How fasting can detox your cells, promote autophagy, and lead to a healthier longevity, based on science and Ayurveda

This essay explores how fasting is good for you in many ways, supporting a healthier and longer life, from both a scientific and Ayurvedic perspective. 

Fasting is not just a fad; it has a solid foundation in both scientific research and ancient practices. Scientific studies show that fasting can trigger incredible transformations at a cellular level, including autophagy: a cellular “spring cleaning” process that recycles waste and removes damaged cells. The ancient health tradition of Ayurveda has also used fasting to reset digestion and balance the body for thousands of years. An integrative approach, combining modern science with ancient wisdom, may help our bodies undergo self-renewal. 

Fasting is not a one-stop solution: counteracting overnutrition, sensory overload, and environmental toxins requires a holistic approach. But strategic fasting could offer a window of opportunity: a chance to press restart on our body’s overtaxed systems. Paired with lifestyle changes, it may support homeostasis and empower us to thrive at any age.

contact: rajat@ayurkula.org

• Why fast? 
• Does the body know what it needs?
• Are different pathways associated with excess and low energy states?
• Can we optimize fasting regimes?
• How autophagy impacts cellular recycling
• The relationship between autophagy and cellular senescence
• Potential therapeutic and regenerative applications 
• Can we get fasting benefits simply via pills?
• Fasting in Ayurveda
• Comparison between Ayurvedic fasting and FMD
• A peek into reduction and rejuvenation therapies in Ayurveda
• My personal experiences with fasting
• The case for an integrative approach
• Cautionary notes

Why should you fast?

As a species, we’re more overweight and overfed than ever. This truth is both physical and mental.

We constantly eat food: breakfast, snacks, lunch, snacks, dinner—and more snacks. We also constantly consume digital stimulation, cycling through TikTok, email, and our text messages. We have no time free of food or screens.

Our interest in fasting (and its mental counterpart, meditation) has skyrocketed in the last few years. Perhaps this is because we recognize the need to counteract our excesses and return to balance.

Unlike most nutritional trends, fasting is not new. Countless scientific studies and ancient practices have shown that fasting is good for you in many ways: it can reset your cellular age, calm inflammation, and more. Food, fasting, and longevity are deeply connected.

The good news is that fasting is also not very complicated. By default, most people should eat dinner early and have breakfast only when they are hungry, which would already give them a 12+ hour eating gap. Skipping one dinner a week would significantly lower energy input and extend also your fast to ~20 hours. Every now and then, you could try a 1-2 day fast as well. Periodic fasting may work better, for many people’s goals, than the perpetual pain and misery of calorie counting.

In this document, we’ll explore the history, science, and different methodologies of fasting.

The historical anthropology of fasting 

Many prehistoric humans fasted out of necessity. If hunter-gatherers didn’t have meat or seasonal food to consume, they had to fast.

Fortunately, our ancestors eventually learned to process, cook, and store food—giving them the ability to avoid starvation and consume many calories quickly. Despite having smaller jaws than apes, we didn’t need to spend the entire day eating and chewing. This helped us rise to the top of the evolutionary pyramid.

(Primatologist Richard Wrangham has written elaborately on this topic in Catching Fire: How Cooking Made Us Human (42).)

Still, voluntary fasting routines continued in many of the world’s cultures, including the Incas, Egyptians, Christians, Jews, Muslims, Hindus, and Buddhists. To this date, many religions observe community-wide fasts, whether before Lent during Navaratri or Ramadan.

In today’s world, we’re neither hunters nor gatherers—but simply accumulators. We often eat not to survive, but just because we’re bored or lonely.

Margaret Visser in her book Much Depends on Dinner (43) says “Boredom arises from the loss of meaning, which in turn comes in part from a failure of connectedness with one another and our past…boredom is an irritable condition, and an exceedingly dangerous one.”

The richest humans of our day often chase longevity through genetic manipulation, drugs, or—going back in time—through fasting.

3 different types of fasting

Fasting refers to extending periods of food deprivation, either daily or periodically. Currently, the three main types discussed are:

• Time-restricted feeding (TRF): In time-restricted feeding, you limit your food intake to a window of 8-12 hours per day. This window is usually linked with your circadian rhythm, preventing late evening and nightly meals.

  • This can enhance circadian gene expression and improve metabolic regulation and sleep (39).

• Intermittent fasting Time (IF): In this method of periodic fasting you restrict calories for certain timed stretches, ranging from 12 – 24 hours. You do this for 1-2 days a week.

  • This gives your digestive system an extended break, which can reshape your gut microbiome and promote beneficial microbial metabolites. These in turn facilitate inter-organ communication (49).

• Extended fasting: Extended fasts last 24+ hours and can range from 2 to 5 days. An example are fasting-mimicking diets (FMDs), which are very low calorie, nutrient-rich diets consumed in 5-day cycles. Fasting-mimicking diets (FMDs) provide limited calories and nutrients during a fasting period.

  • This triggers more profound metabolic shifts like ketogenesis, and can promote tissue regeneration and autophagy.

Each method can potentially reshape our metabolism, gut microbiome, gene expression and immunity in beneficial ways. They all share common benefits related to autophagy, gut health, and mitochondrial function. 

Mechanistically, fasting regulates pathways (like mTOR and AMPK, see (21,74, 76)), reduces inflammation and oxidative stress, alters gene expression, and promotes tissue homeostasis. Animal and human studies show they benefit metabolic, brain, and immune health as we age.  

Fasting Mimicking Diets (FMDs) can help people mimic fasting during long durations, without as intense physical stress.

How Fasting Mimicking Diets work

Fasting mimicking diets are low-calorie diets that mimic fasting—without actually fasting. You can eat small portions of specific foods throughout the day. FMDs are low in sugar and protein, and high in unsaturated fat. An example would be Longo’s FMD which has ~10% protein, 44-55% fats and  34-47% carbs (see Table 1).

FMDs have many of the same benefits as regular fasting, while being easier for many people to undertake. They can induce ketosis, reduce certain growth factors like IGF-1, ease autoimmune conditions, and support healthy aging (61, 63). However, we still need more research to compare FMDs and other fasting protocols in humans. 

The best approach to fasting for you depends on your own individual factors like health status, lifestyle, and personal preferences. The best regimens might combine different models of fasting. Consult a healthcare provider before starting anything.

In the next section, we’ll look at what happens within our bodies when we fast.

Adapted from: Fasting: From Physiology to Pathology (21)

What happens when we fast?

Animals like emperor penguins can survive months without food, but humans rely on a steady supply of glucose. 

Normally, our bodies use glucose for fuel. We create cholesterols and store fat. When we fast, our bodies adapt to use fat, instead of glucose, for fuel. Through a process called fatty acid oxidation, we produce ketones as fuel for our cells. This metabolic shift helps preserve muscle mass and function. It also activates cellular recycling and repair processes like autophagy. 

Here’s what happens when we fast, roughly by time period. 

Restricted Feeding Time (0-12 hours without food)

The body initially uses glucose from food for energy through cellular respiration. As we stop eating, our body transitions into a fasting survival mode. As our glycogen reserves get used up, the body starts tapping into fat stores.

The Fasting Window (12-24 hours without food)

As our glucose levels drop, ketones from fat become our body’s main fuel source. Cellular recycling processes ramp up to remove waste. 

When exactly ketosis kicks in depends on the individual and their stored liver glycogen content at the beginning of their fast. 

Extended Fasting (24+ hours without food)

Prolonged fasting spurs deep ketosis, suppresses appetite, and enhances cellular cleanup. Muscle mass may decline after several days without food.

The amazing fact is that our bodies have an innate capacity to sense nutrient supply and stores and accordingly switch fuels (103).

(The pioneering studies on fasting biochemistry by Cahill (23), Walford and carried forward by Valter Longo (22, 36-40, 45, 53, 58, 59-64, 89), and Kroemer (13, 65, 79, 80, 82, 92) laid the groundwork for the modern fasting approaches we use today.)

Our bodies know what they need

Well-functioning bodies inherently know how to maintain growth and balance. We know when we’re thirsty or hungry, because our body sends us signals based on its need for nutrition (9). 

However, overeating and constant food intake can disrupt our cellular signalling pathways. Overfeeding drowns out our body’s natural signals about its proper function, like someone who is on their phone so much that they can’t hear their own thoughts. 

Fasting helps quiet the noise and allows our cells to recalibrate. It gives our signalling systems a break and lets our bodies re-tune. Today, many wealthy people are taking Ozempic or other pills to mimic what their bodies should be able to do naturally. 

Here’s a quick summary of our body’s nutrient sensors:

Digestive sensors:

Our initial sensors are in our digestive tract, including our mouth, gastrointestinal tract, and gut.

Our mouth contains taste receptors that detect the presence of key nutrients like sugars, amino acids, and fats. These trigger brain signals that influence our food preferences and feelings of satiety. 

Our gastrointestinal tract has taste receptors, amino acid transporters, and receptors that detect fatty acids (like GPR40 and GPR120). These stimulate the release of hormones that regulate digestion and metabolism (like GLP-1 and CCK, see (8)). Our gut has complex sensory mechanisms as well.

Post Digestive sensors:

Our post-digestive sensors happen in our hypothalamus, pancreas, liver, adipose tissue, and kidneys. These sensors track our blood and body fluids. 

To get into a bit of scientific detail: Neurons in the hypothalamus respond to glucose, amino acids, and other metabolic factors to regulate our appetite and metabolism. Pancreatic beta cells sense glucose levels and secrete insulin when it is elevated. The liver regulates glucose production and storage based on levels sensed by glucokinase. Adipose tissue secretes hormones like leptin and adiponectin that signal the body’s energy stores. The kidneys monitor nutrient status via sensors (like mTOR and AMPK) to control processes like electrolyte balance and kidney cell growth and differentiation. 

Let’s explore this further at the cellular level.

Fasting at a cellular level

Our cells are constantly monitoring and adapting to the internal energy state of their mitochondria which are the cellular powehouse. The body tracks the mitochondrial levels of Acetyl-CoA, a molecule resulting from carb, fat, and protein processing, and ATP, the final source of cellular energy resulting from food transformation. 

We need a mix of low and high energy states to be healthy. High and low energy states regulate fundamental processes like autophagy, which is the recycling of cellular components. 

We have a yin-yang of body states: Excess nutrition and lack of activity  suppresses autophagy to maximize growth and eventually impairs our mitochondria ( see notes for more). Fasting induces autophagy to provide internal nutrients and reverses disbalances. 

We can manipulate and fluctuate these energy states through temporary stressors like fasting, exercise, hypoxic breathwork and exposure to cold.

Let’s focus on nutrition.

Excess energy promotes cellular growth

With prolonged overeating, our cells enter excess energy states. This engages pathways whose signals promote growth and proliferation.

A nutrient sensing pathway called mTOR stimulates protein synthesis and cell growth when amino acids are plentiful. Both excess sugar and protein increase circulating levels of  insulin and IGF-1, which ramp up anabolic processes. (41, 63, 98). 

Growth is necessary for our development and sustenance. But growth gone wrong can entail cancer, diabetes, and other fatal lifestyle diseases. The hyperactivation of mTOR, for example, is linked to cancer and diabetes.

When we eat too much in general—including sugar, refined processed carbohydrates, and excess protein—we activate nutrient signaling and growth factors with adverse health effects (117).

This is important to keep in mind, since many trendy low-carb diets emphasize high fat and protein. Some protein is important during fasting periods to help maintain muscle mass and metabolism, but packing in too much protein could weaken the benefits of fasting. Here’s why: eating large amounts of protein can switch on a cellular pathway called mTORC1 and shut off autophagy, our cells’ recycling program.  High protein diets can also increase senescence (115). 

My take? It’s best to stick to your recommended daily protein range during normal feeding. Getting the right balance will allow you to reap fasting’s advantages while supporting your muscles and metabolism. 

Think of the Goldilocks principle: you want a protein intake that’s just right. Too much protein will activate pathways that counter the effects of fasting. Too little protein can cause muscle loss. Finding the sweet spot gives you the best of both worlds.

Low energy states promote resilience and prune bad cells

In contrast, periodic fasting creates a low energy state in cells. This engages different nutrient sensing pathways, like AMPK and SIRT, and stimulates catabolic processes that generate energy (see (9)). 

Fasting activates sirtuins and proteins that can help your body be resilient to stress, accurately maintain genetic information and aid metabolic adaptation (see notes on FOXO and Sirtuins and (94, 124,125)).

The yin and yang of these opposing pathways help maintain our protein, lipid, and energy balances. Imbalances arising from overactive growth pathways or impaired fasting responses contribute to many diseases. Declining autophagy underlies neurodegeneration. 

A coordinated nutrient sensing network allows cells to toggle between fed and fasted modes, ensuring homeostasis across our lifetime. Understanding these molecular mechanisms is key for better health.

Two key processes activated during fasting are cellular autophagy and stem cell regeneration. Let us now focus on them now.

How autophagy works

Fasting induces stress in the body and activates two cellular cleaning systems: the ubiquitin-proteasome system (UPS)  and autophagy (112, 113). 

UPS is our body’s shredder: it chops up defective short-lived proteins. 

Autophagy is our recycling center: it identifies old, long-lived proteins and worn-out cell parts, tags them, and sends them to the lysosome to be broken down. It also selectively degrades damaged proteins and mitochondria (known as mitophagy) that accumulate with age. In addition to cellular cleaning, autophagy supports tissue repair, by sending us regenerative biomolecules and maintaining stem cell populations.

By turning on both protein shredders and recycling centers, fasting helps cells take out the trash and stay healthy. It removes unhealthy proteins that build up over time, acting like a deep cleanse (81).

For simplicity, we’ll refer to all cellular cleaning processes as autophagy.

By default, our bodies undergo basal autophagy all the time at low levels. This default autophagy slows as we age. People with obesity or metabolic dysfunction have impaired basal autophagy. When we have mutations in our autophagy pathways, we’re at increased disease risk. 

Within 24 hours, fasting can induce autophagy even beyond basal levels. If you’re healthy, this can boost your cellular housekeeping levels. If you’re obese,  this fasting can provide an even bigger benefit—because by default, your autophagy is already impaired.

In summary, by stimulating cellular housekeeping, fasting provides a periodic purge that may optimize health. 

How autophagy impacts cellular senescence

You can think of our biological age as the cumulative result of our cellular damage and ongoing damage maintenance (70).

A key part of aging is cellular senescence. Senescent cells are dysfunctional cells that cease dividing but remain metabolically active, often secreting inflammatory factors. They are implicated in ageing and can resist cell death signals. 

Autophagy plays a somewhat mysterious two-faced role in cellular senescence, both helping destroy and preserve senescent cells.

On one hand, it clears out damaged cell parts that can trigger cells to become senescent (67, 32, 114). 

On the other hand, it also seems to help senescent cells stick around. Switching off some autophagy genes can make senescent cells more prone to self-destructing. 

One explanation is that low baseline autophagy delays senescence, but ramped up autophagy in already senescent cells helps them survive. It’s also possible that senescent cells hijack autophagy to selectively destroy the proteins that induce self-destruction in these cells, while ignoring those that clear out damaged mitochondria and other junk. This enhances their survival. 

Autophagy and senescence are intertwined, but the specifics of their relationship are still hazy. It likely depends on the cell type, triggers causing senescence, and how far along the cells are in the process. 

Figuring out exactly how autophagy and senescence interact could reveal how fasting helps clear senescent cells or stops them from building up. This may be important for treating age-related diseases like cancer, Alzheimer’s, and possibly aging itself. More research on this fascinating link is still needed.

How fasting can help fight disease

When it comes to removing toxins, obesity, cancer, Alzheimer’s disease, and promoting regeneration, research suggests periodic fasting could potentially have some intriguing benefits, though clinical evidence remains limited.

Fasting for toxin removal

Studies have found concerning links between exposure to persistent organic pollutants (POPs) and heavy metals and the development of metabolic disorders like obesity and diabetes (1). POPs and heavy metals can accumulate in adipose tissue and organs, especially our livers, over time (2, 95).

Source: Metabolic Syndrome and Endocrine Disrupting Chemicals, Haverinen et al 2021 PMID

Any effort to address metabolic health through diet and fasting should also consider reducing the body’s toxic load. Implementing periodic fasting and adopting a clean, organic diet may help facilitate the release and excretion of stored POPs and heavy metals.

Fasting may aid the removal of toxins stored in fatty tissues over time. Fasting accelerates the breakdown of fat for energy (lipolysis). Some small studies have found this mobilization of fat reserves may facilitate the release and elimination of accumulated toxins.

A study on 10-day fasting in 109 subjects found decreased urinary levels of arsenic, nickel, and lead, suggesting release from tissue storages (28). Another study on a 7-day detox diet combining fasting and fluids in 7 patients with severe atopic dermatitis showed decreased symptoms and reduced lead levels in hair analysis (29). 

Of particular interest and importance is the impact of fasting on cytochrome P450 enzymes, which are involved in drug and toxin metabolism. Some reports indicate that the activity of these enzymes is upregulated during fasting (100, 101).

Our bodies already have effective systems for eliminating toxins through the liver, kidneys, skin and colon. Some gentle detox methods like drinking more water, eating more fiber, exercising, and using saunas may provide some benefits. Rigorous detox regimens are controversial and may carry health risks if not done under medical supervision. 

Too much fasting can backfire on your. Extended fasting beyond 3-5 days may eventually slow our metabolism and detoxification capacity. The body’s ability to eliminate mobilized toxins likely has an upper limit that can be overwhelmed by aggressive, prolonged fasting protocols.

More research is still needed to determine optimal fasting durations and protocols to safely facilitate toxin removal through lipolysis. The detoxification effects of fasting through fat mobilization is an intriguing area warranting further mechanistic and clinical study.

Fasting to fight obesity, visceral fat, and diabetes

The body contains several types of fat including subcutaneous fat underneath the skin, intramuscular fat between muscle fibers, and visceral fat surrounding internal organs; of these, visceral fat located deep in the abdomen is considered the most dangerous type as it is metabolically active and releases compounds that drive insulin resistance, inflammation, and other metabolic abnormalities.

The fat you can pinch on your belly is simply subcutaneous fat. Visceral fat is what intially fills up the internal core cavity of the body and playing a protective role and upon over feeding inflates it to a “pot” belly. It is best measured by tracking your waist size at belly button.

Some studies show fasting mobilizes visceral fat in the abdomen more readily than subcutaneous fat (40). Thus, it might be especially powerful in reducing visceral obesity over time. 

Diabetes mellitus is characterized by impaired insulin secretion from pancreatic beta cells and/or peripheral tissue insulin resistance, both resulting in persistent high blood sugar.

Valter Longo and other research teams were able to record regeneration of pancreatic cells and restoration of insulin production in mice with type 1 and type 2 diabetes (58, 116).

Fasting may have anti-cancer effects

Research indicates that fasting may have widespread anti-cancer effects against many types of cancer (105). In animal studies of colorectal cancer, fasting inhibited the progression and spread of tumors while enhancing the effects of chemotherapy. 

How? It may have helped lower insulin and IGF-1 levels, reduce inflammation, suppress cell proliferation and angiogenesis, and increase cancer cell’s susceptibility to oxidative stress and programmed cell death. Fasting’s metabolic shift resembles calorie restriction, which robustly inhibits cancer in rodents. But showing this in humans remains an ongoing challenge. 

Research led by Valter Longo suggests that cancer cells may become more susceptible to chemotherapy when accompanied by a clinically supervised fast mimicking diet. This may be because cancer cells continue uncontrolled growth even in nutrient deficient environments, but normal cells do not. As a result, cancer cells become more prone to chemo-attack (83).

However, the dynamic between fasting and cancer is complicated. Fasting reduces the glucose available to your cells, putting the brakes on the two nutrients that cancer cells are hooked on for creating energy (118). This cuts off the fuel supply that feeds cancer cell growth. Healthy cells can adapt to using ketones and fatty acids for energy instead of glucose when fasting. Cancer cells, however, struggle to adapt to using ketones. Fasting ramps up autophagy, which can suppress early tumors. But longer-duration, more established cancers can also hijack autophagy to favor their own growth (119,120). More research is need in these areas.

Fasting impacts Alzheimer’s disease

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by dementia and decline in cognitive function due to the accumulation of amyloid plaques and neurofibrillary tangles in the brain.

In Alzheimer’s, a key factor is accumulation of misfolded protein aggregates (like amyloid and tau). By activating cellular cleanup pathways, fasting may aid protein clearance and reduce their toxicity in brain cells (78). In addition the beneficial impact on gut bacteria may also play a role. Mouse studies are promising, but whether benefits translate to human patients is unclear.

Fasting impacts various organs and cellular Processes

Many organ systems and cellular processes throughout the body are impacted by fasting (103). 

Blood levels of insulin and leptin decrease, while ketones and antioxidant capacity increase. Fasting improves cardiovascular health by reducing blood pressure, resting heart rate, and damage from heart attacks. 

The liver generates ketones and becomes more insulin sensitive while reducing lipid accumulation. Inflammation in the intestines is lessened and the microbiome is improved. Muscles increase insulin sensitivity and reduce inflammation, while exercise in the fasted state may further boost muscle growth and endurance. 

The brain enhances cognition, synaptic plasticity, and neuronal stress resistance through increased neurotrophic factors, mitochondrial biogenesis, autophagy, and reduced neuroinflammation. 

Adipose tissue mobilises fat stores through increased fatty acid oxidation. Thus, fasting triggers beneficial metabolic, hormonal, and cellular responses across organs that enhance health and resilience.

Fasting has regenerative potential

When it comes to regeneration, some speculate prolonged fasting may rejuvenate tissues by mobilising adult stem cells.  Emerging evidence suggests fasting may promote cellular reprogramming and a pluripotent-like state (capable of giving rise to several different cell types) through metabolic shifts that alter epigenetics and gene expression (46, 110, 111). 

Fasting induces ketogenesis, autophagy, and mitochondrial biogenesis – processes which may enable cells to more readily respond to reprogramming factors and assume a stem cell-like state. Interestingly the concept of engineered induced pluripotent stem cells (iPSCs) is a  major area of modern stem cell research directed towards longetivity (106, 107, 108, 109). 

However, direct evidence that fasting benefits stem cells is still scarce (35, 27). At the very least, its systemic effects improve cellular health in general.

When it comes to fasting, what you eat during the refeeding period is just as important as the fast itself. The foods you eat after fasting can drive stem cell regeneration, leading to the replacement of damaged, old cells with new healthy ones. So to get the full benefits, you’ve got to pay attention to your nutritional intake when you break the fast too. The refeeding diet makes all the difference (113).

Fasting’s impact on brain, eye, and joint health

Potential regeneration and replacement of long lived protein (7, 30) is another interesting area. Our cells have proteins that carry out all sorts of important jobs. Some of these proteins can stick around for a really long time without being replaced, for example in tissues like the brain (55), eyes, and joints. These are called long-lived proteins. These are associated with central transport channels that mediate molecules going in and out of the cell nucleus.

Over time though, these long-lived proteins can accumulate damage and start to function less well, which is thought to contribute to ageing. Cells have a hard time breaking down and replacing these extra stable proteins. This seems to happen even in stem cells, which normally renew themselves. 

Interestingly, some new research identified long-lived proteins in yeast that either build up abundance over time or get fragmented but are still retained by the cell. This suggests cells may have trouble getting rid of these proteins. 

So could fasting help? Fasting ramps up a cellular recycling process called autophagy, where cells digest and clear out damaged components. Autophagy is usually good at clearing harmful protein aggregates and old organelles. Early evidence (in yeast, mammalian cultures and mouse studies) suggests autophagy may also help degrade some long-lived proteins.

More studies are still needed, but it’s possible that fasting could aid the removal and turnover of worn-out even long-lived proteins, helping maintain the youthfulness of cells. This may be one way fasting helps slow ageing. There’s still a lot to learn about how cells replace or get rid of long-lived proteins and whether fasting plays a role.

What if we want the Benefits Through a Pill Without Fasting

Everybody wants to live long, most notably the rich and famous. There are many methods being explored to extend life. If not secret Holocaust yachts and bunkers, it could include life extension research funded by the likes of Bezos, Zukerberg or Altman. 

While a discussion on hallmarks of aging is beyond the scope of this discussion let us briefly look at how scientists are exploring different compounds and techniques that target the biological processes involved in aging. 

One approach is using senolytics (96), which are drugs that can selectively destroy worn-out old cells called senescent cells. These hang around and secrete inflammatory signals that contribute to many age-related diseases. Mouse studies have shown that getting rid of them can rejuvenate tissues and extend health. Early clinical trials in humans look promising too. The downside is potential side effects from damaging healthy cells. More selective senolytics are needed. 

Related to this is using senomorphics, which modulate the inflammatory signals from senescent cells rather than killing them directly. They might limit harmful effects and avoid risks of completely wiping out these old cells. More research is still needed to translate effects from mouse studies to humans though. 

Another popular strategy is drugs that inhibit the mTOR pathway, which drives cell growth and metabolism. The prime example is Rapamycin (34), which robustly increases lifespan in mice. But it also seems to suppress the human immune system with long-term use. Safer substitutes are being investigated. 

Natural compounds like spermidine (13)  that induce autophagy are also gaining interest (13). This cellular self-cleaning process appears to promote longevity by helping cells clear out damage. Human trials are still in early stages however. 

Some other futuristic ideas involve filtering the blood to remove circulating ageing factors, using diabetes drugs like metformin to mimic anti-aging effects of fasting, or epigenetically reprogramming cells to a more youthful state. Or, we could envisage use of an anti-aging chemical cocktail. But more research is needed to assess if these can really extend human healthspan. 

The science of longevity is rapidly advancing. But translating test tube or animal findings to humans in a safe way remains challenging. For now, healthy lifestyle choices may pack the biggest anti-aging punch for most people.

Ayurveda, Fasting, and Longevity

Ayurveda has a long history of using reduction therapy to treat diseases, focusing on removing food rather than adding food. 

A Sanskrit shloka says लंघनं परम् औषधं|, which means fasting, or reduced intake is the supreme medicine.  

The key thing to understand in Ayurveda is that food is not just what you put in your mouth, but rather includes all sensory stimuli. A holistic fast, therefore, involves abstaining from food, mental, visual, and sound stimuli. Reduction therapies, or langhana, deal with removal of these stimulants. Restraint helps focus the body inwards for healing and recuperation.

If you are stressed and overstimulated, simply avoiding food will not help much. The brain is a critical part of our nutrient sensing pathways. Stress and mental stimuli are associated with all disease conditions, as a result of the dysfunction of the entire hormonal system (123).

In Ayurveda, laghana involves strategic diet regulation, rather than blanket extended fasts. Ayurveda doesn’t take a one-size-fits-all approach to fasting. Fasting in Ayurveda is tailored to each person’s unique constitution and current imbalances to avoid aggravating underlying disease conditions. Not everyone should fast at the same times, in the same way, or for the same durations.

Compared to modern intermittent fasting, Ayurvedic methods advocate gradual transitions, with richer broths, lentils, and rice to nourish us during fasts. The guidance of an Ayurvedic practitioner ensures that the process is safe and suitable for one’s unique constitution. The ultimate goal is the integrated sustenance of body, mind and spirit.

Reduction therapies, or langhana, include activities like breathwork, and exercise, besides fasting. Each of these represent hormetic stressors, which stimulate our protective mechanisms involved in improving metabolism, inflammation, and oxidative stress defense. 

Overview of basic Ayurvedic concepts

At Ayurkula.org, we offer group workshops focussing on basics of Ayurveda and food diversity. We also do individual lifestyle audits to ascertain dosha imbalances and help participants embark on their individual health journeys.

We’ll cover a few concepts here:

In Ayurveda, your constitution (prakriti) is determined by the balance of the three doshas: vata, pitta and kapha. We each have a unique mix of these bioenergies. Your vikriti is your current state of imbalance from your constitutional type. 

Before recommending any fasting or cleanse, an Ayurvedic practitioner will assess your agni. Agni is your “digestive fire,” or how well your body metabolizes food and absorbs nutrients. A strong agni is key to a healthy life.

Practitioners will also check for ama, or toxic residues that accumulate from poor digestion and environmental poisons that clog up our body channels. Excess ama calls for cleansing therapies.

Beyond agni and ama, they’ll look at your bodily tissues (dhatus), blood (rakta), doshas, life stage, and disease conditions.  This serves to understand your basic strength and energy levels to undertake fasting. They’ll also consider the season of the year and other environmental factors. (Late winter and early spring are good seasons for Ayurvedic cleansing therapies involving longer fasts to wash away accumulated kapha.)

If you are a Vata type, you require extra care while fasting to avoid throwing yourself off balance. You should include spices that spark your digestive fire, such as dried ginger. Pitta types need to include foods that help with toxin removal, like prunes and cilantro. Kapha types benefit the most from occasional fasting. For more details on how to approach fasting by dosha imbalance (vata, pitta or kapha) type, please refer to my blog post on this topic. 

People with high ama (toxin), excess kapha, or excess pitta are good candidates for fasting. Excess vata imbalances need to be soothed with caution when using fasting.

Ayurvedic fasting vs. Fasting Mimicking Diets

Table 1 contains a comparison between an Ayurvedic fasting regime with a 5 day FMD.  Different versions of this Ayurvedic regime are often used as a part of treatment for weight loss, disturbed metabolism, and skin conditions, all of which indicate a disturbed and accumulated kapha and pitta dosha. 

The Ayurvedic treatment starts with rekindling of agni, or the digestive fire. During re-feeding the concept is to slowly graduate from light food to heavy. It is worthwhile to note that both Ayurveda and FMD use a predominantly liquid diet in the initial period. The Ayurvedic diet doesn’t count calories or allocate macro food components. 

In addition, the Ayurvedic diet uses ghee/oils and selective spices for tempering and immunomodulating the effect of the prescribed diet. During fasting Ayurveda avoids cold raw juices of fruits and vegetables as the agni is lower during fasting.

In clinical settings, the Ayurvedic extended fasting regime has shown varying results in people. The conditions which have shown most observable impact include skin inflammations, diabetes and cardiovascular issues.

The Ayurvedic approach is driven by the underlying conditions of the person and are summed up in this ancient Sanskrit shloka:

शान्तिरामविकाराणां भवति त्वपतर्पणात्||

त्रिविधं त्रिविधे दोषे तत्समीक्ष्य प्रयोजयेत् ||  

तत्राल्पे लङ्घनं पथ्यं, मध्ये लङ्ह्घनपाचनम्||२१|| 

प्रभूते शोधनं, तद्धि मूलादुन्मूलयेन्मलान्||

Ashtanga Hridya, Sutra Sthana  8-20/21

This shloka summarizes that:

Reducing food intake helps calm the body and mind. There are three doshas: vata, pitta, kapha. The treatment should match the dosha involved.

Reducing intake (langhana) can be of three types based on proper assessment of factors like strength, disease, dosha, etc. In mild health issues, moderate diet reduction helps. For moderate problems, stronger reduction aiding digestion is appropriate. In severe conditions, cleansing therapies (like panchakarma) are suitable. These remove impurities completely unlike just dietary change.

Therefore, fasting in Ayurveda is individually tailored to achieve a suitable frequency, duration and composition. For example it could be weekly, fortnightly or more infrequently, accompanied with or without water, while consuming fruits or light food (ahara). 

Detoxification practices in Ayurveda

Ayurveda emphasizes removing toxins to restore balance and health. Panchkarma refers to Ayurvedic detoxification therapies involving procedures to gently mobilize and eliminate toxins. 

Key panchkarma techniques include:

• Abhyanga: Medicated oil massage 
• Swedana: Heat treatments to induce sweating
• Vamana: Therapeutic vomiting to clear excess Kapha
• Virechana: Herbal purgatives to cleanse Pitta 
• Basti: Medicated enemas to eliminate Vata
• Nasya: Nasal administration of oils
• Raktamokshana: Bloodletting to purify the blood

These are customized based on individual constitution and imbalance. They are preceded by oleation and sweating to loosen toxins, and followed by rest and a gradual reintroduction of diet.

Some recent studies lend support to the Ayurvedic view that these targeted therapies can facilitate toxin removal. A study by Dr. Cline cited a two-phase process for transforming toxins into water-soluble forms for excretion. Phase 1 uses liver enzymes to make toxins more polar and reactive. Phase 2 binds these metabolites to amino acids, glutathione, etc., to make them water-soluble. Dr. Cline noted that providing diverse nutrients supports both phases optimally, assisting the body’s natural detoxification (25). 

Another study by Robert Herron evaluated an Ayurvedic procedure using therapies like oil massage and steam baths to mobilize fat-soluble toxins for elimination. In a cross-sectional comparison, those who underwent the detox had lower PCBs and other toxins versus controls (24). A longitudinal study showed significant decreases in PCBs and pesticides after the 2-week detox. 

The authors propose that lipophilic therapies enhance partitioning of toxins out of tissues. While more research is needed, these studies lend preliminary support to Ayurvedic detoxification.

Used under expert guidance, panchakarma may offer individualized options to approach reduction therapies. Be careful to only undertake it with expert guidance, and be careful of any heavy metal contamination that may result from improperly sourced herbs.

There are many things one can do short of magical solutions and costly panchkarmas. To start, you can drink less alcohol and consume wholesome food. You should always place an initial emphasis on gentler detox methods, like massages, steaming, and teas (coriander, cumin, fennel).

Longevity therapies in Ayurveda

Ayurveda has laid out very specific procedures to tackle problems that arise due to overnutrition, disease, and old age. These procedures involve both reduction (langhana) and re-feeding/rebuilding (brimhana).

Langhana refers to “lightning therapies” like fasting, which reduce metabolic load. Langhana gives the digestive organs a rest while flushing out waste products and toxins. This can include:

• Restricted diet 
• Use of carminatives (pachana) such as buttermilk
• Appetizers (dipana) such as medicated ghee/warm water/haritaki/pippali
• Exercise (vyayama) 
• Breathing exercises (maruta)
• Exposure to sunlight (atapa)
• Fasting
• For those with good body strength, panchkarma elimination techniques like colon cleansing, sweating, and induced vomiting to draw out accumulated toxins (ama) in our lipid cells. 

Afterwards, Brimhana therapies, during the refeeding phase, provide deep nourishment while balancing doshas. Warm, unctuous foods like milk, ghee and nourishing khichadi are advised. Rasayana herbs and rejuvenative tonics like chyawanprash are used to rebuild the body. This addresses the refeeding and rebuilding stage following a fast. 

Ayurveda stipulates careful calibration of both reduction (langhana) and expansion or refeeding (brihmana). It’s important not to fast too often or too frequently. Symptoms of excess reduction (Ati Langhana) include mental confusion, joint pain, body ache, emaciation, excessive thirst, decline in digestive power, and the impairment of hearing and vision. 

Rasayana is the branch of Ayurveda dealing with rejuvenation and gerontology. Rasayanas use herbal and mineral preparations as medicines, foods and lifestyle practices. The goal is to balance doshas, nourish tissues, enhance resistance and promote longevity.  

For more intensive rejuvenation, Ayurveda describes Kuti Praveshika, an indoor retreat for customized rasayana protocols that uses a special controlled environment, diet and medicines. This is a very selective procedure that may extend to thirty or more days, and involves an initial removal of toxins, selective feeding, and the reintroduction of normal food along with person specific herbal Rasayana formulations. Kuti Praveshika allows for deep bodily renewal while strengthening the mind and senses. More clinical research data is awaited on these methods.

If you have got this far and understood that reduction is better than addition, there are many natural things that can replicate some of the pills and pathways we have discussed so far, to name a few:

• Spermidine: Aged fermented cheese, mushrooms, soybean (natto), wholegrain- wheat germ, eggs, crucifers like broccoli, spinach, mangoes. Our gut produces spermidine as well.
• Metamorphin: French lilac, curcumin, cinnamon, berberine, goldenseal, ashwagandha
• Rapamycin: Ashwagandha, epigallocatechin gallate sources: green/oolong tea, strawberries, blackberries, apples, avocado
• AMPK: Exercise, omega 3’s (fish oil)
• NAD+: Vitamin B3, green vegetables, fermented foods, honey, milk, mushrooms
• Sirtuins: arugula, buckwheat, celery, cocoa, extra virgin olive oil, matcha, kale, wine, walnuts, strawberries, walnuts, meat, legumes, soyabean
• Senolytics: Some compounds are contained in natural sources of  quercetin for example-capers, asparagus, blueberries and pippali (long pepper), which finds its initial reference in Yajurveda and is a very common ingredient in many Ayurvedic potions.
• Calorie restriction mimetics (CRM): There are some natural compounds that can induce or mimic autophagy even in a fed state. For example, red wine (containing resveratrol (57)), cheese (containing spermidine), and coffee has also been associated with autophagy. Unfortunately, I believe most of us have an excess of these anyway!

Nutrient sensing in Ayurveda

We now know that there are various nutrient sensing mechanisms in the body like taste receptors, gut hormones, neuronal circuits, etc. Ayurveda also recognized nutrient sensing pathways from ingestion to assimilation, including taste, digestion, and systemic effects. These ancient insights foreshadowed modern discoveries in food science and nutrition.

For example, the taste of an ingested substance represents the first level of nutrient sensing, via receptors on the tongue and palate. The Ayurvedic Rasa theory, which includes sweet, sour, salty, bitter, pungent, astringent flavors, mirrors this initial flavor detection.

The next level of sensing is the post-digestive effect (vipaka) in the gut through mechanisms like microbiome metabolites, intestinal cells, enteroendocrine hormones etc. Finally, the overall pharmacology (prabhava) of any food or drug results from the interaction of its nutrients with various systems like the brain, liver, fat tissue, kidneys and the environment. Ayurveda also described how Rasa transforms into Vipaka and commented on the effects of wider systemic coordination (121,122).

Here is a Sanskrit shloka which describes how any substance, whether of plant, animal or herb origin has five stages of layered impact. It cites Rasa (taste), Guna (quality), Veerya (potency), Vipaka (post-digestive effect) and Prabhava (special effect). It notes that these five aspects are connected and occur in a sequential order during the digestion and metabolism process.

द्र व्ये रसादयः पञ्चावस्थाः

द्र व्ये रसो गुणो वीर्यं विपाकः शक्तिरेव च

संबन्धेन क्रमादेताः पञ्चावस्थाः प्रकीर्त्तिताः

Sarng. Samhita 2/13

Analyzing any herb, food or medicine through these five stages provides an in-depth understanding of its qualities and pharmacological actions. Here is a bit more on each stage:

1. Rasa (taste): There are six tastes, including sweet, sour, salty, etc.
2. Guna (quality): There are 20 kinds of physical properties, like heavy, sharp, dry, light etc.
3. Veerya (potency): This refers to potency and energy, like hot and cold.
4. Vipaka (post-digestive effect): Post-digestive effects can be sweet, sour or pungent
5. Prabhava (special effect): The unique effect from all interactions of environment, substance and body

The Ayurvedic framework provides a time-tested, holistic perspective to understand the journey of food and medicines in the human body. Blending this wisdom with modern advances can power a nuanced, multi-dimensional understanding.

Autophagy in Ayurveda

The ancients were arguably not  speaking of molecular pathways and autophagy. In Ayurveda the concept of agni is central. Just like when overloading a fire with wood, overnutrition extinguishes our agni and desensitizes our nutrient pathways. Therefore we practice the calibrated reduction and re-introduction of food.

This verse in Sanskrit hints that agni digests the food and then, in the absence of food, it beneficially digests the doshas (read aberrant cells and toxins). If you take fasting to an extreme, the agni turns on itself, digesting the dhatus (read muscles and bones). When destruction of dhatus occurs, it “digests” life itself, meaning it leads to death.

आहारमग्निः पचति दोषानाहारवर्जितः| धातून् क्षीणेशु दोषेषु जीवितं ढातुसङ्क्षये||९१||

Ashtanga Hridya  10/91

Unfortunately, in the absence of adopting reduction therapies like fasting, and eating healthy food with a healthy lifestyle, chasing superfoods will yield you no more than costly urine and poop.

Exercise and breathwork in Ayurveda

Ayurveda recognizes the benefits of moderate stress through resistance exercises and breathwork. These form a critical component of any healthy reductive routine (langhana). 

For exercise, you could follow yoga postures according to your body type. For example, Surya namaskar (sun salutation) works for nearly everyone.

There are many options for breathwork, which forms the core of any discussion in Ayurveda. Shlokas from Rig Vedic times, used in soma ceremonies, are all set to certain meters that generate internal heat in the body. 

A good example of pranayama is nissesha rechaka pranayama, which creates an intermittent hypoxic condition using breath holds followed by vigorous breathing. These approaches have also been later found in Tibetan “Tummo” and now by some new age gurus. (This is basically attempting to be like a yogi sitting on a rarified air mountain top or cyclist doing high altitude training!) In Patanjali’s yoga sutra texts from 2nd C. BCE, this breath holding is called bahya kumbhaka.

In summary, Ayurveda employs tailored periods of cleansing and renewal while cautioning against extremes. Fasting is complemented by yoga, pranayama, meditation and positive lifestyle conduct for optimal results. 

My personal experience with fasting

I am 5’9″ tall and currently weigh about 140 pounds with no fat bulges. For the past 15 years, I have followed a natural circadian rhythm style of eating. Having dinner early gives me a 12 hour night time fasting window. 

In the past, a full 24 hour fast always gave me bad leg cramps. Recently, I discovered that drinking mineral water and taking sugar free electrolyte tablets prevents that. Over the last month, I’ve been doing weekly 24-28 hour fasts by skipping dinner. I drink only water and take some electrolytes and a multivitamin pill during the fasts. With no underlying health conditions, I was just curious to experience real hunger.

The result was that my weight dropped around 4 pounds, probably from missing 10,000 calories over the month, and some belly fat was reduced. I feel perfectly fine without any aches or pains. On non-fasting days, I eat my normal healthy diet without counting calories paired with gentle exercise and breathwork.

Since I don’t intend to lose much weight, I may adjust the frequency of the fasts to  bi-monthly ekadashi (eleventh day of each ascending and descending moon) lunar calendar. 

Fasting is not for everyone, so talk to your doctor if you have any medical conditions. But it’s been thought-provoking for me to rediscover what hunger feels like. The interesting thing is that one feels hunger only  at the time of the first missed meal and not after one has switched fuels and gone into a keto mode. For now, I look forward to my weekly fasts.

It is of no use to be 50 whose body works like a 90-year-old—and then aspire to live to 100. Your quest for cutting the crap should start now.

Unfortunately it may be quite some time before the integration of all molecular pathways with double blind placebo studies proves that you should fast—and by that time we will be quite easily dead. Bliss lies somewhere between being a bar hopper and a grasshopper!

Tips for incorporating fasting into your lifestyle

Fasting is very promising for certain conditions, but also has risks if not conducted properly. Depending on your health status, you should take medical guidance before periods of food restriction.

If you’re interested in incorporating fasting into your lifestyle, it’s important to do so in a safe and sustainable manner. Here are some tips to help you get started:

Combining fasting with exercise, stress management, and social engagement may provide greater longevity benefits than fasting alone. Diet, lifestyle and psychosocial factors also impact aging processes.

Research on fasting requires integrative frameworks encompassing metabolic, physiological, genetic, and psychosocial parameters. Holistic modalities like Ayurveda that address diet/fast, mind, exercise, and lifestyle offer insights into optimizing fasting’s therapeutic potential.

While it is helpful and necessary to get validation from cellular and molecular pathways studies, I am really afraid that we could become easy targets of  medicalization of Ayurveda—turning it into an elitist framework far from its ideals (99). Any nutrient, pill or herb is futile if your cells are desensitized and unreceptive. If your body is unwell, you will have to increase dosages to toxic levels to see effects, which will cause other unsought after damage to the body.

The key to health and vitality has been staring us in the face all along: mastering the age-old dance between feast and famine. Like world-class athletes and wise yogis, the secret is learning to tap into the body’s incredible ability to fluidly switch fuels when fasting and feeding. Repeatedly enduring this back-and-forth seems to be the magic bullet behind enduring strength, slim physiques, and mountain-top meditation.

Our ancient metabolic flexibility to run on carbs or ketones, proteins or fats, is what allows us to thrive across the spectrum from times of scarcity to satiety. So let us embrace the wisdom of our bodies and optimize the cycles between fast and feast.

Besides, you will help feed the hungry and save the planet!

contact: rajat@ayurkula.org

Appendix:

Potential Risks and Precautions of Fasting and Fasting-Mimicking Drugs

• Prolonged fasting over multiple days can lead to loss of lean muscle mass, electrolyte imbalances, dizziness, fatigue and irregular heartbeat in some individuals. Medical supervision is advised for extended fasting.
• Extended  low calorie diets under 800 calories per day may slow metabolism as the body adapts. Gradual calorie reduction is generally safer for weight loss. 
•  Fasting is not recommended for those with certain conditions like gout, gastroparesis, or a history of eating disorders, as it may exacerbate symptoms.
• Fasting during menstrual periods (“artava”) is generally avoided in Ayurveda. However if a person feels perfectly normal, it can be undertaken when accompanied by warm soups as indicated in Table 1 rather than a water only fasting.
•  There is limited research on the long-term safety and side effects of fasting-mimicking drugs. Case reports have described adverse effects like insulin resistance and liver toxicity.
• While animal studies and small trials show promise, larger clinical trials are still needed to validate optimal fasting protocols for therapeutic uses in humans.
• Achieving temporary ketosis through periodic fasting should be distinguished from perpetual ketogenic diets. Long-term keto diets require caution as they may adversely affect heart health markers like LDL cholesterol.
• Extended periods of overnight fasting is associated with increased incidence of gall-bladder stones (102). 
• Several studies have associated cardiovascular risk with skipping breakfast (104). That may however be due to an otherwise adverse lifestyle pattern (i.e smoking, alcohol, irregular eating schedules etc.)
• It is important to note that fasting alone without improving overall diet quality will likely have limited long-term benefits. Addressing poor dietary habits and lifestyle factors that contributed to disease is crucial for sustained improvements.
• Fasting is not a replacement for standard medical treatments without a physician’s supervision. Anyone considering fasting should consult their doctor, especially those on medications or with medical conditions, for example diabetes.

Notes on Key Concepts

• Acetyl-CoA: A metabolite that conveys the carbon atoms of glucose, fatty acids, and amino acids to the TCA cycle to be oxidized for energy production. Serves as a key regulator of cell growth and metabolism.
• Adiponectin: Hormone from adipose tissue that increases insulin sensitivity.
• AMP:  Stands for Adenosine Monophosphate. AMP is sensed by the energy sensor AMPK (AMP-activated protein kinase). When cellular energy is low, AMP levels rise, which activates AMPK.  AMPK then works like a sensor to restore energy balance by stimulating energy production and limiting energy consumption.
• ATP: The primary energy currency of cells. ATP is continually synthesized and consumed by metabolic reactions that require energy input. Cells monitor ATP levels to detect energy deficit and maintain homeostasis.
• Autophagy: Cellular recycling process involving lysosomal degradation of damaged proteins, organelles, and other cell components. Ramped up by fasting, calorie restriction, or other stresses. Critical for cellular homeostasis.
• Calorie restriction mimetics: Compounds that mimic the biochemical and functional effects of calorie restriction, leading to similar health and longevity benefits, without requiring restricted food intake. Potential mimetics include sirtuin activators, mTOR inhibitors, and agents that induce ketosis or target insulin-IGF1 signalling.
• CCK: Cholecystokinin, a hormone released from intestinal cells that stimulates digestion and satiety. 
• Cellular reprogramming: Experimentally converting mature cells into stem cell-like states. This ‘resets’ the epigenetic state of the cells to make them functionally younger.
• Cytochrome P450 enzymes: These enzymes are a family of liver enzymes that play a major role in metabolising toxins and drugs. They help break down and deactivate foreign compounds like medications, environmental pollutants, and even some hormones.
• During fasting, many Cytochrome P450 enzymes are upregulated – meaning their activity increases. This ramping up of P450 activity enhances the body’s ability to clear out toxins and drug metabolites.
• Fasting Mimicking Diet (FMD): Very low calorie, low protein, low carb but high micronutrient diet consumed in cyclic fasting periods to mimic fasting responses.
• FOXO (Forkhead box O) refers to a family of transcription factors that play a key role in regulating metabolism, cellular proliferation, stress tolerance, and longevity. In response to low nutrient signals, FOXO becomes activated and can upregulate genes involved in gluconeogenesis, antioxidant defence, cell cycle arrest, and apoptosis. FOXO activity is inhibited by insulin/IGF-1 signalling, but increases during fasting states to orchestrate adaptive stress responses and maintain metabolic homeostasis. Modulating FOXO-mediated transcription appears central to the health and lifespan benefits conferred by fasting and calorie restriction.
• Glucokinase: Enzyme in liver and beta cells that phosphorylates glucose, acting as a glucose sensor.
• GLP-1: Glucagon-like peptide-1, an incretin hormone released from intestinal cells in response to nutrient sensing. Stimulates insulin secretion. Other GLP-1 targeting drugs include Ozempic, Wegovy
• GRP 40: GRP stands for Gastric Releasing Peptide. GRP 40 is a receptor that binds to a hormone called gastrin-releasing peptide (GRP). When GRP binds to GRP 40, it triggers the release of insulin from pancreatic beta cells. So GRP 40 helps potentiate or increase insulin secretion.
• GRP 120: This is a receptor that binds to omega-3 fatty acids like DHA and EPA. When omega-3s bind to GRP 120, it can help reduce inflammation and improve insulin sensitivity.
• Hormesis: Refers to the phenomenon by which exposure to mild, intermittent stressors activates adaptive cellular response pathways that enhance the body’s resilience. Activities like hypoxic breathwork, moderate exercise, and occasional fasting or calorie restriction represent hormetic stressors that stimulate protective mechanisms involved in metabolism, inflammation, and oxidative stress defence. By triggering hormesis through brief periodic stress, these practices may upregulate genes that boost mitochondrial function, antioxidant enzymes, protein chaperones, and autophagy – conferring anti-aging and longevity benefits. Hormetic stressors provoke an adaptive response that strengthens the body and improves overall cellular fitness.
• Hypothalamus: Region of the brain involved in appetite, metabolism, temperature regulation. Contains glucose/nutrient sensing neurons.
• IIS – Insulin/IGF-1 Signalling pathway: This pathway regulates metabolism and growth in response to insulin and IGF-1 (insulin-like growth factor 1). Defects in this pathway can lead to diabetes or accelerated ageing.
• IGF-1 – Insulin-Like Growth Factor 1: This growth factor has insulin-like effects including stimulating growth and inhibiting cell death. It works alongside insulin to control growth and metabolism.
• iPSCs – Induced pluripotent stem cells. Adult somatic cells are genetically reprogrammed into a pluripotent state by introducing key transcription factors. Allow patient-specific stem cells.
• Ketogenesis: Liver converts fatty acids into ketones like acetoacetate, β-hydroxybutyrate, and acetone during fasting or carb restriction. Ketones circulate to tissues as an alternative energy source. 
• Ketosis: Metabolic state where the body uses ketone bodies derived from fat as its main fuel source in the absence of adequate glucose. Achieved after prolonged fasting.
• Leptin: Hormone produced by adipose tissue that signals satiety and energy stores to the brain.
• Long-lived proteins: Proteins that persist for extended periods within cells without being broken down. Can accumulate damage over time.
• Metformin:  A diabetes drug that acts in part by mimicking effects of fasting or calorie restriction. It activates AMPK, an energy sensing pathway involved in the health benefits of fasting.
• Mitochondria: Mitochondria are oval-shaped organelles found in the cytoplasm of nearly all eukaryotic cells. They generate the majority of ATP through the process of oxidative phosphorylation, which involves oxidation of nutrients and transfer of electrons across the electron transport chain to oxygen. This electron transport creates an electrochemical proton gradient that drives ATP synthase to produce ATP. Mitochondria contain their own DNA and replicate independently. They are sometimes described as “cellular power plants” because they produce energy in the form of ATP. During states of overnutrition coupled with physical inactivity, excessive amounts of acetyl-CoA and other carbon substrates derived from carbohydrates, fats and proteins are delivered into the mitochondria. However, low ATP demand means that these substrates accumulate and are incompletely oxidized. This leads to mitochondrial membrane hyperpolarization and disturbance of the proton gradient. Excess electrons entering the electron transport chain also increase production of reactive oxygen species. These changes impair pH regulation and cause oxidative damage. The resulting mitochondrial dysfunction negatively affects cells and can eventually contribute to insulin resistance, metabolic disease, neurodegeneration, and other conditions across the body. Strategies like caloric restriction, exercise, and intermittent fasting help maintain mitochondrial function by balancing substrate delivery with energy utilization.
• mTOR – Nutrient sensing pathway:  inhibited during fasting. Mechanistic target of rapamycin, a nutrient sensor pathway that regulates growth and metabolism. Responds to amino acids. Regulates growth, proliferation and autophagy. Implicated in ageing processes. TOR is, therefore, a sensor of both carbohydrates and amino acids.
• NAD+ – Nicotinamide adenine dinucleotide: This is a key coenzyme involved in cellular metabolism and energy production. Levels of NAD+ decline with age, and restoring NAD+ has been shown to promote longevity.
• Pancreatic beta cells: Insulin-secreting cells in the pancreas that sense glucose levels.
• Plasma exchange:  A technique to filter the blood and remove substances in plasma, like inflammatory factors produced by senescent cells.
• Pluripotent: Cells that have the potential to differentiate into any cell type in the body. Includes embryonic stem cells
• Rapamycin:  A drug that inhibits the mTOR pathway, which is involved in cell growth and metabolism. Rapamycin has extended lifespan in mice but may cause side effects like insulin resistance in humans.
• Senescent Cells:  Dysfunctional cells that cease dividing but remain metabolically active, often secreting inflammatory factors. Implicated in ageing. Can resist cell death signals. 
• Senolytics: Compounds that can selectively eliminate senescent cells. Senescent cells are old cells that have stopped dividing but produce inflammatory signals. Getting rid of them may rejuvenate tissues.
• Senomorphics: Agents that can suppress inflammatory signals produced by senescent cells, without killing the cells entirely. This may limit harmful effects of senescent cells.
• Semaglutide:  An injectable diabetes drug that mimics effects of the hormone GLP-1. It aids weight loss and lowers post-meal blood sugar, which may have anti-aging effects. 
• Sirtuins: NAD-dependent protein deacetylases responsive to cellular energy states ( low/high Acetyl-CoA). Example is SIRT1. The removal of aberrant acetylation or acylation modifications may restore protein function. DNA methylation and histone deacetylation appear to act as synergistic layers for the silencing of genes in cancer (124,125).
• Spermidine: A natural compound that can induce autophagy, or cellular self-digestion. This is thought to promote longevity by helping cells clear out damage.
• Stem cells: Cells that can divide and renew themselves over long periods. Essential for tissue repair and maintenance.
• Taste receptors: G protein-coupled receptors on the tongue and in the gut that bind to nutrients like sugars, amino acids, and fats. Examples are the T1R family (bind sweet and umami) and T2R family (bind bitter). 
• Ubiquitin–proteasome system (UPS): The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular protein clearance pathways. The UPS contains proteasomes that rapidly degrade short-lived proteins as well as misfolded and unfolded polypeptides. In contrast, autophagy eliminates long-lived proteins, insoluble protein aggregates, and dysfunctional organelles like damaged mitochondria. Autophagy engulfs these cellular components in vesicles called autophagosomes and delivers them to lysosomes for breakdown. By selectively removing abnormal proteins and worn-out organelles, autophagy complements UPS function in preserving cellular protein and organelle quality control (112).
• Visceral Fat: Metabolically harmful fat located in the abdominal cavity around organs like the liver. Mobilized readily during extended fasting.

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Click to expand

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All content is for educational purposes only. Please consult your medical practitioner before attempting any fasting, therapeutic, nutritional, exercise or meditation related activity.