#281 ‒ Longevity drugs, aging biomarkers, and updated findings from the Interventions Testing Program (ITP) | Rich Miller, M.D., Ph.D.
Dr. Rich Miller, Director of the Paul F. Glenn Center for Biology of Aging Research at the University of Michigan, provides an update on the Interventions Testing Program (ITP). He discusses successful lifespan-extending drugs in mice like rapamycin and 17α-estradiol, notable failures such as resveratrol, and the discovery of novel aging rate indicators.
Deep Dive Analysis
16 Topic Outline
Overview of the Interventions Testing Program (ITP)
Superiority of UMHET3 Mice for Aging Research
ITP Study Design: Outcomes, Metrics, and Power Analysis
Challenges and Process of Drug Formulation and Delivery
Notable ITP Successes: Rapamycin and its Impact
Healthspan Measures and Collaborative Research Programs
Distinguishing Aging Rate Indicators from Biomarkers of Aging
Key Aging Rate Indicators: UCP1, Macrophages, BDNF, DCX, GPLD1
Importance of Proteomics over Transcriptomics in Aging
Future Frontiers: Bridging Aging Rate Indicators from Mice to Humans
Causes of Death in ITP Mice and Drug Effects
17-alpha-estradiol: Mechanisms of Life Extension and Sex Differences
Unsuccessful Drugs: Resveratrol, Metformin, and Nicotinamide Riboside
Over-the-Counter Successes: Meclizine and Astaxanthin
Fisetin and the Senescent Cell Hypothesis
Optimism for Future Discoveries and Program Impact
6 Key Concepts
Interventions Testing Program (ITP)
A National Aging Institute initiative that evaluates potential life-extending interventions, primarily drugs, in mice. It aims to identify compounds that slow aging and extend healthy lifespan, using a genetically heterogeneous mouse model across three independent research laboratories.
UMHET3 Mice
A genetically heterogeneous mouse model used by the ITP, derived from four different inbred strains. Unlike standard inbred mice, UMHET3 mice are not genetically identical, better reflecting human genetic diversity and providing more robust, reproducible results for aging research.
Aging Rate Indicators (ARIs)
Measures that indicate how quickly an organism is aging, akin to a speedometer. These are distinct from biomarkers of aging (odometers) because they can be detected even in young adults and change consistently in the same direction across various slow-aging models.
Cap-Independent Translation
A mechanism of protein synthesis where ribosomes bind to messenger RNA (mRNA) at sites other than the 5' cap. This allows for selective translation of certain proteins, independent of mRNA transcription levels, and plays a significant role in molding the proteome in slow-aging mice.
Xenobiotic Metabolism Enzymes
Enzymes, primarily in the liver, that process foreign compounds like drugs. These enzymes often exhibit radical differences between sexes, leading to variations in drug absorption, conjugation, and excretion rates, which can impact drug concentrations and efficacy.
Senescent Cells
Cells that have stopped dividing and accumulate with age, often secreting inflammatory factors. While their existence is acknowledged, the guest expresses skepticism about their uniform definition and the extent of their role as a primary driver of aging, noting that they are often rare even in aged tissues.
11 Questions Answered
The ITP's main goal is to identify drugs that can slow aging and extend the lifespan of mice, providing insights into the biology of aging and potential pathways for human longevity interventions.
UMHET3 mice are genetically heterogeneous, meaning no two are identical, which better reflects human genetic diversity and leads to more generalizable results. In contrast, B6 mice are inbred and homozygous, making them prone to specific diseases and less representative of a diverse population.
The ITP uses a statistical test (Wang-Allison test) that looks at the proportion of treated versus control mice still alive when 90% of the total pooled population has died, rather than relying on the age of the very last mouse to die.
These differences are likely due to sex-specific variations in xenobiotic metabolizing enzymes in the liver, which can lead to different rates of drug absorption, conjugation, and excretion, resulting in varying blood concentrations between male and female mice.
This suggests that even at an advanced age (equivalent to 55-60 in humans), there are still ongoing aging processes that are susceptible to drug intervention, indicating that some age-related damage is not irreversible and can be slowed down.
Aging rate indicators (ARIs) are like a speedometer, measuring how quickly an organism is aging, and can be observed in young adults. Biomarkers of aging are like an odometer, indicating how much aging has occurred, and are typically only useful when an animal or person is already old.
RNA levels are poorly correlated with actual protein levels (only about 30% correlation in aging studies), and it is proteins that perform functions in the cell. Focusing solely on RNA misses 70% of the changes that control protein levels, leading to an incomplete or potentially misleading understanding of biological processes.
The mechanism is still obscure, but it significantly extends lifespan in male mice, even beyond females, and does not benefit females. It does not bind well to traditional estrogen receptors, suggesting an alternative target or pathway, possibly involving the production of specific estriol family steroids in males.
Resveratrol did not extend mouse lifespan in ITP studies, and its status as a sirtuin activator and its efficacy in other models have been widely questioned. The amount found in red wine is negligible for any effect, and much of its initial hype has been disproven by rigorous scientific inquiry.
Both Meclizine (an antihistamine for seasickness) and Astaxanthin (a food dye/antioxidant) significantly increased the lifespan of male mice by about 10%. This is notable as they are the first over-the-counter winners, though their mechanisms and effects on maximum lifespan require further investigation.
Fisetin did not extend the lifespan of male or female mice in ITP studies. Furthermore, it did not appear to remove senescent cells (as measured by markers like P16) from the brain, liver, muscle, or kidney tissues, suggesting it failed to act as a senolytic in this context.
19 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.
5. Verify Drug Formulation & Bioavailability
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.
5 Key Quotes
If you want to see if your drug works, you sort of have to test it on people who are not identical genetically to one another. Yet that sort of thing, which is so obvious in human analogies, is ignored by nearly all mouse scientists.
Rich Miller
The drugs that we consider, we have four of these now, that give more than a 10 percent increase in lifespan in terms of proportional change of healthy lifespan are doing about three times better than some hypothetical drug that abolished cancer in people or abolished heart attacks in people.
Rich Miller
The inevitable conclusion, which I would have bet a lot of money against, is that by the time you're 20 months of age in a mouse, which is sort of like 55 or 60 years old in a person, damage will have occurred that's irreversible. But apparently there's still some further stages of that process that occur afterwards, after we started to administer the drug at 20 months of age, which are dependent on aging, and the drug inhibits.
Rich Miller
RNA is very poorly correlated with protein, and it's the protein that counts. There's a lovely pair of studies from the Jackson labs... the correlation between the RNA and the protein was 30%.
Rich Miller
People are very easy to fool. It's easy to come up with eight or 10 things that people believe because they read them on the internet or they watched them on Fox News or whatever. And they're just wrong about this. But people are very, very gullible.
Rich Miller
1 Protocols
ITP Drug Testing and Validation Protocol
Rich Miller- Receive drug nominations and evaluate biological plausibility, potential efficacy, and safety for mice.
- Formulate drug into food, ensuring correct dosage and stability (e.g., encapsulation for rapamycin).
- Conduct pilot studies for 8 weeks with mice receiving the formulated food.
- Measure drug concentrations in tissues (e.g., liver, plasma) from pilot mice to confirm absorption and bioavailability.
- Analyze mRNA changes in liver from pilot mice to confirm biological activity of the drug.
- If pilot studies are successful, proceed with a full lifespan experiment using 50 males and 50 females per drug at each of the three ITP sites, compared to 100 male and 100 female controls per site.
- Administer drugs in food ad libitum, with euthanasia at specific times (e.g., 9-10 AM) using rapid CO2 exposure to minimize stress.
- Measure primary outcomes: proportional hazard (median lifespan) and maximum lifespan (using Wang-Allison 90th percentile test), stratifying results by site.
- For successful drugs (Stage 2 studies), conduct additional healthspan assessments (e.g., grip strength, motor tasks, cognition, pathology) and collect tissues for collaborative research.