How to Slow Aging: Periodic Fasting, Estrogen, and Autophagy – Part 2

By: Michael Lam, MD, MPH; Justin Lam, ABAAHP, FMNM; Carrie Lam, MD


Read Part 1 | Part 3

Autophagy: Fasting for Cell Regeneration

What is autophagy? Basically, it’s the process in which your body disposes of dead or deteriorating cells, changing them into enzymes that can then be used by your body to develop proteins. Literally, autophagy means “self-eating.” Your body consumes itself on a regular basis through this process. Periodic fasting increases autophagy.

And that’s a good thing. Because that’s the way your body regenerates itself over and over.

Autophagy increases during times of cellular stress. This kind of stress occurs when there is a lack of nutrients or growth factors. During fasting, not only is there stress, but also a lack of nutrients. Therefore, fasting is beneficial for increasing autophagy and the renewing of your body’s cells.

Autophagy is also the process of cleaning up unneeded parts of cells that sometimes evolve into pre-cancer cells. So, autophagy also protects your body from potential cancer development.

It also enables cells to withstand stress from either external or internalThere are four main processes that increase autophagy. Fasting is a major one. Ketosis and exercise turn on autophagy. Stress, acute stress, improves autophagy.

The mechanism whereby autophagy is increased through fasting is by inhibiting the mechanism to turn autophagy off.

The cellular pathways that inhibit autophagy are themselves inhibited through periodic fasting. These inhibited pathways include mTOR, AKT, and others. All of these pathways can lead to cancer. Fasting also increases another pathway, AMPK, that then blocks mTOR and some of the other pathways.

Research seems to indicate some of the pathways that inhibit autophagy also are key in forming and enabling the progression of tumors. Currently, some medications used to deal with tumors target these pathways. If the pathways can be significantly reduced, blocked, or even eliminated naturally before tumors form, that would be a much better approach to remediating cancers.

Research indicates restricting calories as much as 20% to 40% affects these pathways. This approach activates some pathways that increase longevity and decreases chronic illness conditions. Periodic fasting does the same thing and is generally easier to accomplish. Most people can handle short-term fasting for anywhere from 12 to 24 hours or slightly more.

Stem Cell Regeneration Renews the Immune System

One of the more promising areas of research into autophagy, its health benefits, and aging has to do with stem cells. In your body, there are stem cells that are dormant. These stem cells can be triggered to transform themselves into any kind of cell in your body.

Research has now shown that periodic fasting can be the trigger for these stem cells to regenerate themselves from their dormant state. The study focused on regenerating stem cells to renew the immune system in cases where chemotherapy has been used.

In this research, subjects (both mice and stage 1 human subjects) showed a significant decrease in white blood cell counts when undergoing fasting regimens. This periodic fasting also brought a change in the mice’s signaling pathways for hematopoietic stem cells, tasked with generating blood and immune cells.

In humans, the immune system declines in effectiveness as you age. This makes you more likely to develop illnesses, both acute and chronic. The research connecting periodic fasting and regeneration of immune cells helps healthcare professionals understand better how to deal with the side effects of chemotherapy and how to remediate those chronic conditions so often experienced by people as they age.

Periodic fasting and healthy foodsPeriodic fasting, no more than two to four days at one time over a period of six months, appears to trigger the process of autophagy to kill damaged and older immune system cells and to trigger dormant stem cells to alter themselves into new immune system cells.

The process appears to be relatively simple overall. When you stop consuming food for the time of fasting, your body attempts to conserve energy. One way it does this is to recycle and renew old and damaged immune cells. Researchers also noticed a decrease in white blood cells while fasting, with an increase once the subjects started feeding again.

The mechanism involved here is the periodic fasting causes your body to burn up its stores of fat, ketones, and glucose as well as breaking down a large portion of white blood cells. The destruction of the white blood cells then triggers dormant stem cells to regenerate themselves as immune system cells.

Researchers found these periods of fasting over several days decreased levels of an enzyme, PKA. This appears to result in increased lifespan in simple organisms and plays a role in the process of stem cell self-renewal and pluripotency. This latter process is the ability of cells to develop into many other kinds of cells. Decreased levels of IGF-1, a growth-factor hormone connected to tumor growth, risk of cancer, and aging, also were seen in fasting.

Lowering the levels of PKA seems to allow the dormant stem cells to begin the process of regeneration into immune system cells. By getting the old and damaged immune cells out of the body through the process of autophagy brought on by periodic fasting, then regenerating new immune cells from dormant stem cells, you basically have a completely new, better functioning immune system following significant periods of fasting.

Another study showed fasting for 72 hours prior to chemotherapy also protected subjects’ bodies from the effects of toxicity. This kind of toxicity is a major side effect of chemotherapy, resulting in damage to the immune system. Periodic fasting of this kind appears to mitigate the effects of this toxicity.

This kind of research suggests periodic fasting for prolonged periods of time may have benefits in other organ systems as well.

Autophagy and Aging

In addition to its role of helping your body rid itself of damaged or dead cells or parts of cells, autophagy plays another important role as well. It slows down the aging process. In fact, research has shown when autophagy is inhibited, organisms age more rapidly.

There is significantly stronger research evidence showing the link between autophagy and increased longevity than any other anti-aging intervention. This includes supplementation with anti-oxidants, hormone replacement, activating telomeres, anti-inflammatory interventions, supplementing with micronutrients, or stem cell therapy.

Decreased Autophagy and Increased Aging

The connection between decreased autophagy and increased signs of aging has been studied for a long time in liver cells. Undigested material internal to these cells is shown by the presence of the protein lipofuscin, a biomarker of declining autophagy. Other biomarkers that indicate lowered autophagy include Lewy bodies that are seen in some neurodegenerative conditions such as Parkinson’s. These Lewy bodies appear to signal declining mitophagy. This condition is most important in the brain, heart, and skeletal muscle where less regeneration occurs through stem cells. In other areas of the body such as the GI tract, skin, and bone marrow, the process of autophagy isn’t as important since apoptosis takes over the task of ridding the body of damaged or dead cells.

Periodic fasting and agingResearch into the aging process shows decreased longevity results partly from an accumulation of cellular components that no longer function because of oxidative damage and from a decline in the process utilized by the body to get rid of these components. Thus, lowered autophagic activity contributes to the process of aging.

Lysosomes play a major role in the process of aging. These organelles are involved in the process of macroautophagy and aid in dealing with the cellular components that no longer function. These lysosomes work with autophagosomes that have limited ability to degrade these cellular components. This fusion of the two bioprocesses leads to autophagy working as it should.

Critical in the process of aging is the accumulation of defective mitochondria. Lysosomes by themselves are inefficient in the removal of these mitochondria. Thus, the combination of lysosomes and autophagosomes is necessary to slow down aging. A lack of the process of autophagy this fusion brings has been linked to cancers, myopathies, and neurodegenerative illness conditions.

Other research indicates lowered levels of proteins such as Sirtuin 1 are present in aged cells. This appears to be linked to lowered autophagy functioning, also. Other proteins are found to be at lower levels in the aging brain (Atg5, Atg7, and Beclin 1), in osteoarthritis (Beclin 1, LC3, ULK1), and in insulin resistance and metabolic syndrome (Sirtuin 1). In neurodegenerative conditions such as Alzheimer’s, IP3 receptor signaling is increased. This indicates a possible lowering of autophagy in these conditions. Even though these connections are correlative in nature, they do support the concept that decreased autophagy leads to increased aging.

Increased Autophagy and Decreased Aging

With all of the research evidence indicating lowered autophagy increasing the aging process, it is logical to assume the reverse is also true. That increased autophagy leads to decreased aging.

Research supports this assumption.

One observation that has been made from research shows autophagy to be increased in C. elegans, roundworms, when the insulin-like growth factor pathway is inhibited. Another observation is that longevity is inhibited when autophagy is decreased by the mutation of ATG genes.

Periodic fasting and calorie restrictionCaloric restriction as is found in periodic fasting has been shown to be the greatest physiologic inducer of autophagy. And, inhibiting autophagy has been shown to decrease the longevity effects of periodic fasting. Restricting calories without bringing on malnutrition is the best anti-aging intervention studied in numerous species. Periodic fasting is one of the best ways to restrict calories without malnutrition .

It appears caloric restriction such as is found in periodic fasting activates autophagy through the mechanism of activating AMPK and Sirtuin 1, starting a positive mutual activation process. Caloric restriction also induces autophagy by inhibiting insulin and/or insulin-like growth factor signaling, inhibiting TOR as well.

Periodic Fasting and Aging

The connection between periodic fasting and autophagy seems clear. However, there is more to the effect of periodic fasting on aging than just increasing autophagy.

Research has shown both humans and mice who live to an old age show changes in their glucose metabolism. Mice have been shown to produce fewer free radicals during fasting. This finding most likely is due to them burning less glucose and more fatty acids during this time.

One of the keys to this process is a hormone, adiponectin, made by fat cells. This hormone decreases the production of glucose and stimulates the body to burn fat for fuel instead. The research showed the mice had three times the amount of adiponectin in their blood; these mice also had lower triglycerides in their blood, indicating a higher level of fat metabolism.

Burning fat instead of glucose for fuel results in a lower level of oxygen radicals, which in turn lowers cell damage and increases longevity. Research confirmed this by showing far less free radical cell damage as measured by a much higher incidence of a chemical modification on carbonyl groups in the subjects of the research.

Read Part 1 | Part 3

© Copyright 2018 Michael Lam, M.D. All Rights Reserved.


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