#040 Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate & HDAC Inhibitors
Dr. Eric Verdin, President and CEO of the Buck Institute for Research on Aging, discusses lifestyle interventions like exercise, nutrition, and fasting to regulate aging. He highlights his lab's work on cyclic ketogenic diets improving midlife mortality and memory, and the roles of NAD+ and HDAC inhibition.
Deep Dive Analysis
18 Topic Outline
Introduction to Dr. Eric Verdin and His Research
Understanding mTOR, PPAR-alpha, and HDACs
Projected Human Lifespan and Lifestyle Interventions
Role of Insulin Signaling and Carbohydrates in Aging
Mechanisms of Fasting's Benefits on Healthspan
Cyclic Ketogenic Diet Study in Mice: Lifespan and Memory
Beta-Hydroxybutyrate as a Nutrient and Signaling Molecule
Exogenous Ketone Esters and Ketogenic Diet Safety
PPAR-alpha Activation and Ketogenic Diet Benefits
Challenges of Translating Mouse Studies to Humans
Emerging Biomarkers for Predicting Biological Age
NAD+ Levels and Their Decrease During Aging
Mitochondrial Function and SIRT3 in Aging
Autophagy and its Regulation by Fasting
Ketogenic Diet vs. Intermittent Fasting for Humans
Benefits of Time-Restricted Eating
Prolonged Fasting and its Duration
Buck Institute's Mission and Future of Aging Research
8 Key Concepts
mTOR
mTOR functions as a master regulator of cell growth and metabolism, activated by protein/essential amino acid intake and the IGF-1 signal. While it promotes growth, most aging research suggests limiting its activation through strategies like fasting or caloric restriction to delay aging.
PPAR-alpha
PPAR-alpha is a transcription factor absolutely critical for ketogenesis, activated by caloric restriction, fasting, and carbohydrate restriction. It promotes the uptake, utilization, and catabolism of fatty acids by upregulating genes involved in fatty acid transport and oxidation.
HDACs (Histone Deacetylases)
HDACs are enzymes that remove acetyl groups from histones, which are proteins around which DNA is wrapped. By removing these groups, HDACs decrease the expression of certain genes, thus acting as epigenetic regulators.
HDAC Inhibitors
HDAC inhibitors are compounds that block the activity of histone deacetylases, leading to an increase in histone acetylation and, consequently, increased expression of certain genes. Beta-hydroxybutyrate is a class one HDAC inhibitor, functioning at millimolar concentrations achievable during fasting.
Beta-Hydroxybutyrate (BHB)
BHB is a ketone body produced by the liver from fat during fasting or carbohydrate restriction, serving as an energy source for the brain. Beyond its role as a nutrient, BHB also acts as a signaling molecule by inhibiting Class I HDACs, increasing the expression of genes like FOXO3, which protects against oxidative stress.
NAD+
NAD+ is a critical intermediary metabolite that acts as a 'currency' for energy circulation within cells, transferring electrons during food oxidation. Its levels decrease during aging, leading to less efficient intermediary metabolism and impaired function of enzymes like sirtuins, which rely on NAD+ for their beneficial activities.
Autophagy
Autophagy is a vital cellular cleanup mechanism that is activated when cells are deprived of nutrients, such as during fasting. It involves the breakdown and recycling of damaged cellular components, contributing to cellular health and potentially extending healthspan.
Epigenetic Clock
The epigenetic clock refers to changes in DNA methylation patterns that occur predictably with age and can be used to estimate an individual's chronological age with high accuracy. Researchers are exploring its potential as a biomarker for biological age.
9 Questions Answered
The main lifestyle interventions are exercise and nutrition, which are considered the cornerstone. Additionally, research focuses on identifying molecules that mimic these effects (calorie restriction mimetics or exercise mimetics) and developing rejuvenation approaches to repair existing aging damage.
Higher carbohydrate intake activates the insulin signaling pathway, which has been linked to faster aging in animal models. Recent human studies suggest a direct correlation between total carbohydrate intake and all-cause mortality, with lower carbohydrate intake associated with lower mortality.
Fasting and ketogenic diets benefit healthspan by decreasing carbohydrate intake (reducing insulin signaling), restricting protein intake (decreasing mTOR signaling), and inducing ketosis. Ketosis, particularly through beta-hydroxybutyrate, acts as a signaling mechanism that regulates gene expression.
Beyond its role as an energy source for the brain, beta-hydroxybutyrate functions as a signaling molecule. It acts as a Class I histone deacetylase (HDAC) inhibitor, which increases the expression of certain genes, including FOXO3, known for its role in protection from oxidative stress and delaying aging.
A long-term ketogenic diet is challenging due to the significant discipline required, its 'anti-social' nature (restricting alcohol, bread, pasta, and many fruits), and the fact that individual genetic polymorphisms (e.g., in PPAR-alpha) can make it unsuitable or even dangerous for some people.
Promising biomarkers include those derived from facial recognition and blood metabolites analyzed by artificial intelligence, which can estimate biological age. Additionally, the epigenetic clock, based on changes in DNA methylation, shows a high correlation (96%) with chronological age and is emerging as a reliable marker.
The decrease in NAD+ levels during aging is a mystery, but two major theories exist: increased activation of PARP enzymes due to accumulating DNA damage, which consumes NAD+, and a paralyzed NAD+ salvage pathway (e.g., inhibition of the NMPT enzyme by chronic inflammation or a high-fat diet).
Liver glycogen can be largely depleted within 4 to 6 hours of fasting, though physical activity can accelerate this process.
Significant ketosis typically begins around 16 hours of fasting, at which point ketone body levels in the blood will start to slowly rise.
17 Actionable Insights
1. Exercise for Healthspan & Lifespan
Incorporate exercise into your routine, as it is described as the surest and best intervention to increase both healthspan and lifespan.
2. Prioritize Good Nutrition
Focus on understanding and implementing good nutritional practices, as nutrition is considered a cornerstone for healthspan and lifespan, especially when combined with exercise.
3. Practice Daily Time-Restricted Eating
Establish a daily fasting period by restricting your eating window to activate beneficial pathways like insulin suppression, TOR suppression, and autophagy. Aim for at least a 14-hour daily fast (e.g., eating within a 10-hour window).
4. Avoid Frequent Meals & Snacks
Do not follow the traditional recommendation of three meals and three snacks daily, as this pattern is considered the ‘worst possible way’ to eat based on current research on fasting periods.
5. Limit Total Carbohydrate Intake
Reduce your total carbohydrate intake, as high carbohydrate consumption activates the insulin signaling pathway, which is linked to faster aging and higher all-cause mortality.
6. Activate Autophagy via Fasting
Engage in fasting to activate autophagy, an important cellular cleanup mechanism that is beneficial for healthspan.
7. Suppress mTOR for Anti-Aging
Practice caloric restriction, prolonged fasting, intermittent fasting, or a low-protein ketogenic diet to suppress mTOR activity, which is associated with healthspan extension.
8. Increase Beta-Hydroxybutyrate Levels
Engage in fasting or carbohydrate restriction to increase beta-hydroxybutyrate, which functions as an HDAC inhibitor to increase FOXO3 expression, protecting against oxidative stress and delaying aging.
9. Ketogenic Diet for Memory
Explore a ketogenic diet, as it was observed to improve memory in older mice to levels better than younger mice and prevent age-related memory decline.
10. Moderate Protein on Ketogenic Diet
If following a ketogenic diet, ensure protein intake is not excessively high to avoid increased IGF-1 signaling, which can potentially increase cancer risk.
11. Fast 16+ Hours for Ketosis
If aiming for significant ketosis through fasting, extend your fasting window to at least 16 hours, as ketone levels typically begin to rise around this time.
12. Consider NAD+ Precursors (Caution)
Explore supplements like nicotinamide riboside or nicotinamide mononucleotide to potentially replenish decreasing NAD+ levels during aging, but be aware that the underlying cause of NAD+ decline is not fully understood.
13. NAD+ for Noise Hearing Protection
Consider taking nicotinamide riboside before exposure to acute loud noise (e.g., rock concerts) as it protected mice from noise-induced hearing loss, an effect dependent on SIRT3.
14. Monitor Well-being During Interventions
When undertaking long-term health interventions, pay close attention to how you feel, as individual responses vary and validated biomarkers for aging are still emerging.
15. Elderly: Increase Protein Intake
If elderly, consume more protein to lower all-cause mortality and mitigate muscle mass loss, which is approximately 10% per decade starting in midlife.
16. Activate PPAR-alpha for Ketogenesis
Practice caloric restriction, fasting, or carbohydrate restriction to activate PPAR-alpha, which is critical for ketogenesis and may mediate some beneficial effects of the ketogenic diet.
17. Understand Ketogenic Diet Challenges
If considering a ketogenic diet, be prepared for strict carbohydrate restriction and high discipline, as it is a difficult diet to sustain long-term due to its significant carbohydrate restrictions.
8 Key Quotes
Exercise is king, nutrition is queen, put them together and you have a kingdom.
Dr. Eric Verdin (quoting Jack LaLanne)
The people who ate the least amount of carbohydrates showed the lowest all-cause mortality.
Dr. Eric Verdin
These older mice on the ketogenic diet showed actually better memory than younger mice.
Dr. Eric Verdin
Beta hydroxybutyrate, in addition to being a nutrient, as we just discussed, is also a signaling molecule.
Dr. Eric Verdin
NAD is one way that our body is utilizing within the cell to, to convert, to transfer energy. It's almost like the Brinkman truck that carries the money.
Dr. Eric Verdin
If you are, if it's accelerated destruction, bringing more into it is sort of like pouring more NAD in the leaky sink.
Dr. Eric Verdin
I view this on a global population basis as not a realistic goal to expect that everyone is going to be on this ketogenic diet.
Dr. Eric Verdin
Based on what we are doing and learning, this is the worst possible way that you can possibly eat.
Dr. Eric Verdin
2 Protocols
Cyclic Ketogenic Diet (Mice)
Dr. Eric Verdin- Start the diet at one year of age (equivalent to a 30-year-old human).
- Feed mice a fat and protein diet with essentially zero carbohydrates for one week.
- Switch to a normal diet for one week.
- Repeat this one-week-on, one-week-off cycle to maintain stable weight.
Continuous Ketogenic Diet (Mice)
Dr. Eric Verdin (describing John Ramsey's study)- Feed mice a ketogenic diet continuously.
- Allot fixed portions to the mice, providing the same amount of calories they would consume on a normal diet, to prevent overeating and obesity.