What are the main lifestyle interventions to regulate aging?

The four broad categories considered are exercise, nutrition, molecules that mimic exercise or calorie restriction, and rejuvenation approaches. Exercise and nutrition are seen as the cornerstones.

How does carbohydrate intake affect aging?

Activating the insulin signaling pathway, which is influenced by carbohydrate intake, is linked to faster aging. Studies suggest a direct correlation between higher carbohydrate intake and all-cause mortality.

What are the benefits of fasting for aging?

Fasting, including intermittent and episodic fasting, has growing evidence for increasing lifespan and healthspan. It may work by decreasing insulin signaling, restricting protein intake, and inducing ketosis.

What did the ketogenic diet study in mice reveal about memory?

Mice on a cyclic ketogenic diet showed better memory than younger mice, and did not experience the typical age-related memory decline, suggesting a significant cognitive benefit.

How does beta-hydroxybutyrate affect the brain?

Beta-hydroxybutyrate is a ketone body that the brain can use for energy, sparing glucose. It also acts as a signaling molecule that inhibits HDACs, potentially regulating gene expression related to oxidative stress and aging.

Why do NAD+ levels decrease with age?

The exact reasons are still mysterious, but theories include increased activation of PARP enzymes due to DNA damage and a paralyzed salvage pathway for NAD+ recycling, potentially due to inflammation and high-fat diets.

Can interventions effective in mice be translated to humans for longevity?

While mice are not humans, and many drug trials fail in translation, the identified mechanisms provide a crucial first step. Further research and human trials are necessary to confirm efficacy and safety.

What is time-restricted eating and its benefits?

Time-restricted eating involves consuming all food within a specific daily window, allowing for a fasting period. This is considered by some researchers to be one of the most important dietary strategies for health, potentially more impactful than just what or how much you eat.

Dr. Eric Verdin on Ketogenic Diet Longevity, Beta-Hydroxybutyrate, HDAC Inhibitors & NAD+

FoundMyFitness

Education4 min read55 min video

Dec 13, 2017|218,024 views|4,097|409

Dr. Eric Verdin Buck Institute for Research on Aging ketogenic diet ketosis beta-hydroxybutyrate class 1 HDAC inhibitor NAD+nicotinamide riboside mTOR autophagy fasting caloric restriction

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Key Moments

TL;DR

Dr. Verdin discusses diet, exercise, and molecules to extend healthspan and lifespan.

Key Insights

Lifespan projections suggest children born today could live over 100 years.

Exercise and nutrition are cornerstone interventions for aging.

Reducing carbohydrate intake may correlate with lower all-cause mortality.

Ketogenic diets and fasting show promise in animal models for increasing healthspan and improving memory.

Beta-hydroxybutyrate, a ketone body, acts as both an energy source and an epigenetic signaling molecule.

NAD+ levels decline with age, impacting cellular efficiency and sirtuin function; replenishment strategies are being explored.

Biomarkers of aging, including facial analysis and epigenetic clocks, are emerging to assess biological age.

PROJECTIONS FOR LONGEVITY AND INTERVENTIONS

Current projections suggest a significant increase in human lifespan, with children born around 2007 having a 50% chance of reaching 104 years old. This advancement is driven by progress in understanding and intervening in the aging process. Dr. Verdin highlights four broad categories crucial for extending healthspan and lifespan: exercise, nutrition, molecular mimics of exercise or caloric restriction, and rejuvenation therapies aimed at repairing age-related damage. He emphasizes that exercise and nutrition are currently the most established and effective cornerstones in the field of aging research.

THE ROLE OF NUTRITION AND METABOLIC PATHWAYS

Nutrition plays a critical role, with ongoing research re-evaluating macronutrient roles. Emerging data suggests a strong correlation between lower carbohydrate intake and reduced all-cause mortality, challenging previous low-fat dietary recommendations. The insulin signaling pathway, a major regulator of aging, is activated by carbohydrate consumption. Consequently, reducing carbohydrate intake, as seen in fasting or ketogenic diets, can downregulate this pathway, potentially slowing the aging process. This includes the potential benefits derived from ketosis, where the liver produces beta-hydroxybutyrate.

KETOGENIC DIETS, BETA-HYDROXYBUTYRATE, AND COGNITIVE FUNCTION

Studies on mice have demonstrated that cyclic ketogenic diets initiated in midlife can increase median lifespan and significantly enhance healthspan, particularly concerning memory. Older mice on ketogenic diets exhibited better memory performance than younger mice, suggesting a protective effect against age-related cognitive decline. Beta-hydroxybutyrate, a primary ketone body, serves not only as an alternative energy source for the brain but also as a signaling molecule. It acts as an inhibitor of histone deacetylases (HDACs), epigenetic regulators linked to aging and gene expression, potentially protecting against oxidative stress.

NAD+ AND MITOCHONDRIAL HEALTH IN AGING

NAD+ is a critical metabolic cofactor essential for energy transfer within cells and for the proper functioning of enzymes like sirtuins, which are vital for cellular health and aging regulation. NAD+ levels are observed to decrease with age, correlating with reduced cellular efficiency. While strategies to replenish NAD+ through supplements like NMN and NR are gaining popularity, it's crucial to understand the cause of this decline. Potential reasons include accelerated destruction due to DNA damage repair (PARP activation) or issues with the NAD+ salvage pathway, possibly exacerbated by inflammation or high-fat diets.

THE CONNECTION BETWEEN NAD+, SIRTUINS, AND MITOCHONDRIA

Mitochondrial function is paramount for healthy aging, and NAD+-dependent enzymes, particularly sirtuins, play a key role. Sirtuin 3 (SIRT3), located in the mitochondria, is essential for maintaining mitochondrial efficiency and function. Studies have shown that NAD+ supplementation can protect against age-related hearing loss, an effect that is dependent on SIRT3. Efficient mitochondria are crucial for generating energy through oxidative phosphorylation, a process less reliant on glucose and more dependent on healthy mitochondrial networks, which are supported by NAD+ and sirtuins.

BIOMARKERS OF AGING AND FUTURE DIRECTIONS

Identifying reliable biomarkers of aging is crucial for personalized interventions. Emerging technologies utilizing artificial intelligence are developing biomarkers based on facial recognition and blood metabolites to estimate biological age. Epigenetic clocks, which measure DNA methylation patterns, also show promise. These tools can help determine if an intervention is beneficial or detrimental to an individual's biological aging process. The field is moving towards translating basic aging research into human applications, with significant interest from pharmaceutical and venture capital sectors.

INTERMITTENT FASTING AND TIME-RESTRICTED FEEDING

While ketogenic diets show promise, they can be challenging to maintain long-term due to social and dietary restrictions. Intermittent fasting (IF) and time-restricted feeding (TRF) are presented as more accessible alternatives. TRF, which involves eating within a specific daily window, has significant implications for health by allowing for essential fasting periods. This contrasts with current dietary recommendations of frequent meals. Entering ketosis typically requires a fasting period of around 16 hours, highlighting the importance of daily fasting windows for activating beneficial metabolic pathways.

THE ROLE OF PROTEIN INTAKE AND CALORIC RESTRICTION

Protein intake is a significant factor in aging pathways. Limiting protein can reduce IGF-1 signaling and mTOR activity, both linked to aging and cancer risk. While caloric restriction is a proven longevity intervention in animal models, human responses vary significantly due to genetic diversity. Some individuals may experience harm from caloric restriction. The lack of validated biomarkers for personalized assessment makes long-term interventions a cautious endeavor, underscoring the need for individualized approaches based on biological response.

Mentioned in This Episode

●Supplements

●Software & Apps

●Tools

●Organizations

●Concepts

●People Referenced

Common Questions

Yes, based on projections of lifespan progression over the last century, a child born around 2007 had a 50% chance of living to 104. This highlights the potential impact of lifestyle interventions on healthspan and lifespan.

Topics

Beta-hydroxybutyrate Insulin Signaling

Mentioned in this video

personJack Lalanne

A pioneer in American fitness, known for his emphasis on exercise and nutrition.

conceptpentose phosphate pathway

A metabolic pathway that produces NADPH and precursors for glutathione synthesis, relevant to oxidative stress.

personSin-Ichi Ohno

Researcher whose work in the 1990s identified the insulin signaling pathway as a major regulator of aging.

personTrey Ideker

Researcher involved in the development of epigenetic clocks based on DNA methylation.

personJohn Newman

A colleague in Dr. Verdin's lab who co-authored research on ketogenic diets and mouse longevity.

supplementnicotinamide mononucleotides

Another precursor to NAD+ that is taken by many people with benefits hoped for in reversing aging processes.

softwareNAMPT

An enzyme in the NAD+ salvage pathway that can be inhibited by inflammation and high-fat diets.

softwareSirtuin 3

A mitochondrial sirtuin important for mitochondrial function and energy production, which relies on NAD+.

softwareSirtuin 1

A key sirtuin enzyme involved in aging regulation that relies on NAD+

toolPARP

organismC. elegans

conceptDrosophila

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