<div> <div><span> Richard Miller is a professor of pathology and the Director of the Center for Aging Research at the University of Michigan. He is one of the architects of the NIA-funded Interventions Testing Programs (ITPs) animal study test protocol. In this episode, Rich goes through the results of the long list of molecules tested by the ITP—including rapamycin, metformin, nicotinamide riboside, an SGLT-2 inhibitor called canagliflozin, and more. Many of the discussed outcomes have had surprising outcomes—both positive and negative findings.</span></div> </div> <div> <div> <p><span> We discuss:</span></p> </div> <ul type="disc"> <li>Rich's interest in aging, and how Hayflick's hypothesis skewed aging research (3:45);</li> <li>Dispelling the myth that aging can't be slowed (15:00);</li> <li>The Interventions Testing Program—A scientific framework for testing whether drugs extend lifespan in mice (29:00);</li> <li>Testing aspirin in the first ITP cohort (38:45);</li> <li>Rapamycin: results from ITP studies, dosing considerations, and what it tells us about early- vs. late-life interventions (44:45);</li> <li>Acarbose as a potential longevity agent by virtue of its ability to block peak glucose levels (1:07:15);</li> <li>Resveratrol: why it received so much attention as a longevity agent, and the takeaways from the negative results of the ITP study (1:15:45);</li> <li>The value in negative findings: ITP studies of green tea extract, methylene blue, curcumin, and more (1:24:15);</li> <li>17α-Estradiol: lifespan effects in male mice, and sex-specific effects of different interventions (1:27:00);</li> <li>Testing ursolic acid and hydrogen sulfide: rationale and preliminary results (1:33:15);</li> <li>Canagliflozin (an SGLT2 inhibitor): exploring the impressive lifespan results in male mice (1:35:45);</li> <li>The failure of metformin: reconciling negative results of the ITP with data in human studies (1:42:30);</li> <li>Nicotinamide riboside: insights from the negative results of the ITP study (1:48:45);</li> <li>The three most important takeaways from the ITP studies (1:55:30);</li> <li>Philosophies on studying the aging process: best model organisms, when to start interventions, which questions to ask, and more (1:59:30);</li> <li>Seven reasons why pigs can't fly (2:08:00); and</li> <li>More.</li> </ul> <div> <span>Learn more: </span><a href="https://peterattiamd.com/"><span>https://peterattiamd.com/</span></a></div> <div> </div> <div> <span>Show notes page for this episode: <a href="https://peterattiamd.com/RichardMiller">https://peterattiamd.com/RichardMiller</a> </span></div> <div> </div> <div> <span>Subscribe to receive exclusive subscriber-only content: </span><a href="https://peterattiamd.com/subscribe/"><span>https://peterattiamd.com/subscribe/</span></a></div> <div> </div> <div> <span>Sign up to receive Peter's email newsletter: </span><a href="https://peterattiamd.com/newsletter/"><span>https://peterattiamd.com/newsletter/</span></a></div> <div> </div> <div> <span>Connect with Peter on</span> <a href="http://facebook.com/PeterAttiaMD"><span>Faceboo</span></a><span>k</span> <span>|</span> <a href="http://twitter.com/PeterAttiaMD"><span>Twitter</span></a> <span>|</span> <a href="http://instagram.com/PeterAttiaMD"><span>Instagram</span></a><span>.</span></div> </div>
Actionable Insights
1. Aging is Malleable and Slowable
Recognize that healthy lifespan can be significantly extended through interventions, with effects potentially exceeding those of curing specific diseases like cancer. This fundamental understanding should guide medical research and personal health strategies.
2. Interventions Can Start Later
Be aware that effective anti-aging interventions, such as rapamycin, can often be initiated in middle age (e.g., 60 human-equivalent years) and still provide substantial benefits. This challenges the notion that interventions must begin in youth to be effective.
3. Longevity Responses are Sex-Specific
Acknowledge that responses to longevity interventions are frequently sex-specific, with some drugs showing benefits only in males (e.g., 17-alpha estradiol, canagliflozin) or differential effects (e.g., rapamycin). Research and personal application should consider these differences.
4. Prioritize Rigorous Intervention Testing
When evaluating longevity interventions, prioritize studies that use genetically heterogeneous animals, are statistically powered to detect meaningful effects (e.g., 8-10% lifespan extension), and demonstrate reproducibility across multiple independent sites. This approach ensures reliable and generalizable findings.
5. Consider Intermittent Rapamycin Dosing
When considering rapamycin or rapalogs, an intermittent dosing strategy (e.g., weekly) may be preferable. This approach aims to inhibit mTOR complex one for longevity benefits while minimizing negative consequences from continuous mTOR complex two inhibition.
6. Target Post-Meal Glucose Peaks
Explore interventions that specifically target and reduce post-meal glucose peaks, even if they don’t significantly alter overall average glucose levels (e.g., Acarbose, Canagliflozin). This strategy may contribute to lifespan extension, particularly in males.
7. Acarbose: Human Longevity Candidate
Consider Acarbose as a strong candidate for human clinical trials aimed at extending healthy lifespan. It is FDA-approved with a long, well-documented safety history, lowering barriers for human evaluation.
While metformin did not show significant lifespan extension in ITP mouse studies, human epidemiological data suggests it may offer mortality benefits even for non-diabetics. This warrants further investigation in human clinical trials (like TAME) rather than dismissing its potential based solely on mouse models.
9. Avoid Resveratrol for Longevity
Do not rely on resveratrol or sirtuin activators for lifespan extension. Rigorous testing in mice on a normal diet has shown no longevity benefit, despite popular claims and initial studies on metabolically stressed animals.
10. Avoid NR for Longevity
Do not rely on nicotinamide riboside (NR) for lifespan extension. Studies in mice at recommended doses did not show a longevity benefit or consistent major changes in NAD levels in tissues.
11. Avoid Telomere Length as Biomarker
Do not rely on telomere length as a biomarker for aging or anti-aging interventions. While telomere biology is important for cancer, it is not a reliable measure for the overall aging process.
12. Frame Research on “What Slows Aging”
Focus scientific inquiry and personal learning on “what can slow aging” rather than “what causes aging.” This reframes the problem to be more actionable and conducive to developing interventions that postpone multiple aspects of aging.
13. Select Research Models Wisely
When conducting scientific research, select the model organism (e.g., worms, flies, mice, marmosets, humans) based on the specific biological question being addressed, as each offers unique advantages for different types of studies.
14. Anti-Aging Impacts All Diseases
Understand that interventions slowing the fundamental aging process are expected to postpone a wide range of age-associated diseases relevant to each species, even those not typically observed in the model organism.