#281 ‒ Longevity drugs, aging biomarkers, and updated findings from the Interventions Testing Program (ITP) | Rich Miller, M.D., Ph.D.

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.

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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 that 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 the 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];
• Optimism about future findings [2:16:30]; and
• More.

An overview of the Interventions Testing Program (ITP) [3:45]

• The ITP was developed by the National Aging Institute (NIA) under the leadership of Huber Warner about 20 years ago
  • We are now finishing our 20th year
  • We’ve sent in applications and may get five more years of funding
• The ITP represents work being done by three different research laboratories
  • 1 – Rich’s at the University of Michigan
  • 2 – Randy Strong’s at the University of Texas Health Science Center at San Antonio
  • 3 – And a program at the Jackson Labs where David Harrison was in charge
    • David will be stepping down next April and he will be replaced by Ron Korstanje as the first new appointment for the ITP leadership at the Jackson Labs

The ITP tries to find drugs that will slow aging and extend mouse lifespan 

• We have a national announcement every year internationally
  • Anyone who wants to suggest a drug sends us an application and they tell us why they think we should test their drug and why they think it will be good and not hurt the mice
  • We have a committee that evaluates those and then we pick 5-7 each year to see if giving them to the mice will extend lifespan 

ITP findings and more about their studies 

• We’ve had four published significant hits 
  • Another two or three that are significant, but really small
  • And two others that are in-press that should be accepted soon 
• We give these drugs to mice at varying doses to see if it’s dose sensitive
• We look at the methodology
• We make tissues that we can give away to other investigators for collaborative studies
• We try to reason about mechanisms of aging and control points for aging based upon which drugs work and which drugs don’t work
• A lot of people see this as a stalking horse for the important goal of finding drugs that would extend lifespan by slowing aging in people (and Rich agrees)
  • That is an important element, but there are many steps between a mouse drug and a human drug 

The other major things that our program does is it really gives us a lot of insight into the biology of aging, and it should give us many clues as to what to look at that may be successful 

How many candidates typically get nominated for testing? 

• It varies a lot from year to year
• This year was our winner with 28 suggestions
• They have enough money to test 5-7 of them
• In a typical year, 10-15 drugs are nominated, from which they pick 6
• Sometimes we fill up those slots with things that we want to do
  • For instance, we found a couple of years ago that captopril (FDA approved in people for blood pressure) gave a really small increase in lifespan in mice
    • Mice don’t die of hypertension, they don’t get strokes, etc., so Rich was betting against that, but it was a really small effect
    • We decided in the current year to try captopril again, but at a higher dose
• Some of the slots each year at taken up with other doses, other dosage forms
• Often, if a drug works when you give it to young adults, we next test it in middle-aged mice 
  • Everyone would like to know whether a drug would only work if you give it to young adults
  • We would love to find drugs that work in middle age, so that often fills up one of those available slots

What is the budget? What does the NIA provide to the three laboratories? 

• They give $1 million a year to each of the three sites in direct costs 
  • The actual cost to the taxpayer is probably about 50% more than that because each university will also receive indirect costs to pay for the building and the heat and the police force and the library and the president and all of that stuff
  • In total, it’s about $4.5 million per year
    • Peter thinks this is a relatively poultry sum of money when you consider the insights that come out of the ITP (that’s his way of lobbying for the budget being increased)
• In the first 10 years they had half a million dollar and the NIA thought they were doing good work so they doubled their budget

There are 17 divisions within NIH, of which NIA is one. What is the NIA’s annual intramural and extramural budget? 

• Rich doesn’t know but it’s one of the larger institutes now (it didn’t used to be)
  • However, that’s misleading because more than half of their budget goes to Alzheimer’s disease
    • They have, through a variety of negotiations, been designated the lead agency for Alzheimer’s
• Their budget is big, but their budget for all of biology is only ⅙ of the NIA budget
  • And for the kind of biology that Rich cares about, it’s much, much less
• A lot of the good biology is what happens to bone aging
  • What happens to eye aging
  • What happens to aging of the immune system
• All of that is interesting research, but the stuff Rich cares most about is aging as a global phenomenon
  • What you can do to slow aging
  • How it is that aging increases your risk of almost everything you don’t want to happen to you
  • That part of the NIA budget is small

Is there an opportunity for philanthropic giving to plus-up the NIA contributions? 

• Rich doesn’t think the NIA accepts donations
• However, a philanthropist, should he or she be listening to this podcast, can certainly set up independent arrangements
  • For instance, if they wish to have support for all three sites in the ITP, one can imagine a situation in which a foundation makes awards
  • The universities do have the flexibility to take gifts and target them to specific research groups or specific research projects, either independently or as a consortium

How the mice used by the ITP are superior for research relative to mouse models used in most research [11:15]

Tell us about the standard, off-the-shelf mouse model 

• One of the hallmarks of the ITP is the mouse model used is different from some of the more typical mouse models used in biomedical research
• Most requests for aged mice to the National Aging Institute were for the same kind of inbred mouse: its formal name is C57BL/6, and everybody calls it the B6 mouse 
  • This is the standard mouse and it’s a really bad thing for science, not just aging science, but that science in general relies on an inbred mouse
•  Problems with inbred mice: it’s a single genotype and it has been shown many times now that if you have a drug that works in BL6 mice, it might or might not work in another kind of mouse
  • It might have the opposite effect in another kind of mouse
• People study the BL6 mice in the mistaken belief that it’s sort of like mice in general, despite the now really quite convincing evidence that it isn’t

The ITP made the decision to use a genetically heterogeneous mouse called UM-HET3 

{end of show notes preview} 

Richard Miller M.D., Ph.D.

Richard A. Miller, M.D., Ph.D., is a Professor of Pathology, Associate Director of Research for the Geriatrics Center, and Director of the Paul F. Glenn Center for Biology of Aging Research at the University of Michigan.  He received the BA degree in 1971 from Haverford College, and MD and PhD degrees from Yale University in 1976-1977.  After postdoctoral studies at Harvard and Sloan-Kettering, he began his faculty career at Boston University in 1982 and then moved to his current position at Michigan in 1990. 

Dr. Miller has served in a variety of editorial and advisory positions on behalf of the American Federation for Aging Research and the National Institute on Aging, and served as one of the Editors-in-Chief of Aging Cell.  He is the recipient of the Nathan Shock Award, the AlliedSignal Award, the Irving Wright Award, an award from the Glenn Foundation, and the Kleemeier Award for aging research.  He has been a Senior Scholar of the Ellison Medical Foundation, and is a Fellow of the American Association for the Advancement of Science and a member of the American Association of Physicians.  At Michigan, he directs the Paul Glenn Center for Aging Research. 

His research program includes ongoing studies of the mechanisms that link stress, nutrients, and hormones to delay aging in mice, development of new approaches to slow aging and disease through drugs and targeted mutations, and studies of the ways in which cells from long-lived birds, rodents, and primates differ from those of short-lived species.

For fun he sometimes photographs wildlife or landscapes; you can check it out here. [RichMillerLab.com]