Autophagy Benefits – Fasting on Cellular Repair and Longevity
Autophagy, the body’s natural self-eating mechanism for cellular repair, can promote longevity by removing damaged cells. Autophagy benefits are achieved via practices like fasting, which supports aging and recovery by reducing inflammation, improving metabolic function, and supporting cellular repair.
What is Autophagy?
Autophagy is a self-eating mechanism the body uses for cellular repair. A catabolic process that replaces misfolded proteins, dysfunctional cells, and damaged organelles to replace them with new, functional ones. (1) (2)
The name comes from the Greek words auto meaning self and phagus or eating, thus self-eating. The body is programmed to use this protective mechanism to regenerate the cells.
Tapping into autophagy is associated with longevity, being one of the primary mechanisms via which the body sustains survival and improves function. The cells’ autophagic ability decreases with time, partly explaining aging and the accumulation of damage. (1) (2)
How does autophagy work in the body?
Autophagy works by creating vesicles with double membranes, known as autophagosomes which carry dysfunctional proteins to the lysosomes, where they’re broken down. (3)
This process eliminates dysfunctional cellular components, preventing oxidative stress, inflammation, and accelerated aging.
Who invented autophagy?
Although autophagy was actively researched in the past, in the 1990s the spectacular experiment of Yoshinori Ohsumi brought it to life. He won the Nobel Prize for discovering the fundamental importance and underlying mechanisms of autophagy, gene mutation, and adaptation response. (4)
How to measure autophagy in the body?
A practical method to measure autophagy in humans via blood samples.
- PBMC Autophagy Flux Assay: Autophagic flux can be directly measured from human blood samples. Whole blood samples are treated with chloroquine, a lysosomal inhibitor, and peripheral blood mononuclear cells (PBMCs) are isolated to measure the autophagic protein LC3B-II.
- This method allows for the quantitative measurement of autophagic flux in an organotypic human sample and is easy to perform in most biochemical research labs. It could also provide an important biomarker for diseases of aging.
Longevity, Autophagy and Fasting
There is a clear link between fasting and anti-aging. Partly that is explained by the protective mechanism of autophagy. Data shows fasting and calorie restriction to be potent stimulators of autophagy. (2) Eating less or eating less frequently support catabolic activity, due to which fasting stimulates autophagy.
Inducing autophagy seems to be associated with protective mechanisms that improve cell functionality and safeguard the body from diseases. Research shows autophagy’s protective role against infectious, degenerative, cardiovascular, and cancerous diseases. Additionally, fasting and caloric restriction has been found to down-regulate gene expression associated with or involved in oxidative stress. (5) (6) (7)
Reduced autophagic activity or autophagic dysfunction is associated with aging, neurodegeneration, and other diseases. (8) Fasting shifts the energy source, reducing glucose and insulin levels while increasing ketone levels. This metabolic shift brings forth significant changes to metabolic health.
Longer fasting can stimulate SIRT-1 expression, a protein that plays a critical role in aging and cellular stress. This enzyme influences gene expression that modulates cellular stress response and longevity, exerting a protective cardiometabolic effect. Beyond, longer fasts can also increase gut microbiota diversity, increasing the abundance of key bacteria in the gut related to longevity. (9) (10)
Overall, autophagy seems to play an important role in promoting longevity. Periods of food abstinence (CR, IF) seem to stimulate the internal process of cellular repair which comes with numerous benefits on energy, health, and metabolism.
How to Induce Autophagy?
Autophagy is primarily regulated by the interplay of two cellular pathways: (41)
- mTOR: mechanistic target of rapamycin (42) stimulated by eating which upregulates mTOR, a nutrient-sensor, singalling growth. Amino acids and glucose stimulate it more than fats.
- AMPK: AMP-activated protein kinase (43) Activated in energy conservation mode, during fasting or calorie restriction. This energy stress seen as low ATP levels signals to the body to conserve energy.
This switch from eating and anabolism (mTOR) to fasting and catabolism (AMPK) allows cells to initiate autophagic processes, breaking down damaged organelles and proteins to recycle their components for energy and repair. Together, this dynamic ensures cellular health and adaptation during metabolic stress.
The mechanism is largely the same amongst the various methods used to induce autophagy. The cells undergo some form of stress, be it physical exercise, carbohydrate deprivation, or cold exposure, via which they upregulate autophagy.
Intermittent Fasting
How fast fasting induces autophagy is dependent on numerous factors. Generally, longer fasts between 17-48 hours are more effective at stimulating autophagy than shorter fasting. However, daily intermittent (16/8) fasting can also promote most of these benefits in a recurrent way, which is more sustainable. Longer fasting is way more intense, less safe, and practiced less frequently, as a cleanse.
More metabolically flexible people that are adapted to fats or fasting are likely to induce autophagy earlier, in the 16-20 hour of fasting.
Ketogenic Diet
Training the body to shift to fats for fuel creates a strong metabolic shift. The increase in ketones and decrease in glucose partly carry the benefits of fasting, stimulating similar catabolic activity related to autophagy. As a result, benefits like mental clarity, fat loss, and anti-aging are promoted.
Data in animals show ketogenic diet can upregulate autophagy in the liver and the brain. (11) (12)
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Phytonutrients
Certain phytonutrients found in plant-based foods, such as quercetin, resveratrol, and curcumin, can directly influence autophagic pathways. Resveratrol, for example, mimics caloric restriction by increasing NAD+ levels, which facilitates autophagic processes. Phytonutrients also combat oxidative stress and inflammation, enhancing cellular repair mechanisms.
Intense Exercise
Exercising empties glycogen reserves and creates a transient energy deficit at a cellular level. Activity stimulates the muscles to use ATP so the body is forced to create more. During exercise numerous catabolic processes occur, so the scale is tipped towards higher AMPK and lower mTOR activity. This shift initiates cellular autophagy to repair the damage caused during exercise. Both aerobic and resistance training enhance autophagy in muscle. (15) (16)
Heat and Cold Exposure
Cold exposure activates autophagy by inducing mild cellular stress, which promotes the removal of damaged mitochondria through a process known as mitophagy. Similarly, heat exposure, such as in saunas, stimulates the production of heat shock proteins that assist in repairing misfolded proteins and supporting autophagy. Both types of stress activate AMPK and suppress mTOR, facilitating autophagic processes to maintain cellular integrity and resilience.
Calorie Restriction
As fasting, calorie restriction is catabolic in nature. CR mimics the effects of fasting by reducing energy intake. (17) This leads to a catabolic pathway, upregulating AMPK and downregulating mTOR, due to which autophagy is stimulated.
6 Potential Autophagy Benefits
Some of the catabolic activity autophagy stimulates can be beneficial for cleaning up toxins, misfolded proteins and junk cells. Particularly in overweight people, this may assist in burning fat, clearing up liver and brain toxins while resetting energy metabolism.
Inflammation and Oxidative Stress
The body creates free radicals as a result of being alive and performing any physiological function. Metabolizing food will result in production of ROS which partially increase inflammation. Higher calorie consumption and greater carbohydrate intake will increase inflammation more than calorie restriction or lower carbohydrate intake. This is why fasting, or fasting-mimicking mechanisms from the ketogenic diet, calorie restriction, or Resveratrol are commonly linked to anti-aging.
The data shows a clear link between autophagy and lowering inflammation. Autophagy has a profound effect on inflammatory cells, their development, and survival. Due to autophagy’s negative feedback mechanism, it can contribute to controlling inflammatory responses, showing a potential for reducing the risk of disease development. (18) (19) (20)
Neuroprotection and Neurogenesis
As the brain functions it generates waste products inside. The neural circuits work hard during thinking, solving problems, analyzing, creating, and movement. During sleep the brain recovers as memories consolidate, toxins are flushed, and adenosine pathways reset.
With age, the ability to cognitively function reduces due to various reasons. Partly, cognitive decline happens due to a weaker capacity to recover and accumulation of damage overtime.
The hallmarks of the aging brain include:
- amyloid plaque accumulation
- poor glucose metabolism
- lower levels of neurotrophic factors
- mitochondrial dysfunction
- neuroinflammation
Some of the potential mechanisms by which autophagy might improve cognition, act neuroprotective, and slow down brain aging include (21) (22) (23)
- recycling dysfunctional cells and misshaped proteins
- reducing neural inflammation and OS
- increased secretion of BDNF
- increasing ketone levels in the brain
It is known that a dysfunction in autophagy is correlated to Alzheimer’s disease, as the capacity to degrade amyloid plaque decreases. (24)
Impaired glucose metabolism in the brain is one of the critical factors contributing to neurodegeneration. In people with Alzheimer’s, training the brain to tap into fat stores and increase ketone levels is known to be beneficial for sustaining cognitive function.
So far, it seems reasonable that intermittent periods of low-carb or fasting can positively affect neural activity and slow down cognitive decline.
Insulin Sensitivity
Fasting plays an integral role in regulating blood sugar levels as insulin levels lower. This shift allows insulin to reset and improve its function, reducing the metabolic toll on the pancreas from constant carbohydrate consumption.
Autophagy is effective in restoring the capacity to secrete insulin, which translates to better insulin sensitivity. To prevent hypoglycemia, intermittent and not prolonged fasting can be considered. (25)
The data shows a link between autophagy and increased insulin sensitivity, a key factor in reducing the development of type 2 diabetes. Furthermore, autophagy protects pancreatic beta cells, which produce insulin, from oxidative damage and apoptosis. This dual role makes autophagy a promising mechanism for preventing and managing metabolic disorders. (26) (25) (27)
Overall, fasting seems to contribute to metabolic health by reducing the chronic elevation of insulin. A chain of reactions occur alongside fat loss that further improve metabolic function, insulin sensitivity, and increase energy.
Potential Cancer Protection
Autophagy acts as a double-edged sword in cancer, making its role context-dependent. It may prevent chronic tissue damage and cell death that initiate cancer. However, in established cancers it may promote the survival of malignant cells. Autophagy also may suppress tumor initiation by maintaining genomic stability and reducing chronic inflammation. (28)
Lifestyle practices such as fasting and calorie restriction, which enhance autophagy, have been shown to support cellular defense mechanisms. This contribution to a healthier and more balanced bodily environment may reduce the risk of various diseases.
The data is controversial and most research is done on animals. Future research is needed to develop a clear perspective.
Regeneration and Recovery
Exercising strains the muscle, causing microinjuries and an increase in inflammation. Stressors are an essential stimuli for repair. While stimulating anabolic pathways are critical to muscle growth, fasting and exercise are catabolic processes that help improve muscle function, resilience, and resistance to such stressors.
After the microinjury from exercise, autophagy is a natural response to muscle damage that occurs within the inflammation phase of muscle recovery. (29)
Intermittent fasting can stimulate adaptive autophagy which assists in maintaining homeostasis in the body, exerting a protective effect on the cells. (30) This self-renewal process acts as quality-control for the metabolic status of the cell. Autophagy helps regulate stem cell function and activation, to stimulate regeneration. (31) (32)
Autophagy accelerates tissue repair and recovery by removing cellular debris and promoting regeneration. This process is especially important for muscle recovery after exercise, where damaged proteins and mitochondria are cleared to allow for the synthesis of new, functional components.
Anti-Aging and Longevity
As one ages the ability to recover declines. Damage seen as ROS, inflammation, and degraded function seems to accumulate. Improving our capacity to regenerate from stressors is key to extending lifespan.
The data shows a strong link between fasting, autophagy, and longevity. It seems that this natural self-eating process aids in cellular repair. The potential mechanisms by which autophagy supports longevity include:
- enhanced cellular repair and degradation of dysfunctional cells mediated by AMPK dominance (33)
- improving metabolic function by increasing insulin sensitivity (34) (35)
- reducing inflammation by suppressing pro-inflammatory pathways like NF-kB (36)
- improving mitochondria function (mitophagy) and mitigating oxidative stress (33)
- activating Sirtuin-1, an important longevity promoting enzyme (9) (37)
- preserving stem cell function and improving their regenerative capacity (38)
- improved cardiometabolic health by enhancing lipid metabolism and lipid profile (39)
By recycling damaged cellular components, autophagy mitigates oxidative stress, inflammation, and mitochondrial dysfunction—key drivers of aging.
By activating autophagy genes and responses, strategies like fasting or calorie restriction have been shown promising in increasing lifespan and exerting anti-aging effects. (40) (30)
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