Key Moments
281 ‒ Longevity drugs, aging biomarkers, and updated findings from the Interventions Testing Program
Peter Attia MDKey Moments
Longevity research explores drugs, biomarkers, and mouse models to slow aging and extend healthspan, revealing promise and challenges.
Key Insights
The Interventions Testing Program (ITP) systematically tests drugs for their ability to slow aging and extend lifespan in genetically heterogeneous mice.
Genetic heterogeneity in mice (UM-HET3) is crucial for translational relevance, unlike the limitations of inbred strains (B6 mice).
Key metrics for aging research include median lifespan and a statistical measure for maximum lifespan (90th percentile survival).
Successful interventions like Rapamycin, acarbose, and 17-alpha estradiol have shown significant lifespan extension in mice, sometimes even when initiated in old age.
Aging rate indicators (speedometers) offer potential for quicker screening of anti-aging interventions compared to lifespan studies, but their precise mechanism and application are still under investigation.
The study highlights the critical need to move beyond traditional transcriptomics and focus on proteomics and translational regulation for a complete understanding of aging and drug responses.
OVERVIEW OF THE INTERVENTIONS TESTING PROGRAM (ITP)
The ITP, established by the National Institute on Aging (NIA) about 20 years ago, comprises three research laboratories. Its primary goal is to identify drugs that slow aging and extend mouse lifespan. Each year, numerous drug candidates are nominated, and a select few are rigorously tested. The program also delves into the biology of aging, investigating mechanisms and potential control points through detailed pathological analysis and tissue distribution for collaborative studies. While a powerful tool for potential human longevity, the transition from mouse to human drugs involves many steps.
MOUSE MODELS AND TRANSLATIONAL RELEVANCE
A critical aspect of the ITP's methodology is the use of genetically heterogeneous UM-HET3 mice, which share grandparents but have random genetic variation, mimicking human genetic diversity. This contrasts with commonly used inbred B6 mice, which are genetically identical and often suffer from specific diseases, limiting their translational value. Inbred mice are useful for studying single diseases or for transplantation but are problematic for general aging research. The ITP's heterogeneous model ensures that findings are more likely to be relevant to diverse human populations.
STUDY DESIGN AND MEASUREMENT OF AGING
The ITP primarily measures lifespan extension using median lifespan and a 90th percentile survival statistic, which statistically approximates maximum lifespan. The program meticulously plans its studies, using a substantial number of mice per group (hundreds of controls, dozens per treated group) to achieve 80% power to detect significant effects, even accounting for potential site-specific issues. This robust design allows for reliable detection of lifespan extension, with successful drugs yielding increases of 10-20% or more in median lifespan, which is considerably greater than hypothetical cures for major diseases like cancer or heart attacks.
SUCCESSFUL INTERVENTIONS AND AGE OF ONSET
Several drugs have demonstrated success in ITP studies, including Rapamycin, acarbose, 17-alpha estradiol, and canagliflozin. Notably, some of these interventions have shown efficacy even when initiated in middle-aged or old mice, challenging the assumption that anti-aging effects must start in early life. For instance, Rapamycin conferred lifespan benefits regardless of whether treatment began in young or old mice. This finding suggests that aging processes remain drug-sensitive even well into later life, opening new avenues for intervention.
PHARMACOKINETICS, SEX DIFFERENCES, AND FORMULATION CHALLENGES
The ITP carefully addresses drug formulation and dosing. Challenges like Rapamycin degradation in stomach acid led to the development of encapsulated forms. Furthermore, significant sex differences in drug pharmacokinetics and efficacy have been observed, with drugs like canagliflozin and 17-alpha estradiol showing effects predominantly in males. Understanding these sex-specific differences, possibly related to variations in drug metabolism enzymes, is crucial for optimizing interventions and requires further investigation into drug absorption, distribution, metabolism, and excretion.
EXPLORATION OF HEALTHSPAN AND AGING RATE INDICATORS
Beyond lifespan, the ITP is increasingly focused on healthspan, measuring parameters like grip strength, cognition, and muscle mass. They are developing 'aging rate indicators' – akin to a speedometer for aging – that change consistently across various slow-aging models. Proteins like UCP1, macrophages in fat, BDNF, DCX, and GPld1 in tissues and plasma are being investigated. A significant breakthrough is the discovery that these indicators can be modulated by interventions, potentially serving as early biomarkers for drug efficacy, and showing promise for human application.
DEEP DIVE INTO SPECIFIC DRUGS AND MECHANISMS
The conversation detailed the success of Rapamycin, its paradoxical immune-boosting potential in some contexts, and its efficacy across different ages. It also explored the mystery of 17-alpha estradiol, a potent lifespan extender in male mice, whose mechanism and target remain largely unknown. Notable failures, such as resveratrol and NR/NMN, were discussed, highlighting the challenges in translating hype into proven efficacy. Emerging successes like meclizine and astaxanthin, available over-the-counter, offer new avenues for research, particularly due to their accessibility.
THE ROLE OF PROTEOMICS AND TRANSLATIONAL CONTROL
A major takeaway is the critical importance of proteomic analysis over transcriptomic data alone. Studies show a low correlation (around 30%) between RNA changes and protein levels. This suggests that crucial regulatory steps occur post-transcriptionally, including differential RNA translation, sequestration, degradation, and protein degradation. Understanding these translational mechanisms is vital for a complete picture of aging and how interventions work at a molecular level.
CHALLENGES AND FUTURE DIRECTIONS IN AGING RESEARCH
The discussion highlighted ongoing challenges, including the nuanced definitions of 'senescent cells' and a lack of consensus on their role in driving aging. The ITP's findings that fisetin did not extend lifespan or clear senescent cells in their models underscore the complexity. Future research aims to refine aging indicators, explore drug combinations like Rapamycin with acarbose or 17-alpha estradiol, investigate novel interventions like meclizine and astaxanthin, and bridge the gap to human studies by identifying reliable plasma biomarkers.
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Common Questions
The ITP, developed by the National Institute on Aging, aims to identify drugs that can slow aging and extend mouse lifespan. It represents work done by three research laboratories: the University of Michigan, the University of Texas Health Science Center at San Antonio, and the Jackson Labs.
Topics
Mentioned in this video
Led the development of the Interventions Testing Program (ITP) at the National Institute on Aging about 20 years ago.
A collaborator whose lab, along with Johan Auwerx, has used ITP mice DNA samples to map genes related to lifespan.
A colleague of Randy Strong at the University of Texas who devoted time to drug formulation and dosing for ITP.
Physiologist/Neuroendocrinologist who proposed 17-Alpha Estradiol for ITP testing based on how estrogens benefit females.
A former student at Wayne State whose recent papers and grant focus on the effects of 17 Alpha Estradiol in the brain.
Along with Jim Kirkland and Tammeron, suggested Fisetin for ITP testing as a senolytic drug, and later helped evaluate senescent cell markers.
A former lab member who studied the effects of 17 Alpha Estradiol and Acarbose on grip strength and rotarod performance in mice, and later investigated steroids in treated mice.
A top-notch mouse neurobiologist at Michigan, recruited to study cognition with ITP drugs.
Was in charge of the program at the Jackson Labs for the ITP.
Collaborating on the 'Som' project at UCSF, which collects functional test data and muscle/fat biopsies from human volunteers.
Suggested testing Meclizine for ITP after finding it inhibited TOR in a tissue culture assay.
His work at Jackson Labs studied changes in proteins and RNAs with age, revealing a low correlation between the two.
A collaborator in Switzerland whose lab, along with Rob Williams, has used ITP mice DNA samples to map genes related to lifespan, publishing in 'Science'.
Took over Marty Jayor's role at the University of Texas, specializing in drug formulation and measuring drug amounts in feed and tissues.
Conducted work published in 'Science' in 1990, demonstrating that curing cancer or heart attacks in people over 50 would only increase median human lifespan by less than 3%.
One of two labs known to be researching the physiological effects and binding targets of 17 Alpha Estradiol.
Leads the University of Texas Health Science Center at San Antonio site for the ITP and is a pharmacologist.
A scholar at Stanford working with Tony Wyss-Coray, known for deconvoluting plasma signals to identify tissue-specific changes.
Will be replacing David Harrison as the new ITP leadership appointment for the Jackson Labs.
Collaborating on the 'Som' project at UCSF alongside Steven Cummings.
Runs the lab at the Jackson Labs, involved in ensuring drug formulations are at the right dose for ITP experiments.
Collaborated with Jay Olshansky on research published in 'Science' in 1990 about the limited impact of curing major diseases on human lifespan.
Metabolomics expert at Michigan, collaborating on studies to identify plasma metabolites that correlate with internal ARI signals in mice.
Key author of a famous paper that showed senescent cells increase with age in human skin, using beta-galactosidase as a marker.
Director of the National Institute on Aging who mandated testing of Resveratrol, an unusual intervention for the ITP.
A mutant mouse model with characteristics similar to Ames dwarf mice, used in growth hormone studies.
A muscle protein whose cleavage product, irisin, is elevated in slow-aging mice.
A long-lived mutant mouse model with very low growth hormone and IGF1, used in ITP research.
The standard inbred mouse model commonly used in biomedical research, criticized for its lack of genetic diversity and unsuitability for aging studies.
A genetically heterogeneous mouse model used by the ITP, chosen for its reproducible heterogeneity, making it a better model for studying aging and drug responses.
An over-the-counter antihistamine and seasickness remedy, found to significantly increase lifespan in male mice (about 10%) in a recent ITP paper, potentially via TOR inhibition.
An FDA-approved drug for blood pressure in humans, showed a small increase in lifespan in mice in ITP studies.
Used in humans to improve vaccine responses to influenza vaccination in some circumstances.
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