Fasting's hidden benefits: cellular cleanup, immunity and aging

The Short Version

Four physicians and scientists who rarely share a stage make the same unusual argument: the main value of going without food is not the pounds lost but the repair work the body does while it isn't eating. Psychiatrist Chris Palmer describes fasting and calorie restriction as triggers for autophagy and mitophagy, the clearing out of old and defective mitochondria and their replacement with new ones [1]. Pulmonologist Roger Seheult says there is good data that intermittent fasting rebuilds the immune system [2]. Geneticist David Sinclair argues that low insulin during fasting switches on longevity genes, and that longer fasts trigger a deeper cellular cleanup [3][4], while nephrologist Jason Fung calls fasting a way of "renovating your body," clearing out damaged components and keeping insulin, which he links to cancer growth, low [5]. Their evidence ranges from human trials to mouse studies to clinical observation, and they disagree on important details, but together they reframe fasting as a healthspan tool that can matter even for people who don't need to lose weight.

Table of contents

What They Said

Chris Palmer: fasting renews the cell's power plants

Palmer, a Harvard psychiatrist, arrives at fasting through the history of epilepsy treatment [1]. People have observed since the time of Hippocrates that fasting can stop seizures, and he corrects a common assumption: "Most people think going without food is bad, and they equate it with starvation" [1]. In fact, he says, going without food "puts the body into a mode of autophagy and conservation of resources and all sorts of things that are beneficial to human health" [1]. That, in his view, is why "fasting has been used as a therapeutic intervention in almost every culture and almost every religion for millennia," even though it was long dismissed as religious folklore [1].

The medical turning point came in 1921, when a physician used fasting on a child with seizures and found it worked [1]. But Palmer is blunt about the limit: "you can only fast for so long before you starve to death," and when normal eating resumes, seizures "usually come right back, oftentimes with a vengeance" [1]. So Dr. Russell Wilder at the Mayo Clinic designed the ketogenic diet with one purpose: to mimic the fasting state long term [1]. Palmer reports that 50 percent of patients became seizure-free and another 35 percent had at least a 50 percent reduction [1]. When anticonvulsant drugs arrived, about 30 percent of people with epilepsy still didn't respond; among those treatment-resistant patients, once Johns Hopkins revived the diet in the 1970s, about a third became seizure-free, a third had at least a 50 percent reduction and a third saw no benefit [1].

This history matters to the fasting argument because the ketogenic diet was built as a fasting mimic, and the decades of research on it tell us what the fasting state does in the brain. Palmer lists the effects: changes in glutamate, GABA and adenosine, altered calcium channel regulation and gene expression, reduced brain inflammation, a changed gut microbiome and improved insulin signaling [1]. But, he says, "the real magic is that this diet stimulates two processes that relate to mitochondria" [1]. The first is mitophagy, "getting rid of old and defective mitochondria and replacing them with new ones" [1]. The second is mitochondrial biogenesis, meaning that after months or years, "many of their cells in their bodies and brains will have more mitochondria, and those mitochondria will be healthier" [1].

Why would renewing mitochondria matter so much? Palmer argues they aren't just a cell's power cord but more like its motherboard, directing and allocating resources [1]. They help produce and release neurotransmitters such as serotonin, dopamine, glutamate and acetylcholine; they contain the enzyme needed to make steroid hormones like cortisol, estrogen, testosterone and progesterone; and they help regulate the stress response and inflammation, including signaling macrophages to switch between phases of wound healing [1]. He cites a David Sinclair paper proposing that defective mitochondrial function "is possibly the unifying cause of aging and all of the aging-related disorders" [1].

Palmer describes mitophagy as a specialized subset of autophagy, the body's system for recycling old cellular parts through lysosomes [1]. Autophagy always runs at a low level, but fasting, calorie restriction and fasting-mimicking diets strongly stimulate it, and he finds it striking that the body targets old and defective parts first rather than destroying healthy tissue [1]. His conclusion about tools is direct: "the most powerful signal and tool that we have right now is, in fact, related to diet. It's calorie restriction. That is the oldest, truest, best proven way to prevent aging in a wide variety of animal species" [1]. Fasting, intermittent fasting "and then fasting, mimicking diets can also stimulate this process of mitophagy" [1].

Importantly for the insight's point, Palmer separates these effects from what someone was eating before. Calorie restriction, ketogenic diets and carbohydrate restriction, he says, "are inducing metabolic changes in the brain and body," and "regardless of what the person was eating, they are inducing metabolic changes that can be really beneficial to brain health" [1]. His own story shows benefits well beyond the scale: when he tried the Atkins diet to avoid three medications for metabolic syndrome, his numbers normalized within three months while he lost only about 10 pounds, and what struck him most was a dramatic improvement in mood, energy, concentration and sleep [1].

He is also careful about evidence. On mental disorders, "If you're looking for randomized controlled trials, documenting efficacy in large numbers of patients with these disorders, we don't have them" [1]. And he insists that people with serious illness work with professionals and never stop psychiatric medication on their own: weight loss is something people wing, he says, but if you're using it to treat a serious disorder, I think you need serious help [1].

Roger Seheult: fasting and the immune system

Seheult, quadruple board-certified in internal medicine, pulmonary disease, critical care and sleep medicine, discusses fasting as one of several habits that build a stronger immune system [2]. His claim is brief but specific: there is good data, including from USC, that intermittent fasting rebuilds the immune system [2]. Host Lewis Howes flagged the segment on "How fasting plays a role in fighting diseases" as especially powerful for him [2].

The rest of Seheult's conversation shows why he values this kind of intervention. He believes adults should be working on their innate immunity: "kids have great innate immune systems. And that's what we ought to be doing with adults, is trying to figure out how to improve their innate immune system" [2]. He frames chronic illness as a body sitting on the edge of a cliff: people with obesity, kidney disease or diabetes are compensating and getting by until a stressor like the COVID virus knocks out a protective enzyme system and tips them over [2]. Prevention, he says, comes largely down to diet and activity, which our culture has traded for taste and short-term benefits; his analogy is that we've been cramming for quizzes all along and are now sitting the final exam with nothing [2].

Seheult's framework for fasting sits alongside moderate exercise, sleep, time in nature and gradual diet change [2]. He describes a McMaster University trial in which moderate exercise lowered depression, anxiety and inflammatory markers in stressed students, while high-intensity exercise lowered depression less and actually raised interferon levels, part of a pattern called the J-curve, where moderate stress helps and too much harms [2]. That pattern is a useful lens for fasting too, though he doesn't apply it to fasting directly.

He also offers a caution that bears on how fasting's benefits should be read. He distinguishes in vitro results, in a lab dish, from in vivo results in a living person, reminding listeners that "the body is a very complex machine" [2]. And he warns against trying to biohack everything into isolated extracts, citing trials in which high-dose vitamin E and vitamin A given to lung cancer patients accelerated their deaths even though diets rich in those vitamins had looked protective [2].

David Sinclair: hunger switches on the longevity genes

Sinclair, a Harvard professor of genetics, explains fasting's value through the biology of aging itself. He reduces aging to "the loss of information due to entropy," a gradual scrambling of the epigenome, the control system that tells each cell which genes to use [4]. His analogy is a CD: DNA is the music, the epigenome is the reader, and aging is scratches on the disc that make cells play the wrong songs [4]. The question is what slows the scratching, and his answer centers on eating less often.

The history he gives goes back to the 1930s, when Clive McCay put cellulose in rats' food so they couldn't get as many calories, and "those rats lived 30% longer" [4]. In the 2000s, Sinclair's lab and others showed there are longevity genes that protect against aging and disease [4]. His lab showed in 2005 that low levels of insulin and insulin-like growth factor switch on the sirtuins, a family of seven longevity genes, while constant eating does the opposite: "by having high levels of insulin all day, being fed means your longevity genes are not switched on" [4]. Across animals, those that don't eat all the time live up to 30 percent longer, and he calls it a big mistake that modern life means people may never feel hungry [4].

Sinclair describes three pathways that respond to eating less: mTOR, which senses amino acids and suppresses cell growth when turned off; AMPK, which senses energy levels; and the sirtuins, repair proteins that protect against disease [3]. Fasting raises sirtuin activity and lowers mTOR, which turns on the body's defenses: clearing old proteins, improving insulin sensitivity and repairing cells [4]. He explains that even short-term fasting, such as skipping breakfast or eating one meal a day, can activate these pathways [3].

Longer fasts go further. Sinclair says a three-day fast may trigger chaperone-mediated autophagy, a deeper level of cellular cleaning that removes toxic proteins and is linked to disease prevention and potentially age reversal [3]. In the Huberman conversation he credits its discovery to Ana Maria Cuervo and says he fasts for two days about once a month because longer fasts trigger this deeper cleanup [4].

Timing, for Sinclair, may matter more than content. He describes a study by Rafael de Cabo at the NIH in which mice fed within one hour a day lived dramatically longer than mice eating freely, regardless of their diet, and concludes, "it's not as important what you eat. It's when you eat during the day" [4]. His core idea is pulsing: "what you want to do is to get the cells to be perceiving adversity" [4]. In modern life, he explains, we sit around, eat too much and don't exercise, and our cells respond, "hey, everything's cool, no problem," relaxing their defenses so we age faster [4]. "People who exercise and eat less have a slower ticking clock. It's a fact," he says [4].

He connects this to a trade-off. Leucine, growth hormone and testosterone give quick gains, "You'll feel better immediately. But based on the research, it's at the expense of long-term health" [4]. His summary of his philosophy: "I don't burn both candles" [4]. He calls growth hormone pro-aging, noting that mice with low growth hormone live longest; one mouse given calorie restriction plus a dwarf mutation lived five years instead of the usual two and a bit [4].

He links eating less to immunity as well. Aging, he says, is the number one risk factor for most diseases, including how we respond to viruses like COVID-19, because immune systems become less responsive and chronic inflammation increases with age, a state called inflammaging [3]. NAD, critical to energy and cellular repair, declines with age, obesity and never being hungry [3][4]. His framing is healthspan, not just lifespan: the goal is to stay young longer and replace a slow, disease-ridden decline with vitality that ends quickly [3].

Sinclair even notices benefits outside the lab. Since changing his diet, he says, he no longer gets dental plaque, which he attributes to not having sugars in his mouth for bacteria to feed on [4].

Jason Fung: fasting as renovation and cancer prevention

Fung, a nephrologist and author of The Obesity Code, The Diabetes Code and The Cancer Code, argues that fasting is not starvation but a normal human cycle we've forgotten [5]. During fasting, insulin drops, fat burning increases and the body enters autophagy, a deep cellular cleanse that removes damaged components [5]. He likens it to "renovating your body": before you rebuild, you have to clear out the junk [5]. He says studies show fasting increases human growth hormone, improves mental clarity and initiates cellular repair [5].

His focus is cancer. Fung frames it as seed and soil: the seed exists in everyone, but it only grows in the right soil, which he identifies as high insulin, chronic inflammation and constant feeding [5]. He says obesity, diet and metabolic dysfunction are now major contributors, noting that the WHO considers 13 types of cancer obesity-related [5]. In the 1970s people ate three meals a day, while today they average five to six eating events, never giving the body a break; constant eating keeps insulin high, which he says blocks fat burning and keeps the body in growth mode [5]. His line: "If you're always eating, you're always growing—and that's the perfect condition for cancer cells to thrive" [5].

He lists what fasting does, in his view: it lowers insulin, cutting off what he calls cancer's fuel; burns stored fat, reducing obesity-related risk; initiates autophagy, reducing cellular mutations; and doesn't cost muscle if you stay active [5]. He contrasts this with supplements, citing major randomized trials in which vitamins A, D, B, C, E, selenium and omega-3 did not reduce cancer risk, and beta-carotene actually increased it [5]. Vitamins act like fertilizer, he warns, feeding everything including cancer, while fasting prunes back overgrowth [5].

Fung also tackles the fear of "starvation mode." He says data show that after four days of fasting, metabolic rate rises by 10 percent [5]. Hunger comes in waves, usually at mealtimes, and passes if you don't eat, and after two to three days many people report no hunger at all, just mental clarity [5]. He argues fasting complements any eating plan, whether keto, vegan or Paleo, because it tells you when not to eat rather than what to eat [5]. Like Palmer, he points to tradition: fasting was universal across spiritual practices such as Ramadan, Yom Kippur and Lent, not as punishment but as renewal [5].

Where They Agree, and Where They Don't

The core agreement: going without food switches the body into maintenance mode. Palmer calls it a mode of autophagy and resource conservation [1]; Sinclair describes cells perceiving adversity and turning on their defenses [4]; Fung describes a cellular cleanse that clears damaged parts [5]; and Seheult says fasting rebuilds the immune system [2]. All four treat constant feeding as the problem. Sinclair says high insulin all day keeps longevity genes off [4], and Fung says always eating means always growing [5].

Agreement that the benefits go beyond weight. Palmer's own metabolic syndrome resolved with only about 10 pounds lost, and his biggest surprise was his mood and energy [1]. Sinclair's argument is about the epigenetic clock, not the scale [4]. Fung focuses on cancer risk [5], and Seheult on immunity [2].

Agreement on ancient precedent. Palmer says fasting has been used therapeutically in almost every culture and religion for millennia [1], and Fung names Ramadan, Yom Kippur and Lent [5].

Agreement that isolated supplements are not a substitute. Fung says vitamin trials failed to cut cancer risk and beta-carotene raised it [5]. Seheult cites high-dose vitamin E and A trials that accelerated deaths in lung cancer patients [2]. Sinclair says antioxidants largely failed in animals and humans and advises against megadoses, noting "We do need some oxidants for our immune system" [4]. Sinclair does take supplements such as resveratrol and NMN and metformin through his doctor [4], so he differs from Fung and Seheult on whether some supplements can help, but all three favor switching on the body's own defenses over flooding it with antioxidants [2][4][5].

Disagreement: calorie restriction versus fasting. Palmer calls calorie restriction the oldest and best-proven way to prevent aging across animal species [1], and Sinclair's history of the field starts with calorie-restricted rats [4]. Fung, however, argues that calorie restriction lowers metabolic rate, while fasting preserves energy use and encourages fat loss [5]. Sinclair takes a middle position: in the de Cabo study, meal timing mattered regardless of diet, so when you eat may matter more than how much or what [4].

Disagreement: growth hormone. Fung counts a rise in human growth hormone among fasting's benefits [5]. Sinclair calls growth hormone pro-aging: it makes people feel great and build muscle short term but is like burning the candle at both ends, and mice with low growth hormone live longest [4]. The sources don't resolve this; Fung frames the rise as protective during a fast, while Sinclair's concern is chronically high growth signaling.

Disagreement: how long a fast needs to be. Sinclair says even skipping one meal activates longevity pathways [3], but reserves the deeper chaperone-mediated autophagy for longer fasts of about two to three days [3][4]. Fung describes benefits of multi-day fasts, including a 10 percent rise in metabolic rate after four days [5]. Palmer stresses that fasting can't go on indefinitely and that the ketogenic diet and fasting-mimicking diets exist precisely to get fasting's effects in a sustainable way [1].

Different strengths of evidence. Sinclair relies heavily on animal studies: rats, mice and a record-setting dwarf mouse [4]. Palmer has a century of epilepsy data and striking patient cases but says large randomized trials in psychiatry don't exist yet [1]. Seheult's immune claim is a short reference to data including from USC [2]. Fung cites WHO classifications, vitamin trials and metabolic rate data, but the cancer-prevention effect of fasting itself is presented as a mechanism-based argument rather than a named trial [5]. Seheult's own warning that lab results often fail in living bodies is worth keeping in mind across all of them [2].

Why It Works

Autophagy and mitophagy. When the body goes without food, it steps up autophagy, recycling old cellular parts through lysosomes, and it targets old and defective parts first [1]. Mitophagy, a specialized form, removes old and defective mitochondria and replaces them, while mitochondrial biogenesis builds more and healthier mitochondria over months or years [1]. Because mitochondria help control neurotransmitters, steroid hormones, stress responses and inflammation, renewing them could affect far more than energy [1]. Fung describes the same cleanup as clearing out damaged components, which he links to fewer cellular mutations [5].

Chaperone-mediated autophagy. Sinclair describes a deeper level of cleaning, triggered by longer fasts of two to three days, that removes toxic proteins [3][4].

Low insulin and the longevity pathways. Low insulin and insulin-like growth factor switch on the sirtuins [4]. Fasting raises sirtuin activity, lowers mTOR and engages AMPK, which senses energy levels [3][4]. The result, Sinclair says, is clearing old proteins, better insulin sensitivity and cell repair [4]. Fung makes the insulin point from the cancer side: high insulin keeps the body in growth mode, the soil in which cancer seeds can thrive [5].

Hormesis: small doses of adversity. Sinclair's pulsing idea is that cells turn on their defenses when they perceive adversity and relax them when everything seems fine [4]. Seheult's J-curve for exercise, where moderate stress lowers inflammation and heavy stress raises it, shows the same shape in a different system [2]. Sinclair's point that we need some oxidants, and that mitochondria need a few free radicals to function, fits the same logic: a little stress is a signal, not just damage [4].

Immune renewal and inflammation. Seheult says intermittent fasting rebuilds the immune system [2]. Sinclair explains that aging brings less responsive immunity and more chronic inflammation, and that NAD, which supports cellular repair and immune function, declines with age and with never being hungry [3][4]. Palmer lists reduced brain inflammation among the effects of the fasting-mimicking ketogenic diet [1].

The epigenetic clock. Sinclair says people who exercise and eat less have a slower ticking clock, measurable in the methylation patterns that track biological age [4].

Where It Applies, and Where It Doesn't

It applies to people who aren't overweight. Sinclair's reasoning is about aging, not body fat [4]; Palmer says the metabolic changes benefit the brain regardless of what someone was eating before [1]; and Fung says fasting fits any eating plan [5]. That's the core of the reframe: the repair processes are the goal, weight loss a side effect.

It does not replace medical care for serious illness. Palmer's warning is explicit: people with serious mental illness or heavy medication use need professional supervision, and stopping psychiatric medication without it is dangerous [1]. Sinclair uses metformin through his doctor and advises talking to a doctor about drugs like statins [4]. Anyone with diabetes, a history of eating disorders, pregnancy, a chronic illness or a medication regimen should talk to a physician before fasting, especially for more than a day.

Long fasts have limits. You can only fast for so long, Palmer says, and benefits for seizures vanished once eating resumed [1]. That suggests the effects depend on regular repetition, which is why he points to sustainable fasting mimics like the ketogenic diet [1].

Much of the longevity evidence is from animals. The 30 percent lifespan gains, the one-hour feeding window and the five-year mouse come from rodents [4]. Palmer's calorie restriction claim is about "a wide variety of animal species" [1]. Seheult's caution that results in a dish or an animal don't always hold in a person applies here [2].

Muscle and growth trade-offs. Sinclair accepts giving up some short-term growth signaling for long-term health and still lifts weights to keep muscle [4]. Fung says fasting doesn't cost muscle if you stay active [5]. People trying to build muscle may have to weigh these trade-offs.

Fasting is not a license to eat poorly. Fung still wants sugar, refined grains, refined oils, processed meats and constant snacking cut [5]. Sinclair eats mostly plants and a vegetable-based dinner [4]. Seheult singles out high-fructose corn syrup as a driver of oxidative stress [2]. Palmer says for some people, just removing highly processed junk food makes a big difference [1].

It's hard at first. Sinclair warns the first two to three weeks of meal skipping are hard and recommends building up gradually rather than going cold turkey [4]. Fung says hunger comes in waves and fades [5].

What To Do With It

1. Stop grazing first. Fung says the shift from three meals a day to five or six eating events keeps insulin high all day [5]. Cutting snacks between meals is the simplest way to give the body the breaks all four experts describe.

2. Skip one meal a day, attached to your sleep. Sinclair's top recommendation is "definitely try to skip a meal a day, that's the best thing," ideally breakfast or dinner so the fast joins the overnight sleep period [4]. He himself skips breakfast, drinks water, tea and coffee and eats one mostly vegetable-based dinner, often in about a two-hour window [4].

3. Ease in over weeks. Expect the first two to three weeks to be hard, and build up gradually [4]. Seheult's broader advice on diet change applies: change one thing at a time, since tastes often adjust after two or three months [2].

4. Consider an occasional longer fast only with medical guidance. Sinclair fasts for two days about once a month to trigger chaperone-mediated autophagy [4], and Fung describes multi-day fasts in which hunger fades after two to three days [5]. Talk to a doctor before trying fasts of this length.

5. Keep eating well when you do eat. Cut sugar, refined grains, refined oils and processed meats [5], limit high-fructose corn syrup [2], and eat mostly plants, as Sinclair does [4]. If a longer fast isn't practical, Palmer notes that carbohydrate restriction and fasting-mimicking diets can stimulate similar processes [1].

6. Pair fasting with moderate exercise and resistance training. Sinclair lifts to maintain muscle and says people who exercise and eat less have a slower clock [4]; Fung says staying active protects muscle during fasting [5]; Seheult's research favors moderate over extreme intensity [2].

7. Don't count on pills to do the same job. Avoid megadoses of antioxidants and vitamins [2][4][5], and if you use supplements or prescription drugs for longevity, do it with a doctor and buy from reputable manufacturers, as Sinclair does [4].

8. Measure rather than guess. Sinclair tracks markers like HbA1c and high-sensitivity CRP over time and says "if you don't measure something, you can't optimize it" [4]. Watch how your mood, energy, concentration and sleep change too, since those were the benefits that surprised Palmer most [1].

9. If you have a serious condition, make fasting part of treatment, not a substitute for it. Palmer's rule is serious help for serious disorders, and never stop medications without your prescriber [1].

Sources

1. Dr. Chris Palmer on Diet, Metabolism, Mitochondria, and Mental Health (Huberman Lab Essentials) · Huberman Lab
2. The Facts About Vaccines, Improving Immunity, and The Medical Side of Mental Health with Dr. Roger Seheult · The School of Greatness
3. How to Stop Aging (Can Humans Become Immortal?) with Dr. David Sinclair · The School of Greatness
4. Dr. David Sinclair: The Biology of Slowing & Reversing Aging · Huberman Lab
5. How To Prevent Cancer With Your Food & Fasting with Jason Fung · The School of Greatness