#333 ‒ Longevity roundtable — the science of aging, geroprotective molecules, lifestyle interventions, challenges in research, and more | Steven Austad, Matt Kaeberlein, Richard Miller
In this roundtable, Drs. Steven Austad, Richard Miller, and Matt Kaeberlein join Peter Attia to explore geroscience, the link between healthspan and lifespan, and the challenges of funding and public perception in longevity research. They discuss evaluating interventions like rapamycin and senolytics, the role of epigenetic changes, and the potential of GLP-1 receptor agonists.
Deep Dive Analysis
16 Topic Outline
Surge in Public Interest in Longevity Science
Healthspan vs. Lifespan: Definitions and Interplay
Challenges in Funding Aging Research at NIH
Aging as a Disease: A Marketing vs. Scientific Debate
Biological vs. Chronological Age and Epigenetic Clocks
Critique of the Hallmarks of Aging Framework
Causality of Epigenetic Changes in Aging
Translating Aging Research from Mice to Humans
Biomarkers vs. Aging Rate Indicators for Human Studies
The Role of Exercise in Slowing Aging
GLP-1 Agonists as Potential Geroprotective Agents
The Controversy and Limitations of Senescent Cell Research
Metformin's Geroprotective Potential and TAME Trial
Rapamycin Dosing Strategies and Mechanisms
Lack of Evidence for Resveratrol and NAD Precursors
Parabiosis and Plasmapheresis as Anti-Aging Interventions
6 Key Concepts
Healthspan
Healthspan is a concept that aims to define the period of life an individual spends in relatively good health, free of disability and disease. While difficult to define precisely and often considered a binary concept, the goal of geroscience is to extend this healthy period of life.
Biological Age
Biological age refers to the physiological age of an individual's tissues and organs, which can differ from their chronological age. While the overall process of biological aging is real and malleable, collapsing it into a single number for an individual is considered problematic and often uninformative by some experts.
Hallmarks of Aging
The 'hallmarks of aging' is a list of biological processes believed to contribute to aging, such as epigenetic dysregulation, cellular senescence, and mitochondrial dysfunction. While useful for communication, some experts argue this framework prematurely narrowed research focus and can lead to oversimplification, hindering deeper mechanistic understanding.
Biomarkers of Aging
Biomarkers of aging are measurable biological characteristics that change with age, like an odometer in a car. They can indicate how much an organism has aged but do not directly measure the *rate* at which it is aging, making them less useful for short-term clinical trials of anti-aging interventions.
Aging Rate Indicators
Aging rate indicators are measures that, in principle, can tell you whether an organism is aging slowly or normally, akin to a speedometer. These are less established than biomarkers but are crucial for quickly assessing the effectiveness of anti-aging interventions, especially in human clinical trials, by showing changes in youth.
Senescent Cells
Senescent cells are irreversibly arrested cells that do not die and typically secrete a pattern of inflammatory cytokines and other factors (SASP). While their accumulation is associated with aging and their removal can show health benefits in some models, the definition is broad, and their precise causal role and therapeutic targeting remain subjects of debate.
12 Questions Answered
The surge is attributed to a combination of factors, including scientific discoveries in the 1990s showing lifespan malleability, evidence that pills can extend health and lifespan in mice, and a new generation of tech entrepreneurs and aging individuals seeking to extend healthy life, though it has also led to commercial hype.
No, experts argue that healthspan and lifespan are linked and generally improve together. Interventions that extend lifespan in mice do so by postponing diseases, both fatal and non-fatal, suggesting that targeting the biology of aging improves both.
Funding is low due to a 'turf war' mentality where disease-specific institutes defend their budgets, a historical reputation problem of aging research being less rigorous, and a lack of understanding among policymakers that aging is the greatest risk factor for most major diseases.
Most experts on the panel agree that aging is not a disease, as it is a fundamental process that acts as a risk factor for many diseases. Calling it a disease is often seen as a marketing ploy to attract funding or facilitate drug approval, but it can confuse scientific discussion and create negative perceptions.
Direct-to-consumer epigenetic age tests are currently considered unreliable and a 'complete mess.' One expert's personal test showed results ranging from 42 to 63 years when his chronological age was 53.75, with high variability even between duplicates from the same company, making them clinically useless for actionable recommendations.
The 'hallmarks of aging' are seen as a double-edged sword: useful for communicating the concept of biological aging and attracting some scientific attention, but also detrimental by prematurely narrowing research focus and discouraging investigation outside the established list.
While epigenetic changes are undeniably associated with aging and are part of the biological process, establishing a direct causal link between specific epigenetic changes and the overall aging process or age-related diseases is complex and requires more mechanistic research beyond mere correlation.
It is not definitively clear whether exercise slows biological aging, though it significantly improves quality of life and longevity. Molecular changes from exercise, such as increased GPLD1 and Irisin, are also seen in slow-aging mice, suggesting a potential link that warrants further investigation.
GLP-1 agonists are of great interest for their potential geroprotective effects, possibly beyond just caloric restriction. However, current studies are mostly in obese or type 2 diabetic patients, making it difficult to disentangle direct geroprotective effects from benefits related to weight loss and metabolic improvement.
The evidence for metformin's geroprotective effects in non-diabetic humans is uncertain and debated. While observational data in diabetics shows reduced risks for dementia, cancer, and cardiovascular disease, methodological flaws in some studies and the question of whether benefits extend beyond glucose regulation in diabetics remain.
There is strong skepticism regarding resveratrol and NAD precursors as anti-aging compounds. Preclinical studies for resveratrol have been largely debunked or shown to work only under highly artificial, toxic conditions, and ITP studies showed no beneficial effect for NAD precursors on mouse lifespan. While the biology of NAD is interesting, current evidence for marketed precursors is not compelling.
The evidence for parabiosis (surgical connection for blood exchange) in mice is compelling, showing rejuvenation, but its translation to humans is uncertain. Plasmapheresis (plasma exchange) is a more pragmatic clinical approach, and while some studies are ongoing, it's unclear if removing 'bad' factors or adding 'good' factors from young blood is more effective, or if it would work in people.
85 Actionable Insights
1. Shift to Proactive Disease Prevention
Advocate for and adopt a proactive medical approach focused on preventing diseases by targeting the biology of aging, rather than a reactive approach that treats diseases only after they occur.
2. Integrate Medicine 2.0 and 3.0 Approaches
Implement a parallel approach combining Medicine 2.0 (treating established diseases) with Medicine 3.0 (proactive interventions targeting aging biology), viewing them as complementary rather than mutually exclusive.
3. Reallocate Research Funds to Aging Biology
Advocate for reallocating a greater proportion of research dollars from disease-specific treatments to foundational biology of aging, as this proactive investment could reduce the overall burden of late-life diseases.
4. Recognize Aging as Primary Risk Factor
Understand that biological aging is the greatest risk factor for most major causes of death, highlighting the critical need for increased research funding in this area.
5. Challenge Aging’s Immutability
Reject the widespread belief that aging is an unchangeable process; recognize that it is malleable and can be influenced through scientific interventions.
6. Focus on Healthspan Extension
Prioritize extending “healthspan” (the period of healthy life) rather than merely extending life in a frail state, which is the core goal of the aging field.
7. Reject Healthspan-Lifespan Trade-off
Dispel the misconception that one must choose between extending healthspan or lifespan, as evidence suggests they are linked and tend to improve together when targeting aging biology.
8. Avoid Calling Aging a Disease
Refrain from labeling aging as a disease, as it is a risk factor for many diseases, and doing so can confuse scientific discussion and policy.
9. Personalize Your Health Definition
Define “health” in terms of your individual ability to perform desired activities, recognizing that personal goals (e.g., gardening vs. heli-skiing) shape what a healthy life means.
10. Plan for Your Marginal Decade
Engage in the “marginal decade” exercise by identifying the most important physical, cognitive, emotional, and social activities you wish to maintain in the last decade of your life. This helps guide personalized health planning.
11. Model Economic Impact of Geroprotective Drugs
Conduct economic modeling to quantify the vast societal benefits of geroprotective drugs, such as increased workforce participation, delayed Medicare eligibility, and reduced healthcare spending.
12. Educate on Prevention for Age-Related Diseases
Emphasize public education about the critical role of prevention in age-related diseases like Alzheimer’s, especially given the limited effectiveness of current treatments despite massive spending.
13. Focus on Aging Biology for Disease Defeat
Believe that defeating major age-related diseases like Alzheimer’s, cancer, and heart disease will ultimately come from understanding and targeting the biology of aging.
14. Address Immune Dysfunction in Aging
Recognize immune dysfunction as a critical factor contributing to poor health outcomes and mortality in older individuals, warranting proactive rejuvenation efforts.
15. Investigate Immune System Rejuvenation
Prioritize research and investment into understanding and proactively rejuvenating the immune system to combat age-related susceptibility to infections and other diseases.
16. Prioritize Scientific Rigor in Longevity
Navigate the longevity field by seeking out scientific rigor and being aware of the “huge gray area” between real science and “snake oil.”
17. Seek Mechanistic Connections for Interventions
Prioritize understanding the “why” behind observed correlations, seeking clear mechanistic connections for interventions, especially those preserved in humans, to build confidence in their efficacy.
18. Design Experiments to Test Causality
To advance understanding of complex biological processes, focus on designing specific experiments that can directly test causal relationships rather than relying solely on observational correlations.
19. Pursue Detailed Mechanistic Understanding
Avoid oversimplifying complex biological processes; instead, delve into specific changes within cell types and their interactions to gain a deeper, more productive understanding.
20. Distinguish Aging Biology from Disease Pathology
Understand that age-related diseases are downstream effects of biological aging, and interventions slowing aging may not be effective once a disease’s pathology has diverged mechanistically from the underlying aging process.
21. Develop “Speedometer” Aging Rate Indicators
Focus on developing “aging rate indicators” that can reliably and quickly show whether an intervention is slowing the aging process in youth, rather than just biomarkers that reflect accumulated age.
22. Differentiate Biomarkers, Aging Rate Indicators
Understand the difference between biomarkers (something that changes with age) and aging rate indicators (something that tells you how fast you are aging), as the latter is crucial for clinical trials.
23. Establish Confidence in Human Aging Rate Indicators
Focus on building robust evidence to establish confidence in human aging rate indicators, which is crucial for their acceptance by regulatory bodies like the FDA and their use in clinical trials.
24. Critically Evaluate Metformin Observational Studies
Exercise critical judgment when reviewing observational studies on metformin’s effects, as some may contain methodological flaws that invalidate their conclusions regarding mortality benefits.
25. Critically Examine Experimental Conditions and Conclusions
Always critically examine the experimental conditions and underlying causes of observed effects, as initial conclusions can be misleading if the baseline pathology is extreme and unrepresentative.
26. Question Long-Held Scientific Metaphors
Critically re-evaluate long-standing scientific metaphors or hypotheses, such as the Hayflick limit and its relation to aging, to avoid blindly following historical assumptions.
27. Avoid Oversimplifying Aging Mechanisms
Be cautious of oversimplified explanations for aging, such as the sole accumulation of senescent cells, as they can hinder productive scientific inquiry and lead to misleading conclusions.
28. Avoid Terminology Hiding Critical Thinking
Be cautious of scientific terminology that, while seemingly convenient, can “trap you into patterns of thought” that are nonproductive and misleading, preventing deeper investigation into complex biological details.
29. Encourage Open-Mindedness in Research Review
Promote a culture among scientific reviewers that values new ideas and approaches, rather than favoring incremental research or proposals that merely align with established frameworks.
30. Support Discovery Science Beyond Hallmarks
Advocate for and engage in more discovery science and “thinking outside the box” in aging research, as over-reliance on the “hallmarks of aging” may have prematurely narrowed the field.
31. Investigate Beyond Hallmarks List
Pursue research into promising areas of aging biology even if they are not explicitly listed as “hallmarks of aging,” as the current list may be incomplete and prematurely narrow the field.
32. Use Hallmarks for Communication, Not Dogma
Leverage the “hallmarks of aging” as a useful conceptual tool for communicating the idea of biological aging and its mechanistic basis, but avoid treating them as an exhaustive or dogmatic list.
33. Critically Evaluate “Hallmarks of Aging”
Approach the “hallmarks of aging” framework with critical thinking, recognizing that its widespread acceptance may sometimes hinder deeper mechanistic investigation and narrow the scope of research.
34. Recognize Hidden Aging Research in Other Fields
Understand that significant research related to aging, such as studies on senescence in cancer or Alzheimer’s, is being conducted across various NIH institutes, even if not explicitly categorized as “aging research.”
35. Realign Disease Funding for Geroprotection
Explore strategies to reallocate existing disease-specific research funds (e.g., NCI funding for cancer) towards investigating disease prevention through geroprotection, to overcome “turf war” issues.
36. Advocate for Aging Research
Support increased funding for foundational aging science by advocating to policymakers, as current lobbying efforts for aging research are significantly underrepresented compared to disease-specific groups.
37. Maintain Optimism for Aging Research
Despite historical underfunding and resistance, maintain optimism that the landscape for biological aging research funding and public support is beginning to shift positively.
38. Address Reactive Mindset in Research
Recognize that the reactive approach to disease is deeply ingrained in pharmaceutical, biomedical, and basic science research, and efforts are needed to shift this fundamental mindset.
39. Adopt Analog Healthspan Definition
Move beyond the binary medical definition of healthspan (free of disability/disease) to an analog, more nuanced understanding that allows for continuous discussion and measurement of health quality.
40. Communicate with “Healthspan” Concept
Utilize the concept of “healthspan” as a clear and useful term to communicate the goal of increasing the healthy period of life to a broader audience.
41. View Biological Age as Multi-faceted
Understand that “biological age” is not a single number but rather a composite of the ages of individual organs and systems (e.g., heart, liver, brain), reflecting overall health.
42. Evaluate Biologic Age Test Predictiveness
When considering biological age tests, question whether their results are more predictive of future years of life than chronological age, which currently remains the single best predictor.
43. Benchmark Biologic Age with Insurers
Consider the adoption of biological age clocks by life insurance companies for their actuarial algorithms as a strong indicator of their validity and practical utility.
44. Monitor Epigenetic Algorithm Advancements
Stay informed about the development of epigenetic algorithms, as they hold potential to eventually replace or complement many traditional biomarkers in measuring biological age.
45. Explore Targeted Epigenetic Modifications
Investigate and support the development of technologies for targeted epigenetic modifications, as they hold potential to modulate specific aspects of biological aging.
46. Investigate Identified Aging Rate Indicators
Explore the dozen or so identified aging rate indicators (e.g., changes in macrophage types, UCP-1 levels) that consistently change in slow-aging mice across various interventions, as these may translate to humans.
47. Conduct Thorough Human Health Evaluations
Recognize the value of comprehensive health evaluations in humans, as they can provide a rich understanding of health status that is often underestimated by animal researchers.
48. Acknowledge Mouse-to-Human Translation Challenges
Be aware that most interventions effective in mouse models do not directly translate to humans due to species differences, side effects, and other factors, necessitating careful human clinical trials.
49. Be Optimistic About Normative Aging Translation
Maintain cautious optimism that interventions and biomarkers targeting normative biological aging (as opposed to artificial disease models) are more likely to translate successfully from mice to humans.
50. Value Rodent Research as First Step
Appreciate the role of rodent-based research as a critical first step in drug development, even if it doesn’t guarantee human efficacy, as most successful human drugs have a foundation in such studies.
51. Test Aging Rate Indicators in Extreme Human Cohorts
Consider testing potential aging rate indicators in human cohorts with extreme differences in health behaviors (e.g., obese smokers vs. healthy exercisers) to identify signals of slowed aging, while acknowledging limitations regarding sensitivity.
52. Explore Epigenetic Algorithms for Mortality/Healthspan
Investigate epigenetic algorithms like Dunedin-Pace, which show correlations with mortality and healthspan metrics, as potential tools for assessing biological aging.
53. Observe Multi-systemic Aging in Long-Lived Animals
Learn from long-lived animal models (e.g., tiny dog breeds) where aging is slowed across multiple systems (cancer, neurodegenerative, digestive, joint diseases), indicating a broad impact on the aging process.
54. Prioritize Exercise for Quality of Life
Emphasize exercise for its profound impact on quality of life and healthspan, even if its direct effect on lifespan is perceived as small, as the improved quality justifies the effort.
55. Investigate Exercise-Induced Molecular Changes
Explore the molecular changes induced by exercise, such as increased GPLD1 (beneficial for brain neurogenesis) and Iresin (beneficial for fat), as these are also elevated in slow-aging mice.
56. Explore Overlap: Anti-Aging Drugs & Exercise
Investigate the shared molecular pathways and effects between anti-aging drugs and exercise, as some anti-aging drugs in mice show similar beneficial molecular changes to those induced by exercise.
57. Prioritize Convenient Drug Delivery for Research
For animal studies, favor drug formulations that allow for easy administration (e.g., mixed into food or water) over laborious methods like injections, to streamline research efforts.
58. Investigate Metformin’s Geroprotective Effects
Despite skepticism and methodological concerns in some studies, consider investigating metformin’s potential geroprotective effects due to consistent observational data suggesting reductions in dementia, cancer, and cardiovascular disease.
59. Consider Metformin for Diabetic Biological Aging
Recognize that metformin likely reduces biological aging in the context of diabetes by effectively managing diabetic symptoms, but its efficacy in non-diabetic individuals for anti-aging purposes is less clear.
60. Understand Metformin’s Cell-Specific Action
Investigate and understand the cell-specific mechanisms of action for drugs like metformin (e.g., concentration in liver and gut, but not muscle) to better predict their effects and potential side effects.
61. Focus on Organ/Tissue-Specific Drug Effects
Shift research focus from broad “body-wide” drug effects to detailed organ-specific and tissue-specific changes, and how these interact, to better understand mechanisms and target therapies.
62. Balance Mechanistic Understanding with Therapeutic Urgency
Recognize that while mechanistic understanding is valuable, it’s sometimes necessary to pursue promising therapies with suggestive evidence and low side effects, even before fully elucidating every cellular mechanism.
63. Consider Once-Weekly Rapamycin (Off-Label)
For off-label use of rapamycin for healthspan, a common practice among prescribing doctors is once-weekly dosing in the 3-10 milligram range, based on current understanding of side effects and efficacy.
64. Understand Rationale for Intermittent Rapamycin
Recognize that intermittent rapamycin dosing (e.g., once weekly) is hypothesized to reduce side effects by allowing trough levels to bottom out, thereby minimizing off-target effects on mTOR complex 2.
65. Be Aware of Daily Rapamycin Side Effects
Understand that daily rapamycin dosing may be associated with a higher likelihood of side effects like bacterial infections or mouth sores, while once-weekly dosing has shown side effect profiles similar to placebo in some trials.
66. Avoid Resveratrol for Longevity
Do not take resveratrol for longevity or anti-aging purposes, as there is no compelling scientific evidence to support its efficacy, despite its continued marketing and public interest.
67. Be Patient with Dispelling Misinformation
Recognize that it takes a long time to dispel widely accepted but unproven health claims (like resveratrol’s benefits), especially when there’s a profit motive, requiring patience and persistent communication of evidence.
68. Be Skeptical of NAD Boosters for Longevity
Approach NAD boosters (NR, NMN) with skepticism regarding their longevity benefits, as current evidence, including strong negative findings from the ITP, is not compelling despite conceptual plausibility.
69. Acknowledge Mixed Evidence for NAD Boosters
Understand that while NAD is a crucial molecule and its decline with age is plausible, the scientific data on whether boosting NAD through precursors increases lifespan or improves healthspan is “decidedly mixed.”
70. Question Value of Expensive Oral NAD Precursors
Be critical of expensive oral NAD precursors (NMN, NR), as data suggests they may break down to niacin in the gut, raising questions about their unique benefits over cheaper alternatives.
71. Consider Risks of NAD Boosters, Especially for Pets
Weigh the potential risks of NAD boosters, such as kidney inflammation and pathology observed in aged mice at high doses, and exercise caution, particularly when considering their use in companion animals.
72. Investigate Parabiosis/Plasma Exchange in Humans
Support detailed investigation into the potential benefits of parabiosis or plasma exchange in humans, as its efficacy could be a “game changer” given the existing medical infrastructure for transfusions.
73. Identify Specific Factors in Young/Old Blood
Focus scientific efforts on identifying the specific beneficial molecules or cells in young blood and detrimental factors in old blood, rather than relying on complex, non-specific interventions like parabiosis.
74. Expect Complex Blood-Based Rejuvenation Mechanisms
Anticipate that any benefits from blood-based rejuvenation strategies (like parabiosis) will likely stem from a complex combination of factors, rather than a single molecule, given the difficulty in identifying simple mechanisms.
75. Consider Therapeutic Plasma Exchange for Aging
Explore therapeutic plasma exchange (replacing old plasma with albumin) as a logistically simpler starting point for clinical trials investigating blood-based rejuvenation, despite its limitations in testing the “young blood” hypothesis.
76. Account for Procedural Effects in Parabiosis Research
When evaluating parabiosis research, consider that the surgical procedure itself can shorten lifespan in rodents, and benefits observed might be influenced by these procedural impacts.
77. Acknowledge Senescent Cell Accumulation & Benefits
Recognize that cells exhibiting characteristics of senescence accumulate with age in various tissues, and their removal has shown some health benefits in animal models, warranting further investigation.
78. Consider Evidence for P16+ Cell Removal
Acknowledge that there is some evidence suggesting that the removal of P16 positive senescent cells can lead to improvements in health and longevity, despite ongoing debate and challenges in replication.
79. Be Precise with “Senescence” Terminology
Be mindful of the precise use of the term “senescence,” as its current association with specific cell types (senescent cells) has “stolen” its broader meaning of aging, leading to confusion.
80. Explore Anti-Aging for Disease Prevention
Consider the potential of anti-aging drugs to prevent age-related diseases like cancer, as evidenced by their ability to postpone cancer and reduce incidence rates in mice.
81. Beware Untested Longevity Products
Exercise caution regarding products marketed for longevity that lack scientific evidence or rigorous testing, as many are sold to “gullible customers” without proven efficacy.
82. Avoid Direct-to-Consumer Biological Age Tests
Do not rely on direct-to-consumer biological age tests for clinical practice or actionable recommendations due to unknown precision, accuracy, and the current “complete mess” of the industry.
83. Be Skeptical of Single Biological Age Numbers
Approach claims of a single “biological age” number with skepticism, as it oversimplifies a complex dataset of individual health metrics into a potentially unhelpful value.
84. Utilize Biomarkers for Objective Measurement
Employ biomarkers as easily measurable indicators to gain objective information about hard-to-measure biological states or behaviors, such as cotinine levels for smoking.
85. Explore Longevity Premium Membership
To deepen your knowledge of longevity science and health, consider subscribing to Peter Attia’s premium membership for exclusive content and benefits.
5 Key Quotes
I'm not interested in life span, don't put me on that boat. I am interested in health span because they are linked together and they go up and down together. Getting people disabused of that false metaphor, the seesaw metaphor, is probably an important goal for the public interface between longevity scientists, aging scientists.
Rich Miller
If you look at the top 10 causes of death in the United States, nine of them have biological aging as their greatest risk factor. And it's not even close yet. Half of 1% of the research budget that's supposed to be focused on improving human health goes to study that risk factor.
Matt Kaeberlein
It's a matter of taking a very rich, complex data set and trying to collapse it to a number. So if someone wants to know how healthy I am, he or she would need information. How good is my eyesight? How good is my hearing? How good is various kinds of cognitive activities? My aerobic endurance, my joints, all of that is pertinent to how my health is and also about projected future health. Then there's no need, once you've got that information, which is very rich to say, ah, there's a number, a single number, a real number on a point on the number line that condenses that in any useful way.
Rich Miller
Don't ever include your best ideas in a grant. They won't get funded. Do standard stuff, save your best ideas for projects that you do on the side.
Steve Austad
The notion that aging is due to senescent cell accumulation is bad for two reasons. It's a grotesque oversimplification. The evidence for this is awful. But even worse, it again cuts off productive thinking.
Rich Miller