#175 - Matt Kaeberlein, Ph.D.: The biology of aging, rapamycin, and other interventions that target the aging process

Sep 13, 2021 2h 40m 20 insights

Matt Kaeberlein is globally recognized for his research on the biology of aging and is a previous guest on The Drive. In this episode, Matt defines aging, the relationship between aging, chronic inflammation, and the immune system, and talks extensively about the most exciting molecules for extending lifespan. He discusses the current state of the literature of testing rapamycin (and rapalogs) in animals and humans, including Matt's Dog Aging Project, and provides insights into how we can improve future trials by conceptualizing risk, choosing better endpoints, and working with regulators to approve such trials. He also examines the connection between aging and periodontal disease, biomarkers of aging, and epigenetic clocks. Finally, they explore some of the biological pathways involved in aging, including mTOR and its complexes, sirtuins, NAD, and NAD precursors. We discuss: <ul> <li>The various definitions of aging [3:25]; </li> <li>The relationship between disease and the biology of aging [16:15]; </li> <li>Potential for lifespan extension when targeting diseases compared to targeting biological aging [22:45]; </li> <li>Rapamycin as a longevity agent and the challenges of targeting the biology of aging with molecules [32:45]; </li> <li>Human studies using rapalogs for enhanced immune function [39:30]; </li> <li>The role of inflammation in functional declines and diseases of aging [50:45]; </li> <li>Study showing rapalogs may improve the immune response to a vaccine [56:15]; </li> <li>Roadblocks to studying gero-protective molecules in humans [1:01:30]; </li> <li>Potential benefits of rapamycin for age-related diseases—periodontal, reproductive function, and more [1:12:15]; </li> <li>Debating the ideal length and frequency of rapamycin treatment for various indications like inflammation and longevity [1:21:30]; </li> <li>Biomarkers of aging and epigenetic clocks [1:29:15]; </li> <li>Prospects of a test that could calculate biological age [1:37:45]; </li> <li>The Dog Aging Project testing rapamycin in pet dogs [1:42:30]; </li> <li>The role of the mTOR complexes [1:58:30]; </li> <li>mTor inhibitor called Torin2, mitochondrial disease and other potential pathways [2:09:45]; </li> <li>Catalytic inhibitors, sirtuins, and NAD [2:19:15]; </li> <li>NAD precursors: help or hype? [2:28:15]; and </li> <li>More. </li> </ul> Learn more: https://peterattiamd.com/ Show notes page for this episode: <a href="https://peterattiamd.com/MattKaeberlein2">https://peterattiamd.com/MattKaeberlein2</a> Subscribe to receive exclusive subscriber-only content: https://peterattiamd.com/subscribe/ Sign up to receive Peter's email newsletter: https://peterattiamd.com/newsletter/ Connect with Peter on Facebook | Twitter | Instagram.

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Actionable Insights

1. Prioritize Biological Aging Interventions

Focus on interventions that target the fundamental biology of aging for a more significant and broad impact on healthy lifespan, rather than treating individual diseases in isolation. This approach is estimated to add decades of healthy life, unlike single-disease cures.

2. Start Prevention Early

Begin prevention efforts as early as possible to mimic the healthy aging trajectory observed in centenarians, who experience a significant phase shift in disease onset.

3. Consider Once-Weekly Rapamycin Dosing

For individuals considering rapamycin, once-weekly dosing (e.g., 5-8mg, potentially with cycling periods like 8 weeks on, 6 weeks off) is a common self-experimentation protocol, though it lacks robust long-term clinical trial data.

4. Rapamycin Safety at Low Doses

Be reassured that rapamycin (and similar mTOR inhibitors like Everolimus or RTB101) at doses considered for anti-aging purposes do not show significant side effects, especially compared to widely used drugs like statins.

5. Lower ApoB & Improve Metabolic Health

Implement strategies (lifestyle, nutrition, or pharmacological) to lower ApoB and improve metabolic health (e.g., regulating glucose and insulin) to dramatically reduce the risk of atherosclerosis.

6. Fasting for Inflammation Reduction

Consider incorporating fasting into your routine, as it appears to reduce chronic inflammatory signaling, which is a critical factor in many age-related declines and diseases.

7. Evaluate Benefits & Risks

When considering any intervention, carefully weigh its potential beneficial effects against the associated risks and potential side effects, as every drug has a dose-dependent response.

8. Understand Aging as Progressive Decline

Recognize that normal aging is a progressive, chronic decline in function, not a healthy state, especially for typical older adults (e.g., 65-70 years old). This perspective should inform the acceptable level of risk for interventions aiming to slow or reverse this decline.

9. Maintain Good Oral Health

Prioritize good oral hygiene and address periodontal disease, as it is highly prevalent in older adults and linked to an increased risk of dementia, cardiovascular disease, and diabetes, likely through inflammatory pathways.

10. Caution with Epigenetic Clocks

Do not rely on current epigenetic clocks or telomere length measurements as definitive or helpful biomarkers for true biological age, as they can be easily manipulated by short-term interventions and lack robust biological explanations.

11. Sirtuins & NAD Precursors: Limited Evidence

Be aware that while sirtuins and NAD precursors (NR, NMN) show ‘a ton of smoke’ for anti-aging benefits in some studies, the evidence for their robust and reproducible efficacy, especially for lifespan extension, is mixed and not as strong as for mTOR inhibitors like rapamycin.

12. NAD Precursors: Safe but Unproven

NAD precursors like NR and NMN are considered very safe with minimal downside (primarily cost); however, their upside for anti-aging effects in humans is currently unclear and lacks definitive clinical trial evidence.

13. Do Not Use Rapamycin Before 25

Avoid using rapamycin in developing individuals, specifically before the age of 25, as its effects on development are not fully understood and could be detrimental.

14. Recognize Functional Declines as Early Aging

Pay attention to functional declines in various organ systems as early indicators of aging, often preceding the diagnosis of overt age-related diseases.

15. Prioritize Minimizing Side Effects

In any treatment, especially for long-term use or in vulnerable populations (like pets or healthy individuals), prioritize strategies that minimize the likelihood of side effects, such as optimizing dosing frequency.

Recognize that social aspects are extremely important for quality of life as people get older, intersecting significantly with biological aging.

17. Peter Atiyah’s Rapamycin Protocol

Peter Atiyah takes 5-8mg of rapamycin once weekly, having previously cycled it (8 weeks on, 6 weeks off), but notes he is ‘flying blind’ without biomarkers to guide this decision.

18. Matt Caberlin’s Frozen Shoulder Protocol

Matt Caberlin used 8mg of rapamycin once weekly for eight weeks to resolve severe frozen shoulder, attributing the improvement to rapamycin’s anti-inflammatory effects (he explicitly states this is not an encouragement for others to do the same).

19. Advocate for Regulatory Changes

Support efforts to change regulatory environments (e.g., FDA) to allow clinical trials of geroprotective drugs in healthy individuals, using quantitative functional endpoints, and to address the challenges of off-patent drugs.

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