#148 - Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the Interventions Testing Program
Dr. Richard Miller, Professor of Pathology and Director of the Center for Aging Research at the University of Michigan, discusses the NIA-funded Interventions Testing Programs (ITPs), a gold standard for testing longevity molecules in mice. He reviews surprising positive and negative findings for compounds like rapamycin, acarbose, 17α-estradiol, canagliflozin, metformin, and nicotinamide riboside, highlighting key takeaways about aging malleability.
Deep Dive Analysis
19 Topic Outline
Early Life, Education, and Interest in Aging Research
Critique of the Hayflick Hypothesis and Telomere Research
The Malleability of Aging and Shifting Research Questions
Introduction to the Interventions Testing Program (ITP)
Key Principles of the ITP: Rigor, Reproducibility, and Heterogeneous Mice
Initial ITP Compounds: Aspirin and NDGA
Rapamycin: A Major ITP Success Story and Late-Life Intervention
Understanding Median vs. Maximum Lifespan Extension
Rapamycin Dosing, mTOR Complexes, and Sex-Specific Effects
Acarbose: Glucose Modulation and Lifespan Extension
Resveratrol: Disappointing ITP Results Despite Initial Hype
The Value of Negative Findings: Green Tea Extract, Methylene Blue, Curcumin
17α-Estradiol: Male-Specific Lifespan Extension
Ursolic Acid and Hydrogen Sulfide: Rationale and Ongoing Research
Canagliflozin (SGLT2 Inhibitor): Impressive Male-Specific Results
The Failure of Metformin in ITP Studies
Nicotinamide Riboside (NR): Negative ITP Lifespan Results
Three Most Important Takeaways from ITP Studies
Philosophies on Studying Aging: Model Organisms and Research Questions
6 Key Concepts
Hayflick Hypothesis
The observation that normal human cells divide a limited number of times in tissue culture before stopping. This phenomenon was misinterpreted by many as a direct representation of aging, leading to a generation of research focused on cellular senescence and telomere shortening as central causes of aging, despite evidence to the contrary.
Interventions Testing Program (ITP)
A gold-standard scientific framework funded by the NIA for rigorously testing whether drugs extend lifespan in mice. It involves concurrent studies at three different labs, using genetically heterogeneous mice, and is statistically powered to detect even modest lifespan extensions.
Genetically Heterogeneous Mice
Mice used in the ITP that are genetically unique, similar to human siblings, by crossing four different inbred grandparents. This approach avoids results specific to a single inbred strain and ensures reproducible heterogeneity, making findings more broadly applicable.
Median vs. Maximum Lifespan
Median lifespan is the age at which half of a population has died, while maximum lifespan (often approximated by the 90th percentile of survival) refers to the age reached by the longest-lived individuals. Drugs that genuinely slow aging are expected to extend maximum lifespan, not just median lifespan, indicating an effect on the underlying aging process rather than just preventing early deaths.
mTOR Complex 1 (TORC1)
A protein complex that acts as a central regulator of cell growth, proliferation, and metabolism. Its inhibition, particularly by drugs like rapamycin, is associated with lifespan extension in various organisms, including mice.
mTOR Complex 2 (TORC2)
Another protein complex involved in cell survival and metabolism, which is not directly inhibited by rapamycin but can be destabilized by it over time. Research suggests that while TORC1 inhibition is beneficial for longevity, the role of TORC2 is more complex, with some longevity-extending mutations actually increasing its activity.
11 Questions Answered
In the 1970s, many scientists were heavily influenced by the Hayflick hypothesis, believing that the limited division of human cells in culture was analogous to aging and that telomere shortening was a central cause, despite this being a misinterpretation.
Yes, the ITP studies have demonstrated that it is possible to slow down the aging process and extend healthy lifespan in mice through various interventions, challenging the previous belief that aging was an unchangeable, complex process.
Genetically heterogeneous mice are used to avoid results specific to a single inbred strain and to ensure that any observed effects are broadly reproducible across a diverse genetic background, making the findings more relevant to a genetically diverse human population.
The most significant early finding was that rapamycin, when given to mice, dramatically extended their lifespan in both males and females, even when started in middle age (equivalent to a 60-year-old human), which was a surprising and fundamental reformulation of how aging was thought to work.
Acarbose likely extends lifespan in mice by blocking the highest peak levels of glucose after meals, rather than by reducing overall integrated glucose levels (hemoglobin A1c was unaffected). This suggests that glucose kinetics, specifically avoiding large spikes, may be important for longevity.
Resveratrol, despite initial hype from studies showing benefits in mice on a highly toxic, high-fat diet, did not extend lifespan in ITP mice fed a normal diet, even at higher doses and different starting ages. The initial findings were likely due to protection against a specific, unusual pathological process rather than true anti-aging effects.
The exact reason for 17α-Estradiol's male-specific effect is unknown, but it works by a mechanism distinct from classical estrogen receptors and does not feminize males. It not only makes males live longer than regular males but also longer than regular females, suggesting a unique sex-specific pathway influencing male longevity.
Yes, Canagliflozin significantly increased median lifespan in male mice by 14% and maximum lifespan by 9%, but had no effect on females. This effect is thought to be related to its ability to block peak glucose levels, similar to Acarbose, though the sex-specific difference is not fully understood.
Metformin did not produce a significant lifespan extension in ITP mice in two separate studies. Possible reasons for this disparity include species-specific differences, the specific dose or continuous dosing schedule used, or the possibility that its benefits in humans (especially diabetics) are not directly translatable to mouse longevity under ITP conditions.
No, Nicotinamide Riboside (NR), a popular NAD precursor, did not extend lifespan in ITP mice at the dose tested. While it's possible that different doses or measurement techniques for NAD levels could yield different results, the ITP study found no lifespan benefit.
The three most important takeaways are: 1) It is possible to significantly extend healthy lifespan with drug interventions; 2) These drugs can be effective even when started in middle age; and 3) Lifespan-extending effects are often sex-specific, working in one sex but not the other.
14 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.
8. Metformin’s Potential Beyond Mice
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.
7 Key Quotes
Aging and telomere length are not the same thing. And if you want to prove that hyperbaric conditions at suitable doses and at suitable time intervals, et cetera, might be good for you, that's a very plausible idea, well worth testing. It's just that you don't test it by measuring telomeres.
Richard Miller
I don't really care what causes aging. What I care about is what is the process that can postpone all the different aspects of aging?
Richard Miller
The literature is filled with reports of a drug that did something good to a mouse at one site, and then no one wants to wait four years to test it out. Doing three tests at the same time gets us around that.
Richard Miller
The notion is that there are some processes really bad for you when you're a 20-month-old mouse or a 60-, 65-year-old person that are still not irreversible, that can be reversed, and that that reversing can be dependent upon inhibition of TOR signals.
Richard Miller
If you're an insurance agent, it's nice to know at the time you sell the insurance policy, what the life extension will be from the time the person buys the insurance policy. But in terms of biology and pathobiology and being able to compare lab A to lab B, drug A to drug B, I think keeping it on the level of what is the change in the overall median is important.
Richard Miller
We certainly have not proven that green tea extract might not be good for people, but it will, we hope, slightly take the wind out of the sails of that discussion if we demonstrate that when we give it to animals, it didn't do any good to them.
Richard Miller
The first point I'd make is the one we began at the beginning of this conversation, which is that, by gosh, you actually can put something in the food that extends healthy lifespan, and it's an enormous effect, 10 times better than a cure for cancer.
Richard Miller