The Benefits of Calorie Restriction Most Likely Largely Result from Increased Autophagy
Calorie restriction slows aging in near all species and lineages tested to date, though its effects on life span are much larger in short-lived species than in long-lived species such as our own. While calorie restriction produces sweeping changes in near every aspect of metabolism, making it a challenging intervention to analyze, the present consensus is that the bulk of its benefits arise due to an increased operation of the cellular maintenance processes of autophagy. A more efficient clearance of damaged and otherwise unwanted proteins and structures in cells should in principle lead to improved cellular operation and tissue function, and a reduction in downstream consequences of cell damage. Since numerous other means of slowing aging in animal models also exhibit increased autophagy, this seems a reasonable working hypothesis.
Calorie restriction (CR) has been shown to be an established life-extension method regulating age-related diseases as well as aging itself. Although different in methodology (usually 20%-40% less than ad libitum intake, a 40% reduction in most cases), CR showed a prolonged lifespan in a wide range of species from yeast to non-human primates, and supports healthy human aging. Furthermore, CR exerts preventive effects on various age-related conditions such as cancer, neurodegenerative diseases, cardiovascular, and other metabolic diseases. The diverse efficacy of CR in counteracting aging and age-related diseases has made it the golden standard of aging intervention studies.
Although the anti-aging effects of CR are reproducible, the exact mechanisms of how CR exerts its anti-aging effects are debatable, because CR regulates several different aspects of physiology. These changes include modifications in the energy-sensing signaling, oxidative stress, inflammation, and other intercellular and intracellular processes. Among the many changes induced by CR, energy production and utilization is the most directly regulated signaling exerted by CR. Since reduced energy intake and changes in nutritional status following CR may change the molecular signaling pathways associated with energy-sensing mechanisms, other mechanisms may be secondary effects to this process.
Based on the induction mechanism of autophagy and its role during starvation, it was predicted that CR might induce the autophagic process. Indeed, under many different settings of nutrient deprivation conditions, including in CR, autophagy is induced to regulate the organism's homeostasis. Although it is clear that CR represents a strong physiologically autophagic inducer, it is uncertain whether autophagy contributes to the anti-aging effects of CR. Recently, several studies have shown that autophagy induction was essential for the anti-aging effects of CR. CR was shown to promote longevity or protect from hypoxia through a Sirtuin-1-dependent autophagy induction process. Another study also showed that life extension through methionine restriction required autophagy activation. Growing evidence supports the notion that autophagy has a substantial role in the beneficial effects of CR. In addition to research on longevity, other studies have shown that CR robustly induces autophagy under various physiological and pathological conditions, and that it has a protective effect in the maintenance of normal functions in the organism.
This analysis is based upon a specific regime of calorie restriction. I'll make a prediction: When future studies look at water fasting lasting >2 days, it will be the immune system re-boot and release of stem cells that provide more benefits than autophagy.
Hasn't calorie restriction been debunked by now? Yet, it always remains a "hot" topic.
In other news:
Anti-Aging Drug Rejuvenates Oral Health
https://www.leafscience.org/anti-aging-drug-rejuvenates-oral-health/
"Scientists have developed a new gene-therapy technique by transforming human cells into mass producers of tiny nano-sized particles full of genetic material that has the potential to reverse disease processes."
https://www.sciencedaily.com/releases/2019/12/191216173700.htm
@Tom Schaefer
Fasting (water or even dry) is a complex process with many things going on. The fasting body has to "eat" its own stores. So it is very close to the definition of autophagy. On a whole-body level. That's why it is quite plausible that fasting enhances the autophagy processes.
Now do the improvements in the the immune system and stem cells come from an improved autophagy or depend on something is not so clear. However, it seems that calorie restriction pathways help. Hence, rapamycin and metformin are so effective.
For me , personally, I see no special effects for water fasts less than 4 days, except the weight loss and lack of energy. Due to the lack of energy I have very good sleep, though :)