Fasting Mimetics Replicate Longevity Benefits Without Fasting
TL;DR
- Longer fasting periods (24-36 hours) are required to deplete glycogen stores and initiate fat metabolism, activating cellular repair and longevity pathways beyond transient metabolic marker improvements seen in shorter fasts.
- Extended fasting (36+ hours) can lead to protein breakdown for gluconeogenesis, initially from organ mass and then muscle, necessitating resistance training to signal muscle necessity and preserve lean tissue.
- Fasting induces blood acidification from ketone production, prompting the body to pull calcium from bones to buffer pH, which can be counteracted by strength training to stimulate bone-building osteoblasts.
- Supplementing with a combination of PEA, OEA, spermidine, and nicotinamide can mimic the cellular benefits of a 36-hour fast, including anti-inflammatory and antioxidant effects, without actual fasting.
- PEA, a natural anti-inflammatory and pain reliever, and OEA, an appetite suppressant that aids in metabolic switching, are key metabolites elevated during fasting that can be supplemented to replicate fasting's benefits.
- Spermidine, known for enhancing cellular autophagy, is crucial for longevity and cognitive function, with intakes of 30mg+ correlating with increased lifespan, significantly higher than average American consumption.
- Mimio, a supplement formulation of PEA, OEA, spermidine, and nicotinamide, has demonstrated the ability to prevent post-meal declines in cellular and plasma functionality and reduce biological age by 2.5 years in eight weeks.
- For women, particularly in perimenopause and menopause, extended fasting can exacerbate hormonal sensitivities like HPA axis activation and thyroid suppression, making fasting mimetics a potentially beneficial alternative.
Deep Dive
The discussion begins by introducing the concept of fasting, specifically highlighting that certain types of fasting have been shown to promote lifespan significantly, independent of caloric restriction. This particular type of fasting involves delaying eating, and the source notes that even without reducing overall calories, this delay can lead to lifespan extension.
The conversation then shifts to the host's evolving perspective on fasting, particularly for women in midlife who are focused on preserving muscle, bone, and organ health. While acknowledging the undeniable benefits of fasting that are not achieved in a fed state, the host expresses a softened view, especially for women who may not want to or cannot engage in prolonged fasting. The guest, Dr. Chris Rhodes, a nutritional biochemist, is introduced. His research has focused on the molecular responses to prolonged fasting, notably a 36-hour fast, and he aims to discuss the benefits of fasting and alternatives for those who wish to experience these benefits without extended periods of not eating.
Dr. Rhodes elaborates on the biological mechanisms of fasting, explaining that it shifts the body from using exogenous energy sources (food) to endogenous ones (stored carbohydrates, protein, and fat). This metabolic switch leads to a change in cellular fuel utilization, moving from a glucose-carbohydrate state to a fat and ketone body production metabolism. He describes this as activating a "longevity bio-program" that is inherent in the body but not typically active. In a fed state, the evolutionary signal is to focus on reproduction and fertility, leading cells to "run dirty," producing more waste and damage. Conversely, a fasting state signals survival, longevity, and maintenance, activating metabolic efficiency pathways like autophagy (cellular recycling), switching fuel sources, and down-regulating pathways like mTOR while up-regulating others such as AMPK and Nrf2 for stress protection.
The discussion then explores various fasting lengths, from time-restricted eating (like 16:8) to alternate-day fasting and multi-day fasts (24, 36, 72 hours). Dr. Rhodes explains that a 16-hour fast is generally not long enough to deplete glycogen stores and initiate the metabolic switch to fat and ketone metabolism, which typically occurs around 20-24 hours. While 16:8 fasting can show transient improvements in metabolic markers like glucose and cholesterol, it does not significantly impact cellular processes like autophagy or stem cell regeneration. A 24-hour fast (OMAD - One Meal A Day) begins to induce these early stages of fasting and minimizes time spent in the post-prandial state. Alternate-day fasting, where one eats normally one day and fasts the next, is identified as the type of fasting shown in most studies to promote lifespan significantly, independent of caloric restriction. Multi-day fasts lead to deeper autophagy and are associated with benefits for cancer prevention and immune cell regeneration around the 72-hour mark.
Dr. Rhodes details his doctoral research on a 36-hour fast, identifying a specific metabolic signature that includes a drop in circulating glucose, a rise in ketone levels, and over 300 significantly elevated metabolites. These metabolites act as bioactive biochemical signals that tell cells to run the fasting or longevity program. He specifically mentions anti-inflammatory molecules like endocannabinoids (PEA and OEA), autophagy promoters like spermidine, and increased circulating NAD levels. Ex vivo modeling showed significant improvements in cellular antioxidant capacity, anti-inflammatory capacity, cardioprotective ability, metabolic flexibility, and resilience to stressors after a 36-hour fast in both men and women.
The conversation turns to NAD, a key energy sensor molecule that signals cells to activate caloric restriction and fasting-like pathways through sirtuins. Sirtuins influence DNA expression, impacting cellular functionality. The role of estrogen in NAD salvage is discussed, noting that as estrogen declines with age, women may become less efficient at sustaining NAD pools, potentially impacting their resilience and repair capacity during fasting. However, research suggests that postmenopausal women may exhibit fasting responses more similar to men due to hormonal cycle fluctuations being less pronounced.
The impact of fasting on cortisol and the HPA axis is explored, noting that fasting elevates cortisol, which mobilizes resources but can also lead to anxiety and fat storage if chronically elevated. The menstrual cycle's influence on women's fasting responses is also mentioned, with responses being more similar to men during hormonal dips. The potential for fasting to suppress thyroid function, specifically reducing T3 (active thyroid hormone), is raised, which could compound fatigue and slow metabolism, particularly for women in midlife already susceptible to thyroid issues. However, Dr. Rhodes notes that fasting's anti-inflammatory and immune-regulatory effects may be beneficial for autoimmune conditions like Hashimoto's.
The discussion addresses muscle preservation during fasting, explaining that in deeper fasts (beyond 36 hours), the body may break down protein for gluconeogenesis to fuel the brain. While initially this protein may come from organ mass like the liver, prolonged fasting can lead to muscle loss. Resistance training is identified as the best way to prevent muscle wasting, as it signals to the body that muscle is necessary for survival, prompting it to pull protein from organ mass instead. Cardio, especially endurance cardio, is described as potentially catabolic during a fast.
Bone density loss during fasting is explained by the buffering of blood pH. As ketone bodies increase, they acidify the blood, prompting the body to pull calcium from bones to neutralize it. Strength training is again highlighted as crucial, as it stimulates osteoblast activity (bone building) and can help balance bone resorption.
Dr. Rhodes then delves into specific metabolites identified from fasting research: PEA (palmitoylethanolamide), OEA (oleoylethanolamide), spermidine, and nicotinamide. PEA is described as the body's "rest, relax, and recover" molecule, with anti-inflammatory, mood-enhancing, and pain-relief effects, comparable to CBD or ibuprofen. OEA, found to be elevated in fasting states, stimulates satiety and suppresses appetite, acting as a natural appetite suppressant during fasting. Spermidine is known for enhancing cellular autophagy and has been linked to longevity and cognitive health, with intakes of 30mg or more correlated with increased lifespan and health span. The combination of these four molecules, when supplemented, was found to extend lifespan in C. elegans by 96% and, in a human study, led to a 2.5-year reduction in biological age within eight weeks, along with significant improvements in metabolic markers.
The concept of using these compounds as a "fasting mimetic" to achieve fasting benefits without actual fasting is presented. The formulation (MIMIO) uses specific dosages: 600mg ultra-micronized PEA, 400mg OEA, 8mg spermidine, and 250mg nicotinamide. Clinical studies showed that supplementing with MIMIO not only prevented the negative metabolic and inflammatory effects of eating a meal but also enhanced cellular and plasma functionalities, mimicking fasting benefits. Improvements were observed in metabolic health, including glucose levels, cholesterol, inflammation, and testosterone, as well as hunger control, cravings, and satiety.
The discussion touches on potential future research, including longer-term studies with the MIMIO formulation and investigating other regenerative states like exercise
Action Items
- Create fasting mimetic supplement: Combine PEA (600mg), OEA (400mg), spermidine (8mg), and nicotinamide (250mg) to mimic fasting benefits without fasting.
- Track biological age reduction: Measure biological age using DNA methylation markers after 8 weeks of daily mimio supplementation.
- Evaluate hunger and cravings control: Assess the impact of mimio supplementation on hunger, cravings, and satiety over an 8-week period.
- Analyze metabolite elevation during fasting: Screen remaining metabolites from a 36-hour fast to identify new fasting-mimetic compounds.
Key Quotes
"is the type of fasting that's been shown in the majority of studies to actually promote lifespan and promote it pretty significantly anywhere between you know 30 to 60 and that is independent of caloric restriction so there is something really interesting that's specific to fasting that happens where even if you don't reduce overall calories you still get this lifespan extension from just delaying when you're eating"
Dr. Chris Rhodes explains that alternate-day fasting, a specific type of fasting, has demonstrated significant lifespan extension in studies, independent of calorie reduction. This suggests that the act of delaying eating itself triggers beneficial biological processes.
"so what is happening in the body during a fast essentially it's going completely from exogenous energy sources food that we would be taking in digesting metabolizing and using that for energy to then relying completely on endogenous energy sources so the fuel that we already have inside of our bodies are stored carbohydrates our stored protein our stored fat"
Dr. Rhodes clarifies that fasting shifts the body's energy source from external food intake to internal stores. This transition from utilizing glucose to breaking down stored fats and ketones is a fundamental metabolic change that occurs during a fast.
"so instead of this big you know nutritional repletion state instead your cells are getting this signal where it's like oh there's no food around this would actually be a very bad place to have kids and raise the next generation because if we can't even get enough nutrients how are we going to take care of a kid at the same time so you get this shift over to really survival longevity maintenance repair a lot of these metabolic efficiency pathways that are happening to conserve energy"
Dr. Rhodes describes how fasting signals a survival mode to cells, prioritizing maintenance and repair over reproduction. This shift conserves energy and activates metabolic pathways aimed at increasing longevity, contrasting with the "fed state" which signals abundance and focuses on growth.
"from a biochemical perspective a 16 hour fast is actually not long enough to really get you into a biological state of fasting so like when we were talking about before that switch over from glucose metabolism to fat and ketone metabolism that's only going to happen in your body after you have depleted your glycogen stores so your stored carbohydrates your stored glucose that you have in your body that needs to be totally run through before your body will start you know moving over to fat metabolism and ketone body production as its primary fuel source and that's not going to happen until around 20 to 24 hours of you know zero food intake"
Dr. Rhodes explains that a 16-hour fast is generally insufficient to trigger the metabolic switch to fat and ketone utilization. He states that glycogen stores need to be depleted, which typically takes 20-24 hours of no food intake, to initiate these deeper fasting benefits.
"so this is what i spent my entire phd doing is studying a 36 hour fast so there is indeed a metabolic signature that happens when you get into the true biochemical fasting state and there you're just going to see you're going to see a really big drop in circulating glucose levels you're going to see a big rise in ketone levels that's you know classic standard like we were talking about before we've also done comprehensive metabolomics looking at a before and after from just like an overnight fast to a 36 hour fast at state and we found that there were over 300 significantly elevated metabolites in this is our fasted state versus a baseline state"
Dr. Rhodes details his doctoral research on 36-hour fasts, highlighting the distinct metabolic signature observed. He notes a significant decrease in glucose and a rise in ketones, along with over 300 elevated metabolites in the fasted state compared to a baseline, indicating profound biochemical changes.
"so what we're using right now is 600 milligrams of pea but we're also using ultra micronized pea which is the most bioavailable form and it's about you know four to six times more bioavailable than ordinary pea and we're one of the few companies in the us that actually is using that that form of the product oea we have 400 milligrams spermidine we have 8 milligrams and then nicotinamide we have 250 milligrams and that formulation you know we've tested in the three different clinical studies"
Dr. Rhodes outlines the specific dosages of the four key compounds in the mimio formulation: 600mg of ultra-micronized pea, 400mg of oea, 8mg of spermidine, and 250mg of nicotinamide. He emphasizes the use of highly bioavailable forms, particularly for pea, and notes that this formulation has been tested in three clinical studies.
Resources
External Resources
Books
- "Title" by Author - Mentioned in relation to [context]
Videos & Documentaries
- Full episode (https://youtu.be/Rw-LSSCyE1w) - Mentioned as the location to watch the full episode.
Research & Studies
- Doctoral and postdoctoral work on molecular responses to prolonged fasting (specifically 36-hour fasts) (UC Davis) - Referenced as the focus of Dr. Chris Rhodes' research.
- Clinical studies on 16-hour fasts - Discussed for their effects on transient metabolic markers like glucose and cholesterol levels.
- Studies on alternate day fasting - Cited for promoting lifespan extension, independent of caloric restriction.
- Studies on multi-day fasts - Mentioned for deeper autophagy and immune cell regeneration.
- Peer-reviewed clinical trials on red light therapy - Referenced for benefits to skin, recovery, and hair loss.
- Research on fasting and the menstrual cycle - Discussed for differential effects based on hormonal fluctuations.
- Studies on spermidine and longevity - Cited for correlation with increased lifespan and health span in humans.
- Clinical studies on the mimio formulation - Referenced for demonstrating fasting-like benefits without fasting, including reductions in biological age and improvements in metabolic markers.
- Randomized double-blind placebo-controlled study on mimio supplementation - Discussed for its effects on hunger control, cravings, and metabolic health in an older population.
- Studies of pea against aspirin and ibuprofen - Cited for demonstrating pea's effectiveness in pain relief, particularly nerve pain.
- Studies with pea for menstrual pain - Mentioned as a potential benefit of pea supplementation.
Tools & Software
- Red light therapy panels (Bon Charge) - Discussed for stimulating energy production, improving skin, supporting recovery, and aiding hair loss.
- Methylene blue troches (Troskriptions) - Mentioned for supporting ATP production and improving attention and memory.
- Mathemzymes (Biooptimizers) - Discussed for supercharging protein digestion and increasing amino acid absorption.
- Mimeo formulation (Mimeo Health) - Referenced as a supplement designed to mimic the benefits of fasting.
Articles & Papers
- "Title" (Source) - Discussed as [context]
People
- Dr. Chris Rhodes - Guest, nutritional biochemist and researcher formerly at UC Davis, whose work focuses on the molecular responses to prolonged fasting.
- Dr. Stephanie Estima - Host of the podcast "BETTER! Muscle, Mobility, Metabolism & (Peri)Menopause," discussing her evolving views on fasting, particularly for women.
- David Sinclair - Mentioned as a previous guest who discussed NAD, NMN, and nicotinamide riboside.
Organizations & Institutions
- UC Davis - Institution where Dr. Chris Rhodes conducted his doctoral and postdoctoral work.
- NFL (National Football League) - Primary subject of sports discussion
- New England Patriots - Mentioned as example team for performance analysis
- Pro Football Focus (PFF) - Data source for player grading
Courses & Educational Resources
- Course Name - Learning context
Websites & Online Resources
- boncharge.com/better - Website for Bon Charge red light therapy panels.
- troskriptions.com/better - Website for Troskriptions methylene blue troches.
- biooptimizers.com/better - Website for Biooptimizers Mathemzymes.
- massachips.com - Website for Massa chips.
- vandycrisps.com - Website for Vandy crisps.
- Mimeo Health (mimeohealth.com) - Website for the Mimeo formulation, providing research and clinical studies.
- TikTok channel (@thatnutritiondoctor) - Dr. Chris Rhodes' TikTok channel.
Podcasts & Audio
- BETTER! Muscle, Mobility, Metabolism & (Peri)Menopause with Dr. Stephanie - The podcast where the conversation took place.
Other Resources
- Fasting - Core concept discussed, with varying lengths and benefits explored.
- Time Restricted Eating (16:8) - A popular style of fasting discussed for its transient metabolic effects.
- One Meal A Day (OMAD) - A type of fasting discussed for reaching glycogen depletion and minimizing post-eating states.
- Alternate Day Fasting - Discussed for its significant lifespan extension benefits.
- Multi-day fasts - Mentioned for deeper autophagy and potential for cancer prevention.
- Autophagy - Cellular recycling and cleanup program activated during fasting.
- Mitochondrial efficiency - Enhanced by red light therapy for energy production.
- ATP production - Supported by methylene blue for cellular energy.
- NAD (Nicotinamide Adenine Dinucleotide) - A key molecule involved in cellular energy sensing and longevity pathways.
- NADH - The counterpart to NAD, involved in energy production.
- Sirtuins - Proteins activated by NAD that influence DNA transcription and cellular function.
- Histone deacetylases/acetyltransferases - Enzymes involved in modifying DNA sequences, influenced by sirtuins.
- Estrogen - Discussed for its role in NAD salvage and its decline in perimenopause and menopause.
- Cortisol - The stress hormone, discussed in relation to fasting and its impact on the HPA axis.
- HPA axis sensitivity - Discussed in relation to women's hormonal responses to stress and fasting.
- Thyroid function - Discussed in relation to fasting and its potential impact on T3 levels.
- Hashimoto's thyroiditis - Mentioned as an autoimmune condition that fasting may benefit due to its anti-inflammatory effects.
- AMPK - A pathway activated during fasting related to energy sensing.
- mTOR - A pathway associated with growth and anabolism, downregulated during fasting.
- PPAR alpha - Activated by PEA and OEA, involved in switching metabolism from glucose to fat.
- COX 1 and 2 - Enzymes influenced by PEA, relevant to inflammation.
- Endocannabinoid system - Involved in pain relief, mood, and appetite regulation, influenced by PEA and OEA.
- TRPV receptors - Receptors stimulated by PEA.
- Gut-brain axis - Involved in satiety and appetite suppression, influenced by OEA.
- Vagrant afferent nerves - Signaled by OEA to the brain regarding satiety.
- GLP-1 - A hormone involved in satiety and appetite suppression, compared to OEA.
- Cellular autophagy - Enhanced by spermidine, a key process in fasting.
- Spermidine - A molecule known for enhancing cellular autophagy and longevity.
- Nicotinamide - One of the four key molecules in the mimio formulation.
- Palmitoylethanolamide (PEA) - A molecule involved in the endocannabinoid system, with anti-inflammatory, mood-enhancing, and pain-relief effects.
- Oleoylethanolamide (OEA) - A molecule involved in the gut-brain axis, stimulating satiety and suppressing appetite.
- Nicotinamide Riboside (NR) - A precursor to NAD.
- NMN (Nicotinamide Mononucleotide) - Another precursor to NAD.
- DNA methylation - Used as a marker for biological age reduction.
- Fasting signature - The specific metabolic profile observed during fasting.
- Caloric restriction - Mentioned in relation to lifespan extension studies.
- Ketone bodies - Produced from fat breakdown during fasting.
- Glycogen stores - Depleted during fasting, signaling the switch to fat metabolism.
- Gluconeogenesis - The process of creating glucose from protein.
- Osteoblast activity - Stimulated by strength training, involved in bone building.
- Osteoclast activity - Involved in bone resorption, stimulated by fasting.
- Blood acidification - Caused by ketone bodies during fasting, leading to calcium withdrawal from bones.
- Fasting enhancer - How Mimeo can be used to augment the benefits of fasting.
- Fasting mimetic - A substance that mimics the physiological effects of fasting.
- Fed state - The metabolic state after eating, characterized by growth and repair.
- Fasted state - The metabolic state during fasting, characterized by maintenance and repair.
- Longevity bio program - Cellular pathways activated during fasting that promote lifespan and health.
- Post prandial state - The state after eating, associated with metabolic chaos and inflammation.
- Hormonal crosstalk - The interaction between different hormonal systems.
- Menopause - A stage of life for women characterized by hormonal changes and potential health challenges.
- Perimenopause - The transition period leading up to menopause.
- Sarcopenia - Age-related loss of muscle mass.
- Food noise - The rumination and cravings around food experienced by some women in midlife.
- Anabolic state - A metabolic state that promotes muscle growth.
- Catabolic state - A metabolic state that breaks down tissue.