#281 ‒ Longevity drugs, aging biomarkers, and updated findings from the Interventions Testing Program (ITP) | Rich Miller, M.D., Ph.D.
Dec 4, 2023
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Rich Miller, a leading expert in aging research and Director at the University of Michigan’s Center for Aging Research, shares groundbreaking insights from the Interventions Testing Program (ITP). He reveals successful longevity drugs like rapamycin and the surprising failures of others, such as metformin. The conversation dives deep into aging biomarkers, highlighting their significance in understanding longevity. Miller also discusses the future of translating findings from mouse models to human applications, offering an optimistic vision for age-related research.
Successful drugs like Rapamycin, 17-alpha-estradiol, and Acarbose have shown significant increases in median lifespan and debunked the assumption that starting interventions in middle age would have minimal effects.
The ITP program not only studies lifespan but also measures of health span, including grip strength, glucose homeostasis, tissue pathology, and cognition, providing valuable insights into the drugs' effects on specific organs and functional abilities.
Aging rate indicators have been identified as biomarkers for the rate of aging, serving as valuable tools for understanding the aging process and potential interventions.
Protein analysis plays a crucial role in understanding aging, with proteins like UCP1, BDNF, doublecortin, and GPLD1 showing potential connections to longevity, cognitive function, and other age-related outcomes.
The drugs Meclizine and Astaxanthin have shown promising results in increasing lifespan in male mice, offering a potentially accessible route for anti-aging interventions.
Deep dives
Rapamycin: A Breakthrough in Extending Lifespan
The first significant success in the ITP program came with Rapamycin. It was nominated by Dave Sharp and showed a significant increase in median lifespan when given to mice. This was a major breakthrough as it demonstrated that lifespan extension could occur even when starting the drug at an older age, around 20 months, in mice. Rapamycin also proved to be effective in females. The drug had an immunosuppressive reputation, but research now shows its complex interaction with the immune system. It is important to note that Rapamycin's success opened up further research and testing of other drugs.
17-alpha-estradiol and Acarbose: Lifespan Extension in Males and Females
Two other successful drugs in the ITP program are 17-alpha-estradiol and Acarbose. 17-alpha-estradiol showed a significant increase in median lifespan in both males and females, even when administered in middle age. This drug represented a breakthrough as it defied the belief that starting a drug in middle age would have minimal effects on lifespan. Acarbose, though more effective in males, also showed positive results in both sexes. These drugs extend lifespan by slowing down the aging process and have potential benefits beyond just delaying the diseases associated with aging.
New Insights from Pathology and Organ-Specific Tests
In addition to studying lifespan, the ITP program delves into other measures of health span as well. Stage two studies involve testing for various health indicators and organ-specific measures, such as grip strength, glucose homeostasis, tissue pathology, cognition, and more. These measures provide valuable insights into the effects of the drugs on specific organs and functional abilities. Tissues from the mice are collected and made available for further research, focusing on epigenetic changes and gene expression. These collaborations allow for a deeper understanding of the mechanisms through which the drugs influence aging and health.
The Promise and Potential of Drug Interventions in Aging
The successes achieved through the ITP program demonstrate the potential of drug interventions in extending healthy lifespan and slowing down the aging process. Drugs like Rapamycin, 17-alpha-estradiol, and Acarbose have shown significant increases in median lifespan and have debunked the assumption that starting interventions in middle age would have minimal effects. These drugs target the underlying biological processes of aging and provide hope for longer and healthier lives. Further research and collaboration are needed to fully explore the biological mechanisms and optimize drug interventions for maximum benefits.
Limited knowledge of epigenetic materials and tissue effects
The speaker mentions that the epigenetic materials are not thoroughly understood yet, and it remains uncertain which tissues to focus on when studying these materials. The lack of knowledge about tissue specificity raises questions about the effects of certain drugs and the importance of specific tissues in the aging process.
Identifying aging rate indicators
The speaker discusses the concept of aging rate indicators, which are measures of how quickly an organism is aging rather than how far it has progressed in age. Through studies on slow-aging mice, researchers have identified certain aging rate indicators that consistently change in the same direction in these mice. These indicators may serve as biomarkers for the rate of aging and provide valuable insights into the aging process.
Exploring proteins and tissues in aging mice
The speaker elaborates on the examination of specific proteins and tissues in aging mice. They highlight the presence of proteins like UCP1, which is found in various fat depots and is linked to longevity. The exploration of brain proteins BDNF and doublecortin, as well as the liver protein GPLD1, reveals potential connections to improved cognitive function and other age-related outcomes. Further research is needed to understand the precise mechanisms and effects of these proteins.
Importance of protein-level analysis and proteomics
The speaker emphasizes the significance of proteins in understanding aging and its related processes, explaining that protein levels can differ greatly from RNA levels and provide a more accurate reflection of biological activity. They stress the need for more comprehensive proteomic analysis, studying not only RNA but also various aspects of protein translation, degradation, stability, and location. Exploring these complexities can provide a deeper understanding of the proteome and its influence on aging.
Meclizine and Astaxanthin show potential in extending lifespan in mice
Researchers tested the drugs Meclizine and Astaxanthin in a study on mice and found that Meclizine increased the lifespan by around 10% in male mice. Astaxanthin also showed a similar effect on male mice. However, neither drug had an impact on maximum lifespan or longevity in female mice. The results are encouraging since both Meclizine and Astaxanthin are readily available over-the-counter drugs, potentially indicating a more accessible route for anti-aging interventions.
Fisetin fails to remove senescent cells and extend lifespan
In contrast to previous claims, the drug Fisetin did not remove senescent cells and did not increase lifespan in a study on mice. Researchers evaluated the levels of senescent cells in various tissues and found that Fisetin had no effect on removing these cells. This finding raises questions about the effectiveness of removing senescent cells as an anti-aging strategy, although further research is needed to fully understand the role of senescent cells in aging. The study also highlights the importance of nuanced interpretations and definitions when discussing senescent cells and anti-aging interventions.
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.
We discuss:
An overview of the Interventions Testing Program (ITP) [3:45];
How the mice used by the ITP are superior for research relative to mouse models used in most research [11:15];
Design of ITP studies, outcomes tested, and metrics of interest [19:00];
The process and challenges of drug formulation for mice [30:00];
Four drugs identified by the ITP that extends the lifespan of mice [36:30];
The success of rapamycin and what it tells us about the biology of aging [43:15];
Other measures of healthspan evaluated by the ITP in stage 2 studies [50:45];
Distinguishing aging rate indicators from biomarkers of aging [57:30];
Aging rate indicators identified through the examination of slow-aging mice [59:15];
Why proteomics are essential to understand changes in the cell [1:12:15];
Unraveling aging rate indicators: dose-effect, duration, and future frontiers [1:21:45];
A closer look at aging rate indicators: bridging the gap from mice to humans [1:27:00];
What do laboratory mice die from? [1:38:45];
Distinguishing between a drug that improves an age-sensitive outcome and a drug that improves all aspects of aging [1:42:00];
The ITP study of 17⍺-estradiol: mechanisms of life extension and surprising sex differences [1:43:30];
Unsuccessful drugs studied by the ITP: resveratrol, metformin, and nicotinamide riboside [1:51:30];
Over-the-counter successes in the ITP: meclizine and astaxanthin [2:01:00];
A senolytic drug, fisetin, fails to extend lifespan [2:07:00];
Can targeting senescent cells slow aging? [2:13:00];
