peter attia paul grewal covid-19

#148 – Richard Miller, M.D., Ph.D.: The Gold Standard For Testing Longevity Drugs: The Interventions Testing Program| The Drive With Peter Attia

Introduction

Richard Miller, M.D., Ph.D., is a Professor of Pathology and Director of the Center for Aging Research at the University of Michigan. His current research includes the development of methods to slow aging in mice, cellular mechanisms of stress resistance, and aging in mice and tissue cultures, gene mapping and biomarkers of aging, and comparative biogerontology.

In this episode of The Drive, Dr. Richard Miller, and Peter Attia go through results of the Interventions Testing Programs (ITP) animal study test protocol, and discuss the surprising outcomes of molecules tested by the ITP, including rapamycin, metformin, and many more.

Host: Peter Attia (@PeterAttiaMD)

Key Takeaways

  • Interventions Testing Program developed the gold standard protocol of using mice to testing lifespan drugs
  • “I don’t really care what causes aging. What I care about is what can postpone all the different aspects of aging. Once you rephrase the question you are well on the way to designing experimental paradigms which address the serious question.” – Dr. Richard Miller
  • A good lifespan drug will extend life in the oldest animals in the treatment group compared to the oldest animals in the control group
  • A big surprise is that rapamycin and acarbose have positive lifespan effects even when administered late in life
  • Most longevity drugs have differential effects in males and females
  • Regulation of glucose in males seems to be a potential driver in increasing lifespan and healthspan in mice models
  • Positive impact on longevity: 17-alpha estradiol (in males only), acarbose, rapamycin, canagliflozin (SGLT-2 inhibitor)

The Interventions Testing Program (ITP)

  • The Interventions Testing Programs (ITP) is a program of the National Institute on Aging (NIA) division of the NIH
  • The ITP represents the gold standard of testing lifespan drugs in mice
  • The ideal animal is mice because testing longevity in humans would be too slow and expensive – a 20-month-old mouse is roughly the equivalent of a 60-year-old human
  • The goal of the ITP is to answer a fundamental question: does this drug extend lifespan in mice
  • From a statistical standpoint, the ITP powers to 80% for an 8-10% detection rate
  • ITP is run in parallel at three sites across the country which gives power and tests reproducibility  
  • ITP uses heterogenous mice so every mouse is not the same but there is shared heritability
  • Another interesting feature of ITP: anybody can make a suggestion for a molecule of interest to study and the board and steering committee will vote
  • ITP likes to test single molecules (versus complex), things that are popular in the mainstream, have historical benefits
  • ITP has enough budget to test 5-6 drugs per year; healthspan data (e.g., immune function, cardiovascular benefits, etc.) are reserved for drugs that first prove to extend the lifespan

Ask The Right Questions About Aging

  • Aging started with caloric restriction work
  • Aging and telomere length are not the same thing – telomere biology is critical in cancer biology
  • The real question is what is it that can slow aging
  • Aging is caused by a lot of things aging but there are biological processes that can postpone aging
  • “I don’t really care what causes aging. What I care about is what can postpone all the different aspects of aging. Once you rephrase the question you are well on the way to designing experimental paradigms which address the serious question.” – Dr. Richard Miller

Survival Statistics & Markers Of Successful Drugs

  • A crude measure of maximum lifespan: the age at which 90% of the people live
  • Interventions (e.g., drug, diet) that slow the aging process will extend expectancy of life in those who are already old – this will modify the age of maximum lifespan
  • You want drugs that extend life in the oldest of animals in the treatment group as compared to the oldest animals in the control group
  • Drugs that only extend median are less plausible than drugs that slow aging in the oldest animals

Rapamycin

  • Rapamycin doesn’t directly inhibit mTOR complex 2 – it triggers feedback circuits which destabilize mTOR complex 2 and cause it to be degraded
  • Rapamycin stops and slows cell growth and cell division
  • A big surprise is that rapamycin does have an effect on longevity even if started late in life – 20 months in mice (around 60 years old in humans)
  • A drug that extends the aging process late in life can modify the age of death
  • Rapamycin increased lifespan in both males and females but has a greater impact on males
  • Rapamycin dosing was in food and freely administered

Acarbose

  • Acarbose is a drug typically administered to people with diabetes and blocks the absorption of glucose in the gut
  • Acarbose started at late age had beneficial impacts late in life but less so than rapamycin
  • The longevity effects of acarbose were stronger in males than females
  • Acarbose is FDA approved and has a long history of use so it’s a great candidate for human clinical trials

Canagliflozin, SGLT-2 Inhibitor

  • The widely available drug used for patients with type 2 diabetes
  • Blocks reuptake of glucose so more glucose is excreted in urine
  • Canagliflozin increased median lifespan in males but had no effect in females
  • The absence of effect in females potentially signals something in male mice aging depends on keeping glucose levels down

Nicotinamide Riboside

  • Data suggests aspects of aging and age-sensitive diseases can be altered by making NAD available
  • Nicotinamide riboside is a precursor to NAD
  • In the ITP study, nicotinamide riboside did not extend lifespan in mice
  • It’s possible dosing should have been handled differently – in ITP protocols, dosing is low because the goal is to extend lifespan with minimal side effects

Metformin

  • ITP tested metformin with one dose, under one schedule – surprisingly, metformin failed to extend lifespan in mice
  • It’s possible that metformin is good for humans but not in mice  
  • In mice, metformin succeeded when paired with rapamycin but it’s possible that effect is just rapamycin
  • Human studies have shown mortality risk of diabetics on metformin was better than non-diabetics of the same age and sex
  • We don’t definitively know whether metformin is good for non-diabetics but studying via randomized-clinical trial is worthwhile

The Problem With David Sinclair’s Early Resveratrol Research

  • Early David Sinclair paper indicated that when resveratrol was given to overfed mice, it produced a longevity benefit
  • The mouse diet was consistent of 60% coconut oil, almost poisonous levels – the mice were dying of fatty liver and severe liver inflammation
  • Sinclair study showed protection against the pathological process, not aging
  • Only median lifespan was significant which isn’t as helpful as maximum lifespan
  • Maximum lifespan was extended only in mice with this extremely high-fat diet
  • In the ITP replication study using resveratrol with mice on a normal diet showed no benefit of resveratrol for aging
  • David Sinclair did write a subsequent paper that indicated no change in the median or maximum lifespan in mice with a normal diet
  • Additional note: resveratrol is barely present in wine; you primarily find it in rhubarb

17-alpha Estradiol

  • 17 Alpha-estradiol (17 α-E2) is a natural, non-feminizing stereoisomer of 17 beta-estradiol (17 β-E2)
  • 17-alpha estradiol is a weak estrogen, less active than 17-beta estradiol
  • Theory: giving estrogen to male mice might make them live as long as female mice
  • 17-alpha estradiol was non-feminizing in male mice and reduced fat and inflammation
  • 17-alpha estradiol in mice extended lifespan beyond control group mice – and beyond female mice  
  • In humans, males could take it and extend their lifespan without having any effect on femininity

Overview Of ITP Significance  

  • mTOR matters
  • Less glucose is better than more
  • Sex-specific steroid hormones probably do something relevant  
  • You can put something in the food that extends lifespan and the effect is enormous
  • Medical research should go towards finding drugs that slow aging
  • Surprisingly, drugs can work even when started in middle age
  • Most longevity drugs have differential effects on males and females
Drive with Dr. Peter Attia : , , ,
Notes By Maryann

More Notes on these topics

Top Insights and Tactics From

31 Best Podcasts of All Time

FREE when you join over 12,000 subscribers to the
Podcast Notes newsletter

No Thanks