<p><a href="https://peterattiamd.com/richardmiller2/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=231204-pod-richardmiller2&utm_content=231204-pod-richardmiller2-podfeed"> View the Show Notes Page for This Episode</a></p> <p><a href="https://peterattiamd.com/subscribe/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=231204-pod-richardmiller2&utm_content=231204-pod-richardmiller2-podfeed"> Become a Member to Receive Exclusive Content</a></p> <p><a href="https://peterattiamd.com/newsletter/?utm_source=podcast-feed&utm_medium=referral&utm_campaign=231204-pod-richardmiller2&utm_content=231204-pod-richardmiller2-podfeed"> Sign Up to Receive Peter's Weekly Newsletter</a></p> <p>Richard Miller is a professor of pathology and the Director of the Center for Aging Research at the University of Michigan, as well as a previous guest on The Drive. In this episode, Rich provides an update on the exciting work of the Interventions Testing Program (ITP), an initiative designed to assess potential life-extending interventions in mice. Rich covers the notable successes like rapamycin, 17⍺-estradiol, and acarbose as well as notable failures like nicotinamide riboside, metformin, and resveratrol, providing valuable lessons about the intricacies of the aging process. Rich delves deep into aging biomarkers and aging rate indicators, unraveling crucial insights into the science of geroprotective molecules. Additionally, Rich discusses some surprising successes of recent molecules tested by the ITP and concludes with an optimistic look at future frontiers, including bridging the gap from mice to humans.</p> <p><strong>We discuss:</strong></p> <ul type="disc"> <li>An overview of the Interventions Testing Program (ITP) [3:45];</li> <li>How the mice used by the ITP are superior for research relative to mouse models used in most research [11:15];</li> <li>Design of ITP studies, outcomes tested, and metrics of interest [19:00];</li> <li>The process and challenges of drug formulation for mice [30:00];</li> <li>Four drugs identified by the ITP that extends the lifespan of mice [36:30];</li> <li>The success of rapamycin and what it tells us about the biology of aging [43:15];</li> <li>Other measures of healthspan evaluated by the ITP in stage 2 studies [50:45];</li> <li>Distinguishing aging rate indicators from biomarkers of aging [57:30];</li> <li>Aging rate indicators identified through the examination of slow-aging mice [59:15];</li> <li>Why proteomics are essential to understand changes in the cell [1:12:15];</li> <li>Unraveling aging rate indicators: dose-effect, duration, and future frontiers [1:21:45];</li> <li>A closer look at aging rate indicators: bridging the gap from mice to humans [1:27:00];</li> <li>What do laboratory mice die from? [1:38:45];</li> <li>Distinguishing between a drug that improves an age-sensitive outcome and a drug that improves all aspects of aging [1:42:00];</li> <li>The ITP study of 17⍺-estradiol: mechanisms of life extension and surprising sex differences [1:43:30];</li> <li>Unsuccessful drugs studied by the ITP: resveratrol, metformin, and nicotinamide riboside [1:51:30];</li> <li>Over-the-counter successes in the ITP: meclizine and astaxanthin [2:01:00];</li> <li>A senolytic drug, fisetin, fails to extend lifespan [2:07:00];</li> <li>Can targeting senescent cells slow aging? [2:13:00];</li> <li>Optimism about future findings [2:16:30]; and</li> <li>More.</li> </ul> <p>Connect With Peter on <a href="https://twitter.com/PeterAttiaMD">Twitter</a>, <a href="https://www.instagram.com/peterattiamd/">Instagram</a>, <a href="https://www.facebook.com/peterattiamd/">Facebook</a> and <a href="https://www.youtube.com/channel/UC8kGsMa0LygSX9nkBcBH1Sg">YouTube</a></p>
Actionable Insights
1. Prioritize Functional Anti-Aging Outcomes
When evaluating anti-aging interventions, prioritize evidence of retained youthful function (e.g., improved muscle strength, hearing, cognition, bone health) in addition to lifespan extension, as this confirms a true anti-aging effect rather than just disease postponement.
2. Prioritize Proteomics in Research
Focus on collecting and analyzing proteomic data over solely transcriptomic data in research, as protein levels are poorly correlated with mRNA levels (~30% correlation), and proteins are the functional molecules in cells.
3. Study Non-Transcriptional Proteome Molding
Explore non-transcriptional pathways like differential RNA translation and selective protein degradation (e.g., chaperone-mediated autophagy) that significantly impact protein levels independently of mRNA transcription.
4. Choose Heterogeneous Mouse Models
For biomedical research, especially in aging, use genetically heterogeneous mouse models (e.g., UMHET3) instead of inbred strains (e.g., C57 Black 6) to improve translational relevance and avoid misleading results from a single genotype.
Before initiating long-term drug studies, rigorously test the drug’s concentration in the administered form and its presence in target tissues (e.g., liver, plasma) via pilot administration to ensure proper dosing and biological effect.
6. Rapid Euthanasia for Research Integrity
Employ rapid euthanasia methods (e.g., quick CO2 gas fill) to minimize stress and physiological changes (e.g., adrenaline, glucose, pH) that could confound biochemical and molecular analyses of tissues.
7. Adjust Dosing for Sex Differences
Consider sex-specific differences in drug pharmacokinetics; adjust dosing or administration duration for each sex (e.g., lower dose, stop earlier) to optimize efficacy and avoid toxicity.
8. Screen Drugs Using Aging Rate Indicators
Utilize aging rate indicators (ARIs) as a cost-effective screening tool for potential anti-aging drugs, testing their ability to shift ARIs in young adults within months, which may predict lifespan extension more efficiently than full lifespan studies.
9. Nominate Drugs for ITP Testing
If you are a researcher with a potential life-extending drug, submit an application to the ITP explaining its rationale and safety for testing in mice, as they annually select candidates for lifespan extension studies.
10. Test Drugs in Middle-Aged
When a drug shows efficacy in young adults, further test its effects in middle-aged subjects to determine if benefits extend to later life stages, which is a key goal for anti-aging interventions.
11. Access ITP Tissue Repository
Researchers can request tissues from ITP-treated mice (both winners and losers) for specific organ-specific functional or pathological outcome tests by submitting a request detailing the tissue needed and the research plan.
12. Fund Longevity Research via ITP
Philanthropists interested in longevity research can directly support the Interventions Testing Program (ITP) by setting up independent arrangements or foundation awards to its university sites, thereby increasing funding and accelerating critical longevity research.
13. Combine Rapamycin and Acarbose
Explore the combination of rapamycin and acarbose for potentially synergistic longevity benefits, as this combination yielded the largest lifespan increase (29% in male mice) observed by the ITP.
14. Rapamycin Benefits in Later Life
Consider rapamycin for longevity benefits, as studies show it can significantly extend lifespan in mice even when initiated in late middle age (20 months old, equivalent to 55-60 human years) without diminishing its efficacy.
15. 17-alpha-estradiol for Male Longevity
Consider 17-alpha-estradiol for male longevity, as it significantly extends lifespan in male mice even when initiated in middle age (16-20 months old), without affecting female longevity.
16. Acarbose Benefits in Middle Age
Consider acarbose for longevity, as it extends lifespan in mice (better in males) even when initiated in middle age (16-20 months old), though starting earlier yields greater benefits.
17. Meclizine for Male Longevity
Consider meclizine (an over-the-counter seasickness drug) as a potential longevity intervention, as it significantly increased lifespan by about 10% in male mice.
18. Astaxanthin for Male Longevity
Consider astaxanthin (a food dye/supplement) as a potential longevity intervention, as it significantly increased lifespan by about 10% in male mice.
19. Exercise for Cognitive Enhancement
Engage in regular exercise to potentially improve cognitive function, as exercise increases GPLD1 production in the liver and fat, which is correlated with enhanced cognition.
20. Support Podcast for Longevity Knowledge
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