Fasting Part I: Resetting the clock
What science tells us about fasting, stem cells, and the body's remarkable capacity for renewal
I have been aware of the biological benefits of fasting for some time now but it’s not something that I have personally embraced - until now!
But before I get into that I thought I would use Part I to cover the key aspects and then in Part II I will share my own experience.
So, there is a quiet revolution happening in longevity science, and it doesn’t come in a bottle.
It requires no supplement, no prescription, no expensive intervention. It is, in the most fundamental sense, the absence of something - the deliberate absence of food. What emerges from that absence is one of the most compelling stories in modern biology.
Fasting. Not starvation. Not deprivation. A controlled, intentional, time-defined withdrawal from eating that, depending on the duration, triggers a cascade of physiological events, that researchers at some of the world’s most respected institutions have described as a near-complete reset of the immune system, a regeneration of cellular machinery, and in some contexts, a mobilisation of the body’s own stem cell reserves.
This post is for anyone serious about long-term health.
Why We Fast: The Evolutionary Logic
The human body was not designed for constant feeding. For the vast majority of our evolutionary history, food was intermittent, feast and famine were both realities, and the body evolved sophisticated mechanisms to not only survive scarcity but to use it productively.
When food is abundant and glucose is constantly available, the body runs on a kind of metabolic autopilot. Cells grow, replicate, and consume. The housekeeping systems, the ones that clear out damaged proteins, recycle cellular components, and identify and neutralise dysfunctional cells are kept largely quiet.
When food is withdrawn, something shifts. Insulin drops. Glucose falls. The body begins transitioning from glucose burning to fat burning, generating ketone bodies as an alternative fuel source. At the cellular level, a set of ancient, highly conserved biological processes begins to activate, processes that, under normal fed conditions, remain largely dormant.
Understanding what happens across different fasting windows is the foundation of everything that follows.
The 24-Hour Fast: Cellular Housekeeping Begins
A 24-hour fast is long enough to meaningfully alter metabolic state for most people, though the timeline varies based on activity level, metabolic health, and what was eaten beforehand.
Key processes activated:
Glycogen depletion and metabolic switching. Liver glycogen, the primary short-term glucose store, is typically depleted within 12–18 hours of fasting, depending on activity. As glycogen falls, the body begins increasing fat oxidation and, critically, begins ramping up ketone production. By the 24-hour mark, blood ketone levels are measurably elevated in most individuals.
Autophagy induction. Perhaps the most significant cellular event triggered within the first 24 hours is autophagy, from the Greek for “self-eating.” This is a highly regulated process in which cells break down and recycle their own damaged or dysfunctional components: misfolded proteins, damaged organelles, oxidised lipids. Think of it as cellular maintenance, or more accurately, cellular recycling.
The Nobel Prize in Physiology for Medicine in 2016 was awarded to Yoshinori Ohsumi specifically for his work on autophagy mechanisms1. His research and the substantial body of work it inspired has demonstrated that autophagy plays a critical role in protecting against neurodegeneration, cancer, infection, and ageing. Crucially, one of the most reliable triggers for autophagy induction is nutrient deprivation, and specifically the drop in insulin and mTOR (mechanistic target of rapamycin) signalling that accompanies fasting.
Insulin and IGF-1 reduction. Within 24 hours, fasting produces significant reductions in circulating insulin and insulin-like growth factor 1 (IGF-1). Chronically elevated IGF-1 has been associated with accelerated cellular ageing and increased cancer risk. The periodic suppression of IGF-1 signalling through fasting is one of the proposed mechanisms through which caloric restriction extends lifespan in animal models.
Health benefits supported by evidence:
Improvements in insulin sensitivity (particularly relevant in the context of type 2 diabetes and metabolic syndrome)
Reduction in inflammatory markers including CRP and interleukins
Modest but consistent improvements in LDL particle size and triglyceride levels
Activation of AMPK (AMP-activated protein kinase), often described as the body’s cellular energy sensor, which promotes cellular repair and mitochondrial biogenesis
A 24-hour fast is accessible for most healthy adults. Its effects are real, measurable, and well-supported in the literature, though many of the most dramatic regenerative effects require longer durations.
The 48-Hour Fast: Ketosis Deepens, Repair Accelerates
By 48 hours, the metabolic shift is complete for most people. The body is in full nutritional ketosis. Blood ketone levels, primarily beta-hydroxybutyrate, may reach 1–3 mmol/L or higher. Autophagy is running at significantly elevated levels compared to the fed state and several additional biological events are now coming online.
Human growth hormone (HGH) surge. One of the more striking findings in fasting research is the dramatic increase in growth hormone secretion. A landmark study found that a 2-day fast increased GH secretion fivefold2. This counterintuitive rise, growing hormones during a period of no food intake, serves to preserve lean muscle mass and direct the body toward fat utilisation. This is one reason why extended fasting, done correctly, does not produce the muscle catabolism that chronic caloric restriction often does.
Deeper autophagy and mitophagy. By 48 hours, autophagy is significantly upregulated. Mitophagy, the selective autophagy of damaged mitochondria, becomes more pronounced. Mitochondrial health is central to cellular energy production and is strongly implicated in ageing processes; the clearance of dysfunctional mitochondria is thought to be one of the most important downstream benefits of extended fasting.
Immune system modulation. The immune system begins to undergo meaningful shifts by the 48-hour mark. There is evidence that circulating levels of pro-inflammatory cytokines begin to fall, and that fasting induces a shift in immune cell populations. This is where the connection to stem cells begins to emerge more directly and we will return to this.
Neurological effects. Ketone bodies, particularly beta-hydroxybutyrate, are not merely a fuel source. They are signalling molecules. Emerging research suggests they inhibit the NLRP3 inflammasome (a driver of neuroinflammation), increase BDNF (brain-derived neurotrophic factor, critical for neuroplasticity and cognitive health), and provide neuroprotective effects that have led to significant interest in ketosis as a therapeutic strategy for conditions ranging from epilepsy to Alzheimer’s disease.
Evidence base:
A 48-hour fast sits at the junction where the well-established metabolic benefits of shorter fasting merge with the more profound regenerative effects that begin to emerge with longer durations. It is the territory of serious fasting protocols used in clinical research, and it carries a meaningful evidence base for improvements in metabolic health, inflammation, and cellular maintenance.
The 72-Hour Fast: Stem Cell Regeneration and Immune Reset
This is where the science becomes, in the most precise sense of the word, extraordinary.
The landmark research here comes from Valter Longo’s laboratory at the USC Longevity Institute3, published in the journal Cell Stem Cell in 20144. The study examined the effects of prolonged fasting (defined as 2–4 days) on haematopoietic (blood and immune) stem cells, both in mouse models and in patients undergoing chemotherapy.
The findings were remarkable.
The PKA pathway and stem cell activation:
Extended fasting causes a reduction in IGF-1 and PKA (protein kinase A) signalling. This downregulation appears to act as a signal for the body to break down and recycle old, damaged immune cells and then, upon refeeding, to trigger haematopoietic stem cells to proliferate and regenerate a new immune cell population.
In the mouse studies, after prolonged fasting cycles, researchers observed a near-complete turnover of the immune system, with old and potentially dysfunctional cells cleared and replaced with newly generated cells derived from activated stem cells. The white blood cell count dropped significantly during fasting, then rebounded above baseline after refeeding, reflecting new immune cell generation from bone marrow stem cells.
In the human chemotherapy patients, prolonged fasting was shown to protect healthy cells from chemotoxicity while making cancer cells more vulnerable - a finding with profound clinical implications - but more germane here, it also appeared to support immune system recovery, consistent with the stem cell regeneration hypothesis.
What this means for stem cells specifically:
The prevailing model, supported by multiple independent research groups, is as follows:
Extended fasting (particularly 3–5 days) creates metabolic and hormonal conditions that signal to the body that “times are hard.”
The body responds by downregulating growth and proliferation pathways (IGF-1, mTOR, PKA).
Old, damaged, or senescent immune cells are cleared through apoptosis and autophagy.
Upon refeeding, the removal of fasting stress acts as a trigger: haematopoietic stem cells in the bone marrow receive a regenerative signal and begin producing new immune cells.
The net effect, over repeated fasting cycles, is a gradual renewal of the immune cell pool.
This is not a metaphor. It is a measurable, mechanistic process that can be observed in blood markers and in the genetic profiles of circulating immune cells.
Additional 72-hour effects:
Gut microbiome remodelling: emerging evidence suggests extended fasting significantly alters gut microbial composition, with increases in health-associated species upon refeeding
Dramatic autophagy elevation: by 72 hours, autophagy markers are at peak levels in most tissues
Continued suppression of inflammatory pathways
Potential epigenetic reprogramming: methylation patterns show changes consistent with cellular rejuvenation in some tissue types
Beyond 72 Hours: The Fasting-Mimicking Protocol and Extended Fasting
For durations beyond 72 hours, the science becomes more complex — and the protocols more important5.
Prolonged water fasting (4–7+ days) has been practised therapeutically for over a century, and there is a clinical literature supporting its use in specific conditions including hypertension, rheumatoid arthritis, and certain autoimmune conditions. Studies from the Buchinger clinic in Germany6 which has conducted medically supervised fasting for decades, document broad benefits including significant improvements in metabolic markers, inflammatory conditions, and subjective wellbeing.
However, extended fasting beyond 3–5 days carries increasing risks without medical supervision, including electrolyte imbalances, refeeding syndrome risk, and muscle catabolism if protein intake is not carefully managed on refeeding.
The Fasting-Mimicking Diet (FMD), developed by Valter Longo and his team, represents an attempt to capture the regenerative benefits of extended fasting while making the protocol more accessible and safer. The FMD involves 5 days of a specifically designed low-calorie, low-protein, plant-based diet (roughly 800–1,100 calories per day with a precise macronutrient composition) that tricks the body into believing it is fasting.
Clinical trials of the FMD — published in journals including Science Translational Medicine7 — have demonstrated:
Reductions in IGF-1, blood glucose, and blood pressure
Reduction in visceral fat with preservation of lean muscle mass
Improvements in markers of biological ageing
Reductions in inflammatory biomarkers
Evidence of stem cell-based regeneration in immune cell populations
The FMD is now the most evidence-backed protocol for capturing multi-day fasting benefits in a more manageable format and is available commercially as ProLon8.
Important caveats:
Extended fasting is not appropriate for everyone: contraindications include pregnancy, type 1 diabetes, active eating disorders, certain medications, and underweight status
Most dramatic benefits in human studies involve extended fasting (3–5 days), which requires supervision for many people
The gut microbiome refeeding effect is critically important — what you eat when you break a fast matters enormously
Practical Implications
For those considering incorporating fasting into their health practice:
24-hour fast (1–2x per week): Accessible, well-supported for metabolic health, autophagy induction, and inflammation reduction. A typical protocol is dinner-to-dinner.
48-hour fast (monthly or quarterly): More significant metabolic and regenerative effects. Electrolyte management (sodium, potassium, magnesium) becomes important. Not appropriate without basic health screening.
72-hour fast (2–4 times per year): The zone of meaningful immune regeneration and stem cell activation based on current evidence. Medical supervision advisable, particularly for first attempts. Refeeding protocol matters — light, easily digestible foods rich in polyphenols and fermented foods are preferable.
Fasting-Mimicking Diet (quarterly): The most evidence-backed multi-day protocol for the general population. Provides extended fasting benefits with lower risk and better adherence.
To conclude, now that you have the history and framework of fasting, in Part II I will share my recent experience and why I chose to do it.
So until next time…..
This post is for educational purposes and does not constitute medical advice. Always consult a qualified healthcare professional before undertaking extended fasting, particularly if you have an existing health condition or take medication.