#357 ‒ A new era of longevity science: models of aging, human trials of rapamycin, biological clocks, promising compounds, and lifestyle interventions | Brian Kennedy, Ph.D.
In this episode of The Peter Attia Drive, Brian Kennedy and Attia explore the science of aging, including current research models and the complex relationship between damage accumulation and mortality. They discuss how aging involves both linear accumulation of damage and volatile components affecting disease susceptibility, while examining the limitations of current aging biomarkers and the development of new clinical chemistry-based aging clocks.
The conversation covers several interventions that show promise in slowing the aging process. Kennedy shares insights about compounds like rapamycin, alpha-ketoglutarate, and Urolithin A, explaining their effects on lifespan and cellular function. The episode also addresses the need for increased funding in aging research, suggesting that reallocating resources could advance our understanding of longevity and lead to more effective intervention studies.
This is a preview of the Shortform summary of the Jul 21, 2025 episode of the The Peter Attia Drive
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1-Page Summary
Theories and Models Of Aging
Kennedy and Attia explore the complexities of aging, with Kennedy highlighting ongoing debates about its definition among researchers. He explains that while the Hallmarks and Pillars of Aging are widely recognized pathways, they function as interconnected components rather than separate entities. Kennedy also discusses promising developments in mathematical modeling of aging, particularly through the emerging field of gerophysics.
The conversation reveals that aging involves a linear accumulation of damage over time, combined with volatile components that affect disease susceptibility. Kennedy explains that while damage accumulation is linear, mortality increases exponentially with age as the body's resilience declines and critical failure thresholds are crossed more easily.
Interventions and Compounds to Slow or Reverse Aging
Kennedy discusses several promising interventions for slowing the aging process. He identifies rapamycin as a gold standard compound, noting its effectiveness in extending lifespan through mTOR modulation and inflammation control in animals. The timing of rapamycin administration, particularly around exercise, proves crucial for its effectiveness.
Other significant compounds include alpha-ketoglutarate (AKG), which Kennedy reports can increase lifespan and decrease frailty in animals, and Urolithin A, which affects mitochondrial function. Kennedy also shares his experience with NAD boosters combined with AKG, suggesting potential benefits for exercise performance, though he notes the lack of supporting animal data.
Challenges In Measuring and Validating Aging Biomarkers
Current aging biomarkers face significant limitations, according to Kennedy and Attia's discussion. While first-generation aging clocks predict chronological age and second-generation ones aim to predict mortality, both have shown limitations in clinical applications. Kennedy reveals his development of a new clinical chemistry-based aging clock that outperforms existing methylation clocks in mortality prediction, using about 50 common clinical parameters to provide actionable insights for clinicians.
Increased Funding and Resources in Aging Research Needed
Kennedy emphasizes the significant underfunding of aging research compared to disease-specific research like cancer, despite its potential to impact multiple health conditions. He suggests that reallocating even a small portion of disease-specific funding to aging research could yield substantial improvements. With increased funding, Kennedy envisions conducting larger intervention studies and leveraging AI-driven approaches to advance our understanding of aging and longevity.
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Counterarguments
- The interconnectedness of the Hallmarks and Pillars of Aging, while widely accepted, may oversimplify the complexity of biological systems, and alternative models may propose different frameworks for understanding aging.
- Mathematical modeling, such as gerophysics, is promising but may not yet fully capture the biological variability and complexity of aging processes in real organisms.
- The linear model of damage accumulation in aging is a simplification and may not account for non-linear dynamics, feedback loops, and adaptive responses that occur in biological aging.
- The exponential increase in mortality with age might be influenced by external factors such as socioeconomic status, access to healthcare, and lifestyle, which are not solely biological in nature.
- The effectiveness of rapamycin and its timing may vary significantly among different species, and what works in animal models may not translate directly to humans due to differences in metabolism, physiology, and complexity.
- The benefits of compounds like AKG and Urolithin A in animals may not be replicable in humans, and more rigorous clinical trials are needed to establish their efficacy and safety in human aging.
- The potential benefits of NAD boosters combined with AKG for exercise performance are speculative without robust animal data and may not be supported by further research.
- The development of new aging clocks, while potentially more accurate in mortality prediction, may still face challenges in capturing the multifaceted nature of biological aging and may not be universally applicable across different populations.
- The argument for reallocating disease-specific funding to aging research, while potentially impactful, may overlook the immediate and pressing needs of specific diseases that require dedicated research efforts.
- The assumption that increased funding will necessarily lead to substantial improvements in aging research may not account for the complexities and unpredictability of scientific discovery.
- The reliance on AI-driven approaches to advance understanding of aging and longevity assumes that AI can adequately model biological complexity, which may not always be the case. AI models are only as good as the data and assumptions they are based on.
Actionables
- You can track your own aging biomarkers by regularly monitoring key health indicators such as blood pressure, cholesterol levels, and blood sugar. By keeping a personal health diary or using a health tracking app, you can observe trends over time and discuss them with your healthcare provider to tailor lifestyle changes or interventions that may improve your aging process.
- Incorporate foods rich in compounds like urolithin A (found in pomegranates) and alpha-ketoglutarate (found in certain cheeses and meats) into your diet. While these compounds are being studied for their effects on aging, including them in your diet could potentially offer some of the benefits seen in animal studies, such as improved mitochondrial function and decreased frailty.
- Engage in regular exercise while experimenting with timing your nutrient intake, such as consuming foods high in NAD precursors like dairy, fish, and mushrooms, around your workouts. This could potentially enhance the benefits of exercise on your body's resilience and longevity, similar to how timing of certain compounds is being researched for their synergistic effects with physical activity.
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Theories and Models Of Aging
Kennedy and Attia delve into the complexities of defining aging and the mathematical models that attempt to encapsulate its process.
Debate On Defining Aging and Developing Mathematical Models
Researchers Debate Core Definition Of Aging
Kennedy emphasizes the debate among researchers over the definition of aging, voicing frustrations with non-satisfactory conclusions. He points out that at conferences, the topic often ends with a resigned acceptance of the inevitability of decline, summed up colloquially as "shit happens and then you die."
He further discusses the widely recognized Hallmarks of Aging and Pillars of Aging — pathways within cells thought to be driving the aging process, like inflammation and epigenetic changes. Kennedy underlines that these are not separate entities but rather interconnected components of a complex network striving to maintain homeostasis and equilibrium.
Physicists and Theoreticians Develop Aging Models Using Systems Dynamics, Entropy, and Resilience
Kennedy touches upon the contributions of physicists and theoretical modelers in creating mathematical models based on proven physical principles to better understand aging. He shares his optimism about employing equations to answer questions about aging, although it is an early endeavor. Kennedy, who helped organize the first international conference on gerophysics in Singapore, sees this as a pathway to resolve debates on aging definitively.
Kennedy critiques the casual use of the term "entropy" in the aging field, suggesting it's a placeholder for when a definitive driving force behind aging is not understood. He acknowledges, though, that there is merit to considering entropy related to resilience, as resilience is what maintains health despite transient issues like illness.
Damage Accumulation vs. Exponential Mortality Increase With Age
Aging Involves Linear Accumulation of Damage
Kennedy describes aging as an accumulation of damage, which appears linear when analyzing large datasets such as those from the UK Biobank. He clarifies that while damage is a driver, the process could also involve stochastic events or subtle changes over time. There is a mathematical equation he mentions that fits human data which incorporates these changes in a linear progression.
Linear Damage Process With Volatile Component Determines Disease Susceptibility
He suggests that cancer is a linear aspect of damage accumulating over time due to its nature of accumulating mutations. Kennedy speculates that the linear damage process is overlaid with volatile, episodic changes that contribute to individual variability in aging presentations.
Mortality's Exponential Rise With Age Tied To Crossing Critical Failure Thresholds as Resilience Declines
The discussion between Kennedy and Attia covers a model where aging involves crossing from a healthy state to failure states — such as chron ...
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Theories and Models Of Aging
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Counterarguments
- The definition of aging may be context-dependent, and a single definition might not capture its complexity across different biological systems or scales.
- Some researchers argue that aging is not strictly linear and may involve nonlinear dynamics, feedback loops, and threshold effects.
- The role of genetics and epigenetics in aging suggests that damage accumulation is not the only factor, and some argue that programmed aging theories should also be considered.
- The concept of entropy in biological systems is debated, with some arguing that living organisms maintain order through energy consumption and may not conform to traditional entropy models.
- The relationship between resilience and aging is complex, and some argue that resilience may not decline uniformly across different systems or individuals.
- The Hallmarks of Aging and Pillars of Aging, while interconnected, may not fully explain the aging process, and other factors such as the microbiome and extracellular environment may also play significant roles.
- The idea of crossing from a healthy state to failure states may oversimplify the gradual and multifactorial nature of aging-related decline.
- There is debate over whether interventions can e ...
Actionables
- You can track your daily habits to identify patterns that contribute to your healthspan. Start a journal or use an app to log your daily activities, diet, sleep, and mood. Over time, analyze the data to find correlations between your habits and periods of well-being or decline. For example, you might notice that a consistent sleep schedule correlates with better cognitive function or that certain foods lead to energy slumps.
- Create a "resilience portfolio" by engaging in diverse activities that challenge different aspects of your health. Include a mix of physical exercises, cognitive puzzles, social interactions, and creative pursuits. This approach aims to build overall resilience by stimulating various body systems. For instance, combine strength training with learning a new language and volunteering at a local community center to cover physical, mental, and social resilience.
- Experiment with intermittent challenges to boost your body's ad ...
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Interventions and Compounds to Slow or Reverse Aging
For those interested in the science of aging, Brian Kennedy offers insights into various interventions and compounds that could potentially slow down or even reverse the aging process.
Rapamycin: A Key Intervention With Complex Physiological Effects
Kennedy discusses rapamycin, a compound being tested in humans today, and notes its effectiveness in extending lifespan by modulating mTOR and inflammation in animals. He highlights the importance of timing rapamycin administration, particularly in relation to exercise.
Rapamycin Extends Lifespan By Modulating Mtor and Inflammation in Animals
Kennedy has taken note of rapamycin's status as the gold standard for impacting aging through small molecules, particularly for its modulatory effects on the mTOR pathway and inflammation in animals. He explains how rapamycin disrupts the nutrient pathway and inflammatory signaling feed-forward circle, leading to chronic inflammation which keeps driving mTOR.
Kennedy shares that he has tried Rapamycin and observes that the timing of its administration relative to exercise is crucial, as it impacts the effectiveness of subsequent training sessions.
Potential Therapeutic Uses of Rapamycin in Humans
Various trials, including some ongoing in Columbia or Cornell, examine "gero protectors" like rapamycin that could translate into practical treatments. Not only does rapamycin have the ability to enhance autophagy, change protein translation, and modulate maladaptive inflammation, but it may also offer protective properties by extending lifespan, even in individuals who are metabolically healthy.
Other Promising Interventions and Compounds
Kennedy also mentions other compounds being studied for their potential to extend healthspan and longevity.
Alpha-Ketoglutarate Affects Healthspan and Frailty In Animals
Alpha-ketoglutarate (AKG) emerges as a significant compound in longevity studies, particularly for its effects in enhancing mitochondrial function and reducing frailty in animals. AKG's performance in worm studies led to further trials in mice, showing a time release version of AKG could increase lifespan by 5 to 10% and dramatically decrease frailty. Kennedy refers to a commercially available product that includes AKG, vitamin A, and B complex.
Urolithin A and Its Undisclosed Mechanisms
Urolithin A, a compound that affects mitophagy and mitochondrial biogenesis, has also caught Kennedy's attention. However, the exact mechanism is still under inves ...
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Interventions and Compounds to Slow or Reverse Aging
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Counterarguments
- Rapamycin's long-term effects in humans are not yet fully understood, and its safety profile needs more extensive research.
- The optimal timing of rapamycin administration in relation to exercise may vary among individuals and requires further study to establish guidelines.
- While rapamycin is considered a gold standard in animal studies, its translation to human aging interventions is still speculative and requires more evidence.
- The disruption of the nutrient pathway by rapamycin could have unintended consequences, such as impaired wound healing or immune function.
- Human trials at Columbia and Cornell are promising, but until results are published, the efficacy and safety of rapamycin in humans remain uncertain.
- Enhancing autophagy and modulating inflammation could have complex effects on human physiology, and not all of these effects may be beneficial.
- The effects of Alpha-Ketoglutarate (AKG) observed in animals may not directly translate to humans due to species-specific differences in metabolism and aging.
- The claim that time-release AKG increases lifespan by 5 to 10% is based on animal models, and similar outcomes in humans cannot be assumed without clinical evidence.
- The mechanisms by which Urolithin A affects mitophagy and mitochondrial biogenesis need to be fully elucidated to understand its potential risks and benefits.
- The combination of urolithin interventions with exercise for improved performance is an interesting hypothesis but requires rigorous scientific validation.
- The anecdotal ...
Actionables
- You can track your exercise and supplement intake using a mobile app to find your optimal combination for enhancing performance. By logging your workouts, the timing of your supplements, and any perceived changes in energy or recovery, you can analyze patterns over time to determine what works best for you. For example, if you're experimenting with NAD boosters or AKG, note the timing in relation to your exercise and observe any changes in your performance or recovery.
- Start a personal journal to document subjective health markers before and after trying new supplements like AKG or urolithin A. Record daily entries on energy levels, sleep quality, and any signs of frailty or improved strength. This qualitative data can help you assess whether these interventions have a noticeable impact on your well-being.
- Engage in re ...
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Challenges In Measuring and Validating Aging Biomarkers
Peter Attia and Brian Kennedy discuss the shortcomings of current aging biomarkers, the potentials, and the efforts to create a more clinically useful aging clock.
Limitations of Epigenetic and Methylation Clocks In Predicting Mortality
The effectiveness of first and second-generation aging clocks in predicting mortality and clinical use has been brought into question.
First-Gen Clocks Predict Age; Second-Gen Predict Mortality
Kennedy and Attia explain how the first generation of aging clocks was designed to predict chronological age, whereas the second generation aims to predict clinical outcomes such as mortality. They discuss the idea that second-generation clocks could go beyond current chronological age predictions.
Methylation Clocks Less Accurate Than Age In Predicting Mortality
Kennedy mentions that some first-generation methylation clocks are less accurate than chronological age when it comes to predicting mortality. This raises questions about what exactly these clocks are measuring if not elements of mortality or biological aging.
Development of a Clinical Chemistry-Based Aging Clock
Kennedy shared his development of a clinical chemistry-based aging clock that may show more potential than existing methylation clocks.
Clinical Chemistry Markers Outperform Methylation Clocks and Biomarkers in Mortality Prediction
Kennedy reveals that they developed a clinical chemistry-based clock using NHANES data, which outperforms other parameters in NHANES, including methylation clocks and cardiovascular disease measurements, in predicting mortality. This clock consists of about 50 parameters, with a full blood count providing around 30 of these. The standard markers it utilizes are commonly measu ...
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Challenges In Measuring and Validating Aging Biomarkers
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Counterarguments
- Methylation clocks may still provide valuable insights when combined with other biomarkers, offering a more comprehensive view of aging.
- The accuracy of methylation clocks might improve with further research and refinement, potentially surpassing the predictive power of clinical chemistry markers.
- Clinical chemistry-based clocks, while useful, may not capture all aspects of biological aging that are unrelated to blood chemistry.
- The clinical applicability of any aging clock depends on its integration into healthcare systems and its acceptance by medical professionals, which is not solely determined by the clock's predictive power.
- The use of NHANES data for developing a clinical chemistry-based clock may not be representative of all populations, potentially limiting the clock's generalizability.
- The interpretation of clinical chemistry markers can be complex and may require sophisticated algorithms that are not yet widely available or understood in clinical practice.
- There may be ethical considerations and potential for misuse of aging clocks, especially if they are used to make decisions about the allocation of healthcare r ...
Actionables
- You can request a comprehensive blood panel during your next medical check-up to understand your biological age indicators. Explain to your healthcare provider your interest in clinical chemistry-based aging clocks and ask for a full blood count plus additional relevant markers. This will give you a snapshot of various health parameters that may influence your biological age, allowing you to take proactive steps in managing your health.
- Start a personal health journal to track changes in your clinical chemistry markers over time. After getting your blood panel results, record them in a journal or digital spreadsheet. Include notes on lifestyle changes, such as diet or exercise modifications, and observe how these changes may correlate with improvements or declines in your clinical chemistry markers.
- Engage with a health coach or nutritionist to develop a personalized plan based on your clinical ...
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Increased Funding and Resources in Aging Research Needed
Kennedy has raised the issue of the underfunding of aging research compared to disease-specific areas like cancer research, underlining the vast potential of aging science to benefit multiple health conditions.
Funding Disparity: Aging Research vs. Specific Diseases
Aging Research Is Underfunded Versus Cancer, Despite Its Potential to Impact Many Conditions
Brian Kennedy emphasizes that aging research has historically been underfunded, especially compared to the financial resources allocated to cancer research. He points out the tough financial times faced by the Buck Institute around 2010, illustrating the lack of funding dedicated to the field. It wasn't until around 2017-2018 that aging research began to see a substantial increase in interest and funding. Kennedy asserts that aging research should be funded at levels closer to cancer, addressing the significant disparity between the two.
Peter Attia and Kennedy discuss the general surprise regarding the differences in funding allocation and suggest that even reallocating a small amount of disease-specific funding to aging could yield significant improvements. Kennedy underlines the difficulty in raising funds for aging research, arguing that it is a more strategic investment in translational research than putting money into basic science or pharmaceutical research—areas where pharma companies have long considered but still not fully embraced aging research.
Impact of Increased Resources on Science of Longevity
Resources to Enable Larger Animal and Human Synergistic Intervention Studies
Increased funding in aging research is crucial, per Kennedy, for enabling larger intervention studies in animals and, potentially, humans. These studies could provide valuable insights into aging interventions when translated from mouse models to human applications. Kennedy refers to a successful human product developed from mouse AKG studies as an example of what's achievable. He envisions conducting more substantial and frequent intervention studies and feels that similarly impactful human studies could proceed with sufficient funding.
Funding Could Aid AI-driven Approaches to Reveal Biological Insights
Kennedy is optimistic about the potential of increased funding to support multifactorial clinical and preclinical studies, testing various compounds and combinations that might ...
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Increased Funding and Resources in Aging Research Needed
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Counterarguments
- While aging research may impact many conditions, disease-specific research often has clearer, more immediate goals, which can be more compelling for funding bodies and the public.
- The complexity of aging as a research topic might make it harder to demonstrate clear, short-term wins, which can affect funding decisions.
- Disease-specific research, such as cancer, has a more established infrastructure and a history of public support, which can justify its higher funding levels.
- There is a risk that increased funding in aging research could lead to a reallocation of resources away from diseases that are currently more prevalent or urgent.
- The argument for reallocating funds from disease-specific research to aging research assumes that the benefits of such a shift would outweigh the potential drawbacks, which is not guaranteed.
- The success of translating findings from animal models to humans is not always straightforward, and increased funding does not necessarily equate to successful outcomes.
- AI-driven approaches, while promising, are still in their infancy in many areas of research, and their potential in aging research is not yet fully proven.
- There may be ethical considerations in longevity research that need to be add ...
Actionables
- You can support aging research by choosing to donate to institutions focused on longevity science. Look for reputable organizations like the Buck Institute and allocate a portion of your charitable giving to them. This direct financial support can help bridge the funding gap and contribute to the larger-scale studies needed for breakthroughs in aging research.
- Incorporate longevity-focused lifestyle choices into your daily routine to become a proactive participant in your own aging process. Adopt a diet rich in antioxidants, engage in regular physical activity, and prioritize sleep, as these habits are often subjects of aging research. By doing so, you're applying the principles of longevity science to your life and potentially contributing to the broader understanding of aging through your personal health outcomes.
- Use social media to ...
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