake is limited to 500-600 calories per day twice a week, and the “16/8 method,” in which eating is limited to 8 hours per day, with 16 hours of fasting. These strategies can be called “Intermittent Fasting (IF).” The mechanisms by which IF approaches slow the aging process have been the subject of an increasing number of scientific studies in the past decade.

One of the key receptors involved in aging is the mammalian target of Rapamycin, or mTOR. Rapamycin exerts its anti-aging benefits by down-regulating or reducing the activity of the mTOR receptor. Reducing mTOR activity diverts cellular resources from non-essential anabolic to catabolic processes. In other words, mTOR suppression switches the machinery inside our cells from building and growing to breaking down and recycling damaged parts or “cleaning up” junk and debris. It is well known that when damaged or “senescent” mitochondria, for example, hang around inside cells, they cause inflammation. IF causes depression of mTOR and increases autophagy.

Another key molecule in the aging process is 5’ adenosine monophosphate-activated protein kinase (AMPK). AMPK promotes autophagy by inhibiting mTOR and activating autophagy enzymes directly. AMPK also increases Sirtuin 1, an enzyme that activates autophagy. Aging leads to a reduction in AMPK activity – IF may be especially healthy in the elderly due to its effect on increasing AMPK activity.

A third regulator of mTOR activity is the growth hormone/insulin-like growth factor-1 (IGF-1) signaling pathway. Intermittent fasting reduces IGF-1 signaling, leading to mTOR inhibition and subsequent activation of autophagy. 

The interplay of these molecular mechanisms is shown below.

It is important to maintain appropriate caloric balance to avoid undesired weight loss, especially in this population.

Note: Although I am a physician, the content in this article is not meant to diagnose, treat, cure or prevent illness or disease in the reader – it is for educational purposes only.

References

1. Ozcan M, Abdellatif M, Javaheri A, Sedej S. Risks and benefits of intermittent fasting for the aging cardiovascular system. Cn J Cardiol 2024;40:1445-57.
2. Holczer M, Hajdú B, L}orincz T, Szarka A, Bánhegyi G, Kapuy O. Finetuning of AMPK-ULK1-mTORC1 regulatory triangle is crucial for autophagy oscillation. Sci Rep 2020;10:17803.
3. Turdi S, Fan X, Li J, et al. AMP-activated protein kinase deficiency exacerbates aging-induced myocardial contractile dysfunction. Aging Cell 2010;9:592-606.