#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller

Podcast Summary: The Peter Attia Drive Episode #333 – Longevity Roundtable

Title: Longevity Roundtable — The Science of Aging, Geroprotective Molecules, Lifestyle Interventions, Challenges in Research, and More
Host: Peter Attia, MD
Guests:

Steven Austad: Expert in Aging Biology and Author of Groundbreaking Research on Extending Healthspan
Matt Kaeberlein: Specialist in Genetics, Aging, and Translational Research; Known for the Dog Aging Project
Richard Miller: Pioneer of Anti-Aging Interventions through the Interventions Testing Program (ITP)

Release Date: January 27, 2025

Introduction

In episode #333 of The Peter Attia Drive, Dr. Peter Attia inaugurates a new roundtable format, inviting three esteemed experts in the field of longevity: Steven Austad, Matt Kaeberlein, and Richard Miller. The discussion delves deep into the multifaceted aspects of aging science, examining both molecular interventions and lifestyle factors that influence healthspan and lifespan.

Public Interest and Terminology in Longevity

Peak of 'Longevity' in Public Discourse

Peter Attia opens the roundtable by highlighting a surge in public interest in longevity, likening the popularity of the term "longevity" to the intense search frequency of "Bitcoin." This signals a cultural shift towards valuing extended healthy living.

Healthspan vs. Lifespan

A central theme is the distinction between healthspan (the period of life free from disease and disability) and lifespan (total years lived). Attia raises critical questions:

"What does healthspan actually mean?" [04:26]
"Can you improve one without improving the other?" [20:08]

Defining Healthspan

Richard Miller criticizes the binary definition of healthspan, arguing it is a "useless term" due to its nebulous nature [07:39]. The panel agrees that a more nuanced, analog definition is necessary to capture the gradations of health without resorting to simplistic metrics.

Challenges in Aging Research

Funding and NIH's Budget Allocation

The discussion shifts to the National Institute on Aging (NIA) and its allocation of funds. Matt Kaeberlein notes that only about half of 1% of the NIH budget targets aging research [22:21]. Richard Miller laments the minimal investment despite aging being a primary risk factor for most major diseases.

Turf Wars with Other Medical Research Areas

Richard Miller elaborates on the "defending turf" phenomenon, where prominent disease-specific research areas like oncology or cardiology resist reallocating funds to foundational aging science, viewing it as an encroachment [23:07]. This creates significant barriers for advancing geroscience.

Evaluating Interventions for Aging

Geroprotective Molecules: Rapamycin, Senolytics, Calorie Restriction

The panel examines various geroprotective interventions:

Rapamycin: Discussed extensively for its ability to extend lifespan in mice by postponing diseases. However, the decade-long lag in translating this to humans is attributed to scientific, commercial, and regulatory challenges [08:12].
Senolytics: Controversial due to mixed evidence. Richard Miller shares experiences where senolytic drugs like fisetin failed to reduce senescent cells in mice, highlighting the reproducibility issues [111:12].
Calorie Restriction: A well-supported intervention in mice, but its direct applicability to humans remains under investigation.

Biomarkers vs. Aging Rate Indicators

A critical distinction is made between biomarkers (measures that change with age) and aging rate indicators (metrics that reflect the pace of aging). Richard Miller emphasizes the need for aging rate indicators to "measure how fast you're aging versus normal" [78:07].

Biological Age vs. Chronological Age

Critique of Biological Age Clocks

The validity of epigenetic age clocks is rigorously debated. Steven Austad and Richard Miller express skepticism about assigning a single "biological age" number, citing inconsiderate variations across different clock models [35:19] and the lack of a definitive causal relationship between epigenetic changes and aging [39:51].

Measuring Health and Aging

Peter Attia advocates for a comprehensive assessment of individual health metrics (e.g., VO2 max, muscle mass) over simplistic biological age scores, arguing that personalized evaluations provide more actionable insights [08:02].

Case Studies of Interventions

Metformin

Discussed as a potential geroprotective agent, metformin's effectiveness in non-diabetics remains uncertain. Richard Miller references a forthcoming review challenging the validity of observational studies suggesting metformin reduces mortality in diabetics [122:38]. Steven Austad remains cautiously optimistic, citing the consistent observational data linking metformin to reduced risks of dementia and cancer [124:02].

GLP1 Receptor Agonists

These drugs, such as tirzepatide and semaglutide, are examined for their potential beyond weight loss, particularly in immune function and dementia prevention. However, challenges include dosage optimization and distinguishing effects from weight loss [101:06].

Resveratrol and NAD Precursors

Matt Kaeberlein criticizes the direct-to-consumer market for resveratrol and NAD supplements, labeling much of the evidence as inconclusive and highlighting potential risks like kidney inflammation in mice [116:54]. The panel agrees that while the molecular biology behind these interventions is plausible, empirical support in humans is lacking.

Senolytic Drugs

The roundtable delves into the controversy surrounding senolytics. Richard Miller shares a failed attempt to replicate the effects of fisetin in reducing senescent cells in mice, underscoring the methodological flaws and reproducibility issues plaguing the field [111:12]. Conversely, Steven Austad points to studies showing benefits in genetically modified mice, though he acknowledges the complexity of translating these findings to humans [76:54].

Parabiosis and Plasma Exchange

Parabiosis, the process of joining the circulatory systems of young and old mice, is discussed as a proof of concept for rejuvenation. However, skepticism remains about its applicability to humans due to physiological differences and the complexity of deducing specific geroprotective factors [85:34]. The panel agrees that targeted research into identifying specific rejuvenating factors in young blood is necessary [138:14].

Conclusion and Future Directions

Need for Better Biomarkers

The consensus is clear: advancing geroscience requires robust aging rate indicators that can reliably measure the pace of aging in humans. This would enable quicker, more efficient clinical trials and better funding allocation.

Funding and Research Priorities

Overcoming the funding barriers and turf wars with other medical disciplines remains paramount. The panel advocates for a strategic reallocation of resources towards foundational aging research, emphasizing the potential for vast economic and health benefits [105:00].

Optimism Amidst Challenges

Despite the numerous challenges, the experts remain optimistic about the future of aging research. The involvement of the private sector, increased public interest, and emerging scientific breakthroughs offer hope for meaningful advancements in extending healthspan and lifespan.

Future Roundtables

The episode concludes with plans for future discussions, potentially including additional luminaries like Morgan Levine, to further explore and debate the evolving landscape of longevity science.

Notable Quotes:

Richard Miller: "I think the term healthspan is a useless term because it's so nebulous and binary." [07:39]
Peter Attia: "Once you escape those big causes of death in middle age, we actually do quite well." [14:32]
Matt Kaeberlein: "The direct-to-consumer biological age testing industry is a complete mess and I have no idea who to believe or if any of them are actually giving accurate data." [43:41]
Richard Miller: "Saying aging is a disease confuses that discussion and makes it impossible to see that relationship." [33:52]
Peter Attia: "If you could wave that magic wand and increase funding, it would help." [54:16]
Steve Austad: "There are real opportunities for more resources to be focused on the scientific side and hopefully less focused on the non-scientific aspects of what's going on." [26:44]

Final Thoughts

Episode #333 of The Peter Attia Drive offers a comprehensive and nuanced exploration of the current state of longevity science. Through candid discussions, the experts illuminate both the promise and pitfalls inherent in the quest to extend healthy human life. Key takeaways emphasize the critical need for better biomarkers, strategic funding, and a collaborative approach to overcoming entrenched research silos. As the field continues to evolve, such roundtables serve as invaluable platforms for intellectual exchange and advancement.