Podcast Summary
NAD pathway and longevity: Discussed the potential role of NAD pathway in longevity, compared different molecules for increasing NAD levels, and touched upon other strategies like rapamycin, metformin, fasting, proper hydration, nutrition, and sleep.
When it comes to extending lifespan and improving health span, there are various approaches. Dr. Andrew Huberman, a professor of neurobiology and ophthalmology at Stanford School of Medicine, discussed this topic with Dr. Peter Attia, a medical doctor and expert on health span and lifespan. They focused on the NAD pathway, which has gained attention for its potential role in longevity. They compared different molecules and methods for increasing NAD levels, such as NAD, NMN, and NR. They also discussed their personal experiences and opinions on these supplements. Additionally, they touched upon other topics like rapamycin, metformin, fasting, and the importance of proper hydration, nutrition, and sleep for longevity. Overall, the conversation provided valuable insights into the science behind various longevity-promoting strategies.
Aging approaches: Approaches to slowing down aging include essential behaviors like eating, sleeping, and moving correctly, molecules targeting disease processes, and gyroprotective molecules like Rapamycin that target specific aging hallmarks and pathways.
As we age, the changes are most significant during the first ten years of life, and there are various approaches to slowing down the aging process. These approaches can be categorized into essential behaviors, molecules that target disease processes, and gyroprotective molecules that target hallmarks and pathways of aging. Essential behaviors include eating, sleeping, and moving correctly. Molecules that target disease processes directly delay the onset of chronic diseases like cardiovascular disease, cerebrovascular disease, cancer, neurodegenerative disease, and dementing diseases. Gyroprotective molecules, such as Rapamycin, target specific hallmarks and pathways of aging, like inflammation, senescent cells, and reduced nutrient sensing capacity of mTOR. It's essential to understand that emotional health and happiness also play a significant role in longevity and overall well-being.
Rapamycin and NAD: Rapamycin, an mTOR inhibitor, is the only proven life-extending intervention besides caloric restriction, but its use comes with side effects. NAD, a ubiquitous molecule involved in energy production, lacks solid experimental evidence for its life-extension properties.
Rapamycin, a drug that inhibits the mTOR pathway, is currently the only intervention, along with caloric restriction, that has been proven to extend life across various eukaryotic organisms. The speaker's personal experience with rapamycin includes taking it for two months followed by a one-month break due to side effects, primarily canker sores. The experimental data supporting rapamycin's life-extending properties come from studies on mice, small primates, fruit flies, worms, and even yeast. However, the speaker expresses a stronger conviction in rapamycin's potential due to the actual life extension observed in these studies, as opposed to the theoretical arguments for its mechanism. The speaker also mentions the ongoing dog aging study by Matt Cabral and the need for more funding to continue the research. Regarding NAD, it is a ubiquitous molecule found in almost every cell of the body, primarily associated with energy production and mitochondrial pathways. NAD and NADH act as electron shuttles, and their levels are tightly regulated in the body. While rapamycin's life-extension effects are backed by experimental data, the same cannot be said for NAD interventions, which is an important theme to discuss further.
NAD and Sirtuins functions: Understanding the functions of genes requires both loss and gain of function experiments. Loss of function experiments provide insights but gain of function studies offer more comprehensive information, particularly for genes like Sirtuans.
The role of NAD, a cofactor involved in various cellular processes, is multifaceted. While most NAD is used as a cofactor and recycled, a small fraction is consumed as a substrate by proteins called sirtuins during DNA repair. In the field of human genetics, understanding the functions of genes is crucial. Loss of function experiments, such as knocking out a gene, can provide valuable insights, but gain of function experiments, which involve introducing a gene of interest back into a system, offer more comprehensive information. This is particularly important when studying genes like Sirtuans, where deletion of the gene can lead to unexpected results. The gold standard in genetic research involves both loss and gain of function experiments to gain a more complete understanding of a gene's role. The discovery of the longevity gene Clotho serves as a great example, as it was initially identified through a loss of function experiment, but its true function as a longevity gene was confirmed through gain of function studies. Overall, the interplay between loss and gain of function experiments is essential in the pursuit of knowledge in human genetics.
Caloric restriction and Sirtuins: The potential benefits of caloric restriction for extending human life are uncertain due to negative effects on the immune system, sarcopenia, and risk of falling. Research on Sirtuins, a separate pathway linked to longevity, shows inconsistent results and challenges in manipulating them in mammals
While caloric restriction has been shown to extend life in various model systems, its effects on humans are still uncertain. The joke about no one wanting to be in the treatment group due to caloric restriction's requirements rings true, as the potential benefits of reduced chronic disease risk may not outweigh the negative effects on the immune system, sarcopenia, and risk of falling. The debate about whether Sirtuins, a separate pathway linked to longevity, have any connection to caloric restriction is ongoing. While overexpressing Sirtuins in yeast has been shown to increase lifespan, the same effect has not been consistently observed in other organisms. The only transgenic mouse study that demonstrated a survival advantage came from overexpressing CERT6 in males, but not females. Understanding what changes downstream of Sirtuins, such as improvements in mitochondrial biogenesis and DNA repair, is a promising area of research. However, the complexities of manipulating Sirtuins in mammals and the potential sex-specific differences in response remain challenges to be addressed.
NAD and aging: As we age, our bodies become less effective at repairing DNA damage due to declining NAD levels. Some compounds like resveratrol have shown promise in increasing NAD and potentially slowing down aging, but practical applications remain a challenge.
As we age, our bodies undergo more DNA damage and become less able to repair it effectively. This is due in part to the declining levels of NAD, a molecule that plays a crucial role in DNA repair. The idea that increasing NAD levels could help slow down aging and extend lifespan has gained significant attention. One famous compound believed to activate sirtuins, which are enzymes that use NAD to repair DNA, is resveratrol. However, studies have shown mixed results regarding its effectiveness in increasing lifespan, and the doses required to achieve any benefit are extremely high and impractical for humans. Despite these challenges, the search for effective NAD-boosting interventions continues, as the potential benefits for healthy aging and disease prevention are significant.
Mitochondrial function and NAD levels: Mitochondrial dysfunction with age reduces redox potential, impeding energy transfer and potentially benefiting from red light and near infrared light exposure. NAD production involves NR, NMN, and NAD, and direct supplementation may not be straightforward.
The decline in NAD levels with age is not just a reduction in NAD itself, but a reduction in the overall redox potential, which is essential for facilitating the transfer of chemical energy to electrical energy in the body. The mitochondria's ability to function optimally declines with age, leading to a decrease in redox potential. Some anti-aging approaches aim to improve mitochondrial function by reducing reactive oxygen species, which can impede mitochondrial function. A colleague of the speaker, Glenn Jeffrey, has conducted studies showing that exposing older adults to red light and near infrared light can potentially improve mitochondrial function and spare certain processes involved in vision. The production of NAD, which is important for activating sirtuins, occurs through a pathway involving NR, NMN, and NAD. Directly supplementing with NAD or its precursors may not be straightforward, and more research is needed to fully understand the best ways to support the production and function of NAD in the body.
NAD supplementation and lifespan: Despite ongoing research, there's no definitive proof that NAD supplementation directly extends lifespan. Benefits, if any, are largely anecdotal and come with potential costs, feasibility issues, and side effects.
While there is ongoing research and debate about the benefits of supplementing NAD (Nicotinamide Adenine Dinucleotide) to increase its levels in the body for longevity, it's essential to acknowledge that there's no concrete scientific evidence that proves raising NAD levels directly extends lifespan. The decision to supplement NAD through NR (Nicotinamide Riboside) or NMN (Nicotinamide Mononucleotide) involves several leaps of faith, including the belief that increasing NAD levels will produce a positive effect, and that it's effective in humans. The most common methods to increase NAD levels are through intravenous infusions, orally taking NR or NMN, and caloric restriction. While some people report observing positive effects, such as increased energy and improved hair and nail growth, these benefits are largely anecdotal. It's crucial to consider the costs, feasibility, and potential side effects before making a decision.
Molecular interventions for aging: Despite some successes like Rapamycin, Canagliflozin, and Acarbose, most molecular interventions for aging, including NR, have failed to extend lifespan or health span in rigorous testing, emphasizing the need for thorough investigation and the complexity of aging interventions.
The Interventions Testing Program (ITP) has tested numerous molecules for their ability to extend lifespan in mice, and only a few have passed the rigorous scrutiny of the program. NR, a popular supplement for aging, failed to show any extension of lifespan or health span in the ITP study. However, some successes include Rapamycin, Canagliflozin, and Acarbose, which all showed positive effects on longevity despite not causing weight loss. Another study involving NR and Terastilbean in humans yielded null results, but a sub-analysis suggested a potential benefit for those with lower levels of hepatic fat. These findings highlight the importance of rigorous testing and the complex nature of aging interventions.
NMN benefits: Study shows statistically significant but clinically insignificant increase in glucose disposal with NMN, speaker questions benefits due to regulatory issues and lack of compelling evidence, potential reduction in basal and squamous cell carcinomas requires further research
A study comparing the effects of NMN and a placebo on glucose disposal showed a statistically significant but clinically insignificant increase in glucose disposal with NMN. The speaker questions the significance of this finding and expresses doubts about the benefits of taking NMN or NR due to regulatory issues and the lack of compelling evidence for their effectiveness. However, one potential benefit identified is a possible reduction in basal and squamous cell carcinomas, which are common and strongly associated with sun exposure. The speaker suggests that further research is needed to confirm this potential benefit. Overall, the speaker expresses skepticism about the value of NMN and NR supplementation and suggests that other approaches, such as exercise, may be more effective and cost-effective ways to improve health.
NAD boosters and their effectiveness: The debate over which NAD booster is more effective or bioavailable may not matter much for cellular benefits. Raising NAD levels in the blood may not directly translate to increased NAD in cells, and some potential benefits may be overstated. Regulatory uncertainty and individual responses add complexity to the decision-making process.
While NR and NMN are similar in their ability to increase NAD levels in the body, the debate over which one is more effective or bioavailable may not matter much. Raising NAD levels in the blood may not necessarily translate to increased NAD in cells, especially in cells like skeletal muscles. The marketing material surrounding these supplements may oversell their potential benefits, particularly in relation to longevity. Despite the lack of clear evidence for NAD boosters extending lifespan, some individuals may still find value in taking them for potential health benefits. However, the regulatory landscape around these supplements is complex, with some being classified as drugs and others as supplements, leading to confusion and uncertainty. Ultimately, it's important for consumers to approach these supplements with a critical and informed perspective, and to consult with healthcare professionals before making a decision.
Rapamycin and NAD+: Despite claims, there's no proven link between Sir Toon's caloric restriction and NAD+. The scientific focus is on rapamycin, an older drug with potential in enhancing immune function when dosed intermittently, but its commercial appeal is limited due to its generic status and high cost.
There is no meaningful connection between Sir Toon's caloric restriction and NAD+ (Nicotinamide Riboside) as some may claim. Instead, the scientific interest lies in rapamycin, an older drug that is historically known as an immune suppressant but has shown potential in enhancing immune function when dosed intermittently. Rapamycin is not commercially interesting due to its generic status and relatively high cost, but the scientific community is exploring its potential in new indications. The debate on biological aging tests is ongoing, with some arguing that they can provide valuable insights into one's health status, while others remain skeptical. Ultimately, the most important standard for these tests is their ability to predict remaining years of life more accurately than chronologic age.
Biologic age measurement: Biologic age measurement is not yet precise enough to provide tangible benefits and can cause unnecessary anxiety, focusing on maintaining a healthy lifestyle is more beneficial.
While the concept of measuring biologic age and predicting life expectancy based on various factors can be intriguing, it's essential to keep in mind that such measurements are not yet precise enough to provide tangible, measurable benefits. The biologic age measurement is influenced by several noisy factors, and the technology to accurately sequence and understand the epigenome is not yet advanced enough. Additionally, the anxiety surrounding our mortality and the human tendency to avoid contemplating it can make the idea of measuring our biologic age an unnecessary distraction. Instead, focusing on maintaining a healthy lifestyle and preserving our vitality in the present moment is likely to be more beneficial. The idea that we will need to work harder in our later years to maintain our health is a reality, but the efforts we put in now are crucial.
Midlife Self-Care: Focus on proper nutrition, sleep, and exercise during midlife to build physiological reserve and maintain health and vitality, despite declining power, speed, and energy levels.
The decades between our 50s and 70s are crucial for building up physiological reserve to maintain our health and vitality as we age. Our bodies become less resilient, and we need to focus on self-care, including proper nutrition, sleep, and exercise. We can still put on muscle mass and increase or maintain strength during this period. However, power and speed decline as we age, and it's essential to stay active to avoid injury and the long recovery times that come with inactivity. Energy levels also decrease with age, but good sleep, nutrition, and exercise remain the most effective ways to boost vitality. While supplements and drugs like NAD boosters and rapamycin may offer some benefits, they cannot compare to the impact of healthy habits on our energy and overall well-being. It's a challenge to prioritize self-care with the demands of work and family life, but making the effort is crucial for maintaining our vitality and longevity.
Exercise timing and energy levels: Working out before 9 a.m. may boost energy levels, while a mid-morning workout could leave one feeling tired in the afternoon. Body temperature changes and circadian rhythm might be contributing factors.
The timing and intensity of exercise can significantly impact energy levels throughout the day. While the focus on exercise for health and longevity is essential, it's equally important to consider the energy boost it provides during waking hours. The speaker suggests that working out before 9 a.m. may result in increased energy, while a mid-morning workout might leave one feeling tired in the afternoon. This effect could be related to body temperature changes and the circadian rhythm. As for supplements, the speaker takes NR and NMN, but the observed benefits are minimal. He also takes EPA and DHA in capsule form for cognitive function preservation, vitamin D due to low natural levels, and methyl folate and methyl B12 to lower homocysteine levels, which might improve nitric oxide synthase and overall vascular health.
Supplements and gut health: An individual's supplement routine includes magnesium, creatine, AG products, pendulum probiotic, and fish oil for gut health, energy, and overall well-being. However, behavioral factors like sleep, exercise, and nutrition have a greater impact on health span and lifespan.
This individual prioritizes various supplements and nutrients to support his health, including magnesium in multiple forms, creatine monohydrate, AG products, pendulum probiotic, and a quality fish oil, among others. He emphasizes the importance of anaerobic bacteria in probiotics and the benefits of these supplements for gut health, energy, and overall well-being. However, he also emphasizes that behavioral factors like sleep, exercise, and nutrition have a more significant impact on health span and lifespan than any supplement. Despite this, he views supplements as an insurance policy or an augmentation to a healthy lifestyle. The Titanic analogy suggests that these supplements, while potentially beneficial, are not as essential as the foundational aspects of a healthy lifestyle.
Foundational Elements of Well-being: Focus on exercise, sleep, nutrition, and emotional health for overall well-being and longevity. Be open to new information and reconsider investments in supplements like NR, NMN, NAD, and NAD+.
The importance of exercise, sleep, nutrition, and emotional health cannot be overstated when it comes to overall well-being and longevity. These foundational elements are like the direction of the Titanic in relation to the iceberg – they have a significant impact on our lives. Regarding supplements like NR, NMN, NAD, and NAD+, while some believe in their potential benefits, others, including the speaker, do not see a compelling reason to invest in them at this time. The speaker encourages listeners to focus on their convictions in these areas and to be open to changing their minds in light of new information. The speaker also encourages listeners to subscribe to their newsletter for free, science-related content, and to follow them on social media.