Podcast Summary
Exploring the Potential of Certuans in Aging Research: Ongoing research into certuans, NAD, and DNA repair is shedding light on potential ways to optimize human lifespan, but the idea that drinking wine can make you live longer is a misconception.
The field of aging research is rapidly advancing, and Professor David Sinclair is at the forefront of these advancements. He is a pioneer in studying certuans, a class of molecules with potential implications for longevity. One of the most famous certuans is Resveratrol, found in grapes and wine. However, the idea that drinking wine can make you live longer is a misconception. The conversation explores the role of certuans, NAD, and DNA repair in the aging process. David's expertise in these areas sheds light on the potential benefits of orally administered precursors of NAD. Additionally, his personal use of Resveratrol, metformin, and NMM reveals his dedication to practicing what he preaches. This insightful discussion underscores the importance of ongoing research in the pursuit of understanding and potentially optimizing human lifespan.
The Passionate Pursuit of Extending Human Lifespan: Professor David Sinclair's dedication to understanding and controlling aging, alongside collaboration with experts, has led to groundbreaking research and significant implications for improving human health and longevity.
Aging and its control have been a lifelong passion for Professor David Sinclair. He recognized the potential of emerging technologies to extend human lifespan and saw the urgency in finding solutions for the millions of people who could benefit from them. He sought out the best minds in the field, including Lenny Guaranty from MIT, and collaborated with them on groundbreaking research. Through his expertise in molecular biology and yeast genetics, Sinclair contributed to the discovery of genes that control aging in yeast cells. This passion for understanding and manipulating the aging process has immense implications for the future of human health and longevity. Sinclair's dedication and pursuit of knowledge highlight the importance of addressing the fundamental aspects of aging to improve lives.
Overcoming Obstacles in Scientific Research: The story of David Sinclair illustrates the significance of perseverance and determination in the pursuit of a scientific career, emphasizing the necessity of unwavering passion and a strong desire to achieve goals in this field.
Pursuing a career in scientific research requires tremendous determination and perseverance. David Sinclair's story highlights the obstacles he faced in joining a prestigious lab and obtaining funding. Despite being initially rejected and told to bring his own funding, he did not give up. He applied to different foundations and ultimately secured the necessary funds to continue his research. Sinclair's unwavering passion for understanding aging and longevity led him to fly across continents and sell his car for a five-minute interview. His dedication paid off as he was accepted into the lab and began making significant contributions to the field. This story emphasizes the importance of grit and a strong desire when pursuing one's goals in the scientific realm.
The Power of Unconventional Thinking in Scientific Breakthroughs: Pursuing unconventional paths and trusting innovative thinkers can lead to groundbreaking discoveries, as seen in David Sinclair's study of aging in yeast, which opened up a new field of biology. Persistence and embracing unconventional ideas are crucial in scientific exploration.
Scientific breakthroughs often come from pursuing unconventional paths and trusting in the vision of innovative thinkers. David Sinclair's decision to study aging in yeast, despite initial skepticism from his peers, ultimately led to groundbreaking discoveries and a new understanding of the aging process. Lenny, the visionary behind the project, recognized the potential in studying aging genes and their connection to gene silencing. This unexpected finding opened up a whole new field of biology and sparked continuous research and publications. The conversation also highlights the rapid advancement of genetic knowledge during that time, with the discovery of introns and the use of PCR. Ultimately, this story emphasizes the importance of persistence, resilience, and embracing unconventional ideas in scientific exploration.
The Role of Sirtuins in Yeast Cells and Aging in Humans: Sirtuins, particularly the cert 2 protein, are essential for controlling mating and DNA repair in yeast cells. Distraction of sirtuins can lead to confusion in sex determination and sterility, similar to the aging process in yeast and humans. Additionally, sirtuins play a role in regulating various cellular processes, shedding light on the mechanisms of aging.
Sirtuins, specifically the cert 2 protein, play a crucial role in controlling mating and DNA repair in yeast cells. When the cert 2 protein is distracted by other cellular processes, such as DNA repair, it cannot perform its gene silencing function, leading to confusion in yeast cells regarding their sex and ultimately causing sterility, which is a hallmark of aging in yeast. This distraction of sirtuins is also observed in the aging process of humans. Furthermore, sirtuins, including the cert 2 protein, are not only involved in histone control but also in regulating signaling and metabolism by targeting various proteins in the cell, including those in the nucleus and mitochondria. These findings shed light on the intricate mechanisms of aging and cellular processes controlled by sirtuins.
Insights on Premature Aging from Yeast: DNA breaks in unstable genome regions are the underlying cause of premature aging, and the cert 2 gene plays a crucial role in DNA repair and genomic stability.
Studying the SGS 1 gene in yeast provided valuable insights into the universal process of premature aging. By working on the yeast homologue of SGS 1, David Sinclair and his team were able to observe accelerated aging and sterility in the yeast cells, similar to what happens in humans. This model helped them understand that the underlying cause of premature aging is DNA breaks and recombination occurring in the most unstable regions of the genome. Furthermore, they discovered that knocking out the cert 2 gene resulted in increased genomic instability and decreased DNA repair, leading to accelerated aging. On the other hand, overexpressing the cert 2 gene in yeast cells increased genomic stability and extended their lifespan. These findings open the door to the development of compounds that can mimic the effects of cert 2 without the need for genetic mutations.
The Role of Sirtuin Genes in Extending Lifespan and Promoting Survival Mechanisms.: Sirtuin genes are crucial for mimicking the benefits of calorie restriction and promoting longevity by controlling gene expression and aiding in survival mechanisms.
The gene called sirtuin plays a crucial role in mimicking the effects of calorie restriction, which is known to extend lifespan. This gene family is not only necessary but also sufficient in providing the benefits of calorie restriction when expressed. Knocking out the sirtuin gene leads to the loss of these benefits. Interestingly, there are multiple sirtuin genes, and they work together as a family. In yeast, for example, knocking out one gene can be compensated by others. These sirtuin genes evolved billions of years ago in response to biological stressors such as DNA damage, temperature changes, or nutrient deprivation. They help organisms adapt and survive by controlling gene expression and promoting survival mechanisms.
Conservation of Longevity Pathways and the Potential for Human Lifespan Extension: Extending the lifespan of yeast, worms, and mice could hold promise for extending human lifespan, but safety and regulatory considerations must be addressed. Understanding the biology of aging and its connections to NAD, sirtuins, and calorie restriction is essential.
The longevity pathways involved in survival during adversity are surprisingly conserved across different organisms, from yeast to mice. Manipulating just one gene or using a single drug can extend lifespan in these organisms. This discovery is significant because it suggests that if we can successfully extend the lifespan of yeast, worms, and mice, we have a strong chance of doing the same for humans. The challenge lies in ensuring safety and adhering to regulatory agencies, but the biology underlying aging is ancient and well-preserved. The connection between NAD and sirtuin activity, as well as the link to calorie restriction, further adds to our understanding of the mechanisms involved in longevity.
The Importance of NAD in Cellular Function and Survival: NAD is crucial for cellular processes and its levels fluctuate, impacting aging and DNA repair. NAD levels in mitochondria are especially critical, and new technologies aid in measuring them.
NAD (nicotinamide adenine dinucleotide) plays a crucial role in our survival. Without NAD, our cells would not be able to function properly and we would die within seconds. It was previously believed that NAD levels were constant and any changes could be fatal. However, research has shown that NAD levels actually fluctuate and are important for various cellular processes, including aging and repairing DNA damage. Interestingly, it has been discovered that NAD levels in the mitochondria, the powerhouse of the cell, are even more critical for survival than in the cytoplasm. Measuring NAD levels in the mitochondria is a challenging task, but new technologies like mass spectrometry have been helpful in this regard.
The Importance of NAD in Cellular Functions and Potential Methods to Increase NAD Levels: NAD is a crucial molecule in cellular functions, and researchers are exploring ways to increase NAD production within cells to address limitations and enhance cellular processes.
NAD, or nicotinamide adenine dinucleotide, is a crucial molecule that plays a role in various cellular functions. It cannot be moved in and out of plasma and cells; it is made de novo within the cell. NADP and NADH, although similar to NAD, do not activate certain cellular switches like NAD does. Additionally, high doses of vitamin B3, or nicotinamide, inhibit sirtuins, which are enzymes involved in aging and metabolism. This inhibition occurs due to a negative feedback loop that measures nicotinamide levels. To address this limitation and increase NAD levels, researchers are exploring methods to enhance NAD production within cells.
The role of gene PNC 1 in activating NAD production and sirtuins, and its potential for lifespan extension.: Gene PNC 1 acts as a sensor in the environment, activating defense pathways and potentially extending lifespan. Understanding genetic pathways is crucial for aging research and drug development.
The gene PNC 1 plays a crucial role in activating NAD production and sirtuins, and it can mimic the effects of caloric restriction in increasing NAD availability. PNC 1 is not only activated by caloric restriction but also by stressors such as heat, low amino acids, and high salt. This gene acts as a sensor in the environment and activates defense pathways. The conversation also highlights the discovery of molecules, initially not resveratrol, that can activate the Sirtuin enzyme and potentially extend lifespan. This discovery was made through a collaborative effort and provides a promising avenue for drug development in the field of aging. The significance of understanding genetic pathways and their activation in lifespan extension is emphasized.
The discovery and testing of lifespan extension molecules through a genetics-first approach and the crucial role of Resveratrol.: Resveratrol, discovered through a genetics-first approach, has shown promising results in extending lifespan in organisms with the Sirtuin gene, sparking public interest and boosting wine sales.
The pathway of discovering and testing lifespan extension molecules can vary. In the case of Resveratrol, the scientists followed a genetics-first approach, identifying a molecule and then testing it on organisms. This approach allowed them to find a highly conserved mechanism that could be targeted for longevity. They also found that a specific amino acid, E230, played a crucial role in the activation of Resveratrol. Their experiments in yeast, worms, and flies showed that the compounds extended lifespan only in organisms with the Sirtuin gene. This brought attention to their research, especially when the mouse paper in 2006 showed promising results. The discovery of Resveratrol's potential impact on longevity sparked public interest and even led to a boost in wine sales.
Resveratrol's Potential Impact on Lifespan and Health: Resveratrol, even at lower doses, has shown promising effects on extending lifespan. Combining Resveratrol with caloric restriction may further enhance its benefits, but more research is needed to fully understand its mechanisms and potential synergies.
Resveratrol, when administered to mice on a high fat, high sugar diet, extended their lifespan by approximately 25%. This effect was observed in mature mice, equivalent to middle-aged humans. The dose of Resveratrol used was relatively high - 200 milligrams per kilogram per day. However, lower doses have also shown positive effects on longevity. It is important to note that Resveratrol activates multiple pathways, including the AMP kinase metformin-related pathway. The combination of Resveratrol and caloric restriction showed even greater benefits, suggesting that Resveratrol enhances the response to caloric restriction. Further research is needed to understand the specific mechanisms and potential synergies of Resveratrol with other substances like metformin.
Enhancing the Absorption of Resveratrol for Optimal Health Benefits: Consuming resveratrol with fatty food increases its absorption, potentially improving its health benefits. Despite its low potency and solubility, further research is exploring ways to enhance its absorption.
The absorption of resveratrol, a molecule with potential health benefits, is enhanced when consumed with fat. Resveratrol is not very soluble, which means it doesn't reach high levels in the blood unless accompanied by fatty food. This finding was observed in both mice and humans. It is speculated that the Western diet, which often includes more fat, leads to better absorption of resveratrol compared to a low-fat diet. Despite resveratrol's low potency and solubility issues, overexpressing certain genes like sirtuins still show potential for extending lifespan. Clinical trials have been conducted to explore the effects of resveratrol on humans and to find ways to improve its absorption in the body.
The Potential and Challenges of Resveratrol in Clinical Trials: Resveratrol did not meet expectations in clinical trials, but research continues to develop more potent variants. David Sinclair personally takes resveratrol and believes it may offer cardiovascular protection, along with the use of metformin for its potential anti-aging properties.
Resveratrol, a compound that was once believed to have potential health benefits, did not meet expectations in clinical trials. Although massive doses of resveratrol were initially used due to concerns about its bioavailability, there were no clear signs of toxicity in regular individuals. However, the trial with cancer patients revealed some cases of renal failure, leading to the discontinuation of the study. Although resveratrol was not deemed a viable drug by a large pharmaceutical company, further research focused on developing more potent variants of the compound. Despite inconclusive evidence, the speaker, David Sinclair, personally continues to take resveratrol and believes it may offer some cardiovascular protection. Additionally, he mentioned taking metformin, a medication commonly used to treat type 2 diabetes, which has also gained interest for its potential anti-aging properties.
Combining Molecules for Health and Longevity: A Cautionary Approach: When combining molecules for health benefits, start with a low dose, monitor well-being, and consult experts. Consider including NAD precursors for enhanced effectiveness and choose supplements carefully due to lack of regulation.
Combining molecules like Resveratrol and AMPK activators can potentially have additive effects on health and longevity. It is important to tread carefully in unknown territory and avoid overdosing on these combinations. Starting with a reasonable low dose based on available data, monitoring one's well-being and consulting experts is crucial. The discussion also highlights the inclusion of molecules like Toro still being with NAD precursors to enhance their effectiveness. While there may be conflicts between different pathways and ego involved, the ultimate goal is to make significant contributions to human health. The choice between supplements and pharmaceuticals depends on personal experiences and timeframes. The regulatory environment for supplements remains largely unregulated, emphasizing the need for caution and quality control.
Lack of evidence on the effectiveness of supplements like Elysium's Basis or ChromaDex's NR in humans: The benefits of supplements like Elysium's Basis or ChromaDex's NR in humans are uncertain and require further investigation through human clinical trials.
There is a lack of concrete evidence regarding the effectiveness of supplements like Elysium's basis or ChromaDex's NR in humans. While these supplements may have shown promising results in mice studies, it is uncertain whether they provide similar benefits to humans. Many individuals claim to have experienced positive outcomes, such as improved exercise tolerance, after taking these supplements. However, these anecdotal stories cannot be considered as scientific proof and may be influenced by a placebo effect. To address these uncertainties, human clinical trials are necessary. Additionally, there is an ongoing debate in the scientific community about the transportation of molecules like NR, which adds to the complexity of understanding how these supplements work in the body.
Stability and transportation of NMM and NR are still under study, with NMM appearing more stable. Transport into cells is unclear, but both compounds increase NAD levels.: Ongoing research using NMR and tracer studies will reveal how NMM and NR are transported and utilized in different tissues. Blood measurements may not provide definitive conclusions due to active utilization and recycling by the body.
The stability and transportation of NMM and NR, which are compounds that raise energy levels in the body, are still subjects of ongoing studies. While NMM appears to be more stable than NR, it is not clear how they are transported into cells. There is evidence of an NR transporter, but both compounds effectively raise NAD levels in the body. As these studies are being conducted using whole cells from blood or PBMCs, it is important to note that NMM and NR are actively utilized and recycled by the body, making it difficult to draw definitive conclusions from blood measurements. Ongoing research using techniques like NMR and tracer studies will provide a clearer understanding of where these compounds are preferentially taken up in different tissues.
Promising Effects of NAD Precursors on Female Infertility and Low Fertility: NAD precursors show potential in improving egg quality and fertility in women, while further research is required for male fertility. Be cautious of unauthorized products claiming to be endorsed by David Sinclair or Harvard.
David Sinclair's research on NAD precursors has shown promising effects on female infertility and low fertility. The molecules being developed by companies like Metro Biotech and Jumpstart Fertility have demonstrated improved bioavailability, stability, and efficacy compared to publicly available options. These molecules target a protein called Babara 1, which regulates spindle quality in eggs. Low levels of NAD in the ovary and egg may contribute to infertility, and providing NAD precursors to eggs has resulted in healthier, more numerous eggs that are better suited for fertilization and healthy pregnancies. While there is potential for male fertility opportunities, further research is needed. It's important to note that products with David Sinclair's name that are available over the counter are not authorized by him or Harvard.
Targeting Rare Diseases and Fertility: A Closer Look at Life Bioscience's Research: David Sinclair's company, Life Bioscience, is focusing on targeting rare diseases and conducting fertility trials, while exploring the central tenants of aging and potential connections to the Sirtuin story in yeast.
David Sinclair's company, Life Bioscience, is focusing on targeting rare diseases with high unmet needs. They are also conducting trials in fertility, specifically in IVF clinics next year. Peter Attia highlights the challenge of longevity research and the difficulty of making claims in humans due to the lengthy testing process. In contrast, other companies like Restore Bio are targeting very specific indications that are testable in shorter periods of time. When discussing the central tenants of aging, Sinclair mentions epigenetic change, cellular health communication, inflammation, senescent cells, protein misfolding, telomere loss, genomic instability, metabolic changes, and responses to nutrient inputs. Sinclair believes that there is a unifying theory that explains why these pathways go awry during aging, and he hints at a connection to the Sirtuin story in yeast. However, these findings have not been published yet.
The Loss of Epigenetic Information and Aging Process: The loss of epigenetic information during the aging process leads to cells losing their identity and functioning improperly, highlighting the need for further research to achieve significant changes in human longevity.
The aging process is heavily influenced by the loss of epigenetic information, which leads to the cells losing their identity and functioning improperly. The genome itself remains largely intact in old individuals, but the pattern of gene expression, which is analog information, deteriorates over time. This analog information is constantly adapting to various factors such as diet, exercise, and sleep. However, due to the fragility of analog systems, this information doesn't last long and results in a loss of gene regulation. This loss of regulation causes cells to behave differently and lose their specialized functions. While the field of longevity research has made significant progress, there is still much to learn and discover in order to achieve step function changes in human longevity.
Aging and Gene Expression: Finding Ways to Access Information: As we age, the proteins responsible for DNA repair and gene expression prioritize repair over deactivation, potentially disrupting gene programming. Finding ways to trigger cells to access and utilize information could have significant benefits in terms of longevity and cost savings.
As we age, the proteins responsible for DNA repair and gene expression become distracted from their deactivation function and focus more on the repair function. This response to stresses and DNA breaks is beneficial when we are young, but as we get older, it can disrupt the structure of our chromatin and affect gene programming. However, the exciting news is that the information is still present and accessible. The challenge is to find ways to trigger cells to access and utilize this information at the right time. To accelerate our knowledge, an ideal experiment would involve giving a group of 5000 people certain medications and monitoring their mortality rate over a few years. The potential benefits of such an experiment are immense, both in terms of longevity and cost savings.
Exploring the Potential of Molecules and Genes to Extend Lifespan and Combat Aging-related Issues: David Sinclair's lab has achieved promising results in extending lifespan in mice through the use of natural molecules and genetic modifications. This research offers hope for addressing age-related decline and improving overall wellness in older individuals.
There is great potential to extend lifespan and combat aging-related issues through experiments and combinations of different molecules and genes. David Sinclair discusses the promising results obtained in his lab, where they have been able to extend the lifespan of mice even when starting later in life. They have been using natural molecules, such as NMM, and are now exploring better molecules to achieve even better outcomes. Additionally, Sinclair highlights the ability to genetically modify adult mice quickly and efficiently, which allows for faster experiments and testing of combinations of genes and molecules. The focus is on NAD precursor space and activating all seven sirtuins to replenish what's lost over time. This research offers hope for addressing the age-related decline in NAD and improving overall wellness in older individuals.
Understanding Children's Understanding of Death: Children between the ages of four and seven go through a natural process of understanding death, which remains buried in their subconscious until later in life. Discussing mortality with children can be challenging for parents.
Children go through a natural process of understanding and accepting the concept of death between the ages of four and seven. Initially, they may be in denial and believe that only certain adults will die while others will not. However, by the age of seven, they come to realize that everything around them, including themselves, will eventually die. Interestingly, this understanding is buried deep in their subconscious and does not often resurface until they reach their fifties or encounter significant signs of aging. The conversation also highlights the challenges parents face when discussing mortality with their children, as it can be traumatic and overwhelming for them. Ultimately, at different stages of life, individuals may have varying levels of awareness and contemplation about their own mortality.
Embracing Change and Continuous Learning: The evolving nature of knowledge calls for humility, adaptability, and the willingness to continuously update and revise information in order to stay informed and relevant.
Knowledge and information are constantly evolving. Both Peter Attia and David Sinclair express their understanding of the changing nature of facts and the need for ongoing updates and revisions. They acknowledge that what is known today may not be entirely true tomorrow. This realization requires humility and a willingness to adapt. Sinclair shares his struggle with perfectionism, constantly updating his book and PowerPoint slides even after submitting them. However, he also recognizes the value of getting information down on paper and being able to address burning questions from readers. The conversation highlights the importance of staying open-minded and continuously learning in order to stay informed and relevant.
