By playing, you agree to uListen's Terms and Privacy Policy and YouTube's Terms of Service.
Peter Attia MD#148 - Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the ITP
Summaries, chapters, transcripts, and FAQs on this page are made by uListen, not YouTube.
CHAPTERS
- 0:11 – 5:42
Introduction to Richard Miller and the ITP
Peter Attia introduces Richard Miller and the NIA-funded Interventions Testing Program, run at three sites as a gold standard for testing longevity molecules in mice. He explains why the episode was delayed until the SGLT2 inhibitor and nicotinamide riboside results were close to publication.
- •Miller is a University of Michigan pathologist and director of the Paul F. Glenn Center for Aging Research
- •The ITP runs concurrently at Jackson Labs, Miller's Michigan lab and Randy Strong's lab in San Antonio
- •The episode was timed around pending results on an SGLT2 inhibitor and nicotinamide riboside
- 5:42 – 15:46
Miller's path into aging research and the problem with Hayflick
Miller describes his early wish to fight aging, his M.D./Ph.D. and postdoc path, and his shift into immunology and then broader aging biology. He explains why he thinks the Hayflick limit and telomere work misdirected aging research.
- •Miller decided as a child that aging was bad and that fighting it required becoming a scientist
- •He moved from cell hybridization to immunology and gradually into broader aging biology
- •He argues the Hayflick limit in culture is nothing like aging and that telomeres are not a shortcut to studying aging
- •Attia and Miller agree telomere length is not a valid biomarker, as with the hyperbaric oxygen study
- •Miller credits telomere biology as important for cancer biology and evolution
- 15:46 – 29:01
Origins of the ITP and the case that aging can be slowed
Miller recounts how he and Arlen Richardson sketched the program for NIA's Huber Warner, and how his Milbank Quarterly article came about. He then explains why the field once doubted aging could be slowed and how worm and mouse single-gene mutations changed that.
- •The ITP design was developed by Miller and Arlen Richardson with Huber Warner of the NIA, and three grants went to Miller, Harrison and Strong
- •At a Gordon conference, researchers voted on average two or three out of ten for aging being a single process
- •Cynthia Kenyon's DAF-2 work and the Ames dwarf mouse overturned claims that no single gene could extend lifespan
- •Miller says the key question is what can slow aging, not what causes it
- 29:01 – 37:46
ITP design: statistical power, three sites, and heterogeneous mice
Miller explains the program's core design principles: large numbers of mice, parallel testing at three sites, and genetically heterogeneous four-way cross mice. He also explains why such mice are rarely used elsewhere.
- •Each site uses 50 males and 50 females per drug plus 100 controls per sex, aiming to detect 8-10% extensions
- •Running three sites gives instant reproducibility
- •The UM-HET3 four-way cross gives genetically unique but reproducible mice, unlike a single inbred strain
- •The NIA dropped its heterogeneous colony for lack of demand
- 37:46 – 44:47
Selecting compounds and the aspirin results
Miller describes how compounds are proposed and chosen, the budget constraints, and how clinical evidence and FDA approval factor in. Aspirin is the example: a low dose helped males, but higher doses did not replicate it.
- •The first year accepted four suggestions, including aspirin and NDGA
- •Aspirin at a very low dose gave an 8-10% effect in males only; higher doses did not extend lifespan
- •Each new drug costs roughly half a million dollars, limiting how many follow-ups can be run
- •Human clinical data and FDA approval weigh heavily in choosing compounds
- 44:47 – 56:24
Rapamycin: late-life start, median versus maximum survival
Rapamycin was proposed by Dave Sharp and, because of a reformulation delay, was first tested in 20-month-old mice, where it still worked strongly in both sexes. The discussion covers what this means for late-life interventions and how median and maximum survival should be interpreted.
- •Rapamycin needed reformulation to survive the stomach, forcing a late start at about 20 months
- •Miller bet against it working at that age and was wrong
- •Median is when half have died; a 90th-percentile measure better indicates slowed aging
- •Miller says the ITP does not use incremental lifespan after treatment start
- 56:24 – 1:07:18
Late-start results, rapamycin dosing, mTOR complexes, and sex differences
Miller compares late starts for acarbose and 17α-estradiol with rapamycin. He then discusses mTORC1 versus mTORC2 findings from his lab and the three-fold higher blood levels of rapamycin in females.
- •Rapamycin works equally well started early or late; acarbose works about half as well late; 17α-estradiol works as well at 16 or 20 months in males
- •Rapamycin is given daily in food in the ITP
- •Gonzalo Garcia found long-lived mutant mice lower mTORC1 and raise mTORC2, so the picture is more complex than 'inhibit 1, spare 2'
- •Female mice had two to three times higher rapamycin blood levels than males at the same dose
- 1:07:18 – 1:15:54
Acarbose and the peak-glucose hypothesis
Acarbose was proposed by David Allison and Daniel Smith as a caloric-restriction mimic. Miller says the mouse data suggest it works by blunting peak glucose rather than changing average glucose, and he argues it is a strong candidate for human trials.
- •Acarbose blocks starch digestion, blunting glucose peaks
- •Hemoglobin A1C did not fall in mice, unlike in human diabetics
- •Weight effects of acarbose were inconsistent across populations
- •Miller says its long safety record makes it an obvious human trial candidate and he has urged testing in dogs
- 1:15:54 – 1:27:00
Resveratrol and the value of negative results
Miller explains why the original resveratrol longevity claim in mice on a toxic high-fat diet was misleading and says the ITP tested it by directive from the NIA director. At higher doses and two start ages it had no effect, and he discusses the reaction and later the rationale for testing green tea extract and other compounds.
- •The original resveratrol benefit appeared only in mice on a 60% fat diet dying of fatty liver crushing the lungs
- •Resveratrol was the one compound tested at the NIA director's instruction, at doses chosen with Sinclair's advice
- •It had no lifespan effect in the ITP
- •The ITP prefers single compounds but will test popular remedies like green tea extract, and negative results are still a public service
- 1:27:00 – 1:33:27
17α-Estradiol and sex-specific effects
Miller explains 17α-estradiol, a non-feminizing estrogen isomer, and how it greatly extends male lifespan but has no effect in females. The discussion covers dose effects and how little is known about the molecule as a drug.
- •It was proposed by Jim Simpkins as a non-feminizing estrogen that might make male mice live as long as females
- •Treated males outlived normal females, but females saw no benefit across three studies
- •A higher dose extended maximum as well as median lifespan
- •Miller says the molecule appears under-investigated
- 1:33:27 – 1:35:48
Ursolic acid and hydrogen sulfide
Miller gives the tentative rationale for ursolic acid and describes the hydrogen sulfide study proposed by the late Jay Mitchell. A control-food error forced a repeat, with results expected in about a year.
- •Ursolic acid was proposed in connection with bile acid and retinoid receptor pathways, though Miller is only about 50/50 sure of the rationale
- •Jay Mitchell suggested SG1002, which breaks down to produce hydrogen sulfide
- •A wrong control food forced the lab not to publish the first run
- •The repeat will be known in about a year
- 1:35:48 – 1:42:58
Canagliflozin and the male-specific lifespan effect
They discuss the SGLT2 inhibitor canagliflozin, which extended male lifespan but not female. Miller and Attia examine possible explanations involving glucose, cancer types, and the hypothalamus.
- •Canagliflozin raised male median lifespan 14% and maximum 9%, with no female effect
- •Females had slightly higher drug blood levels, so exposure does not explain it
- •About 80% of deaths in both sexes are cancers, with hematopoietic cancers about 30%
- •Miller notes the effect may not be through glucose, given clinical data on tumors and heart attacks
- 1:42:58 – 1:48:48
Metformin's failure and the TAME rationale
Attia calls metformin's failure the biggest ITP surprise. Miller lists reasons it might fail in mice yet work in people, criticizes the statistics of another lab's positive male result, and explains why an observational study motivates the TAME trial.
- •Miller tested one dose on one continuous schedule, with no significant effect in either sex
- •Another lab's male result had a P value of .046 using a test other than the log-rank
- •Possible explanations include species differences, dose and schedule
- •An observational study found diabetics on metformin had lower mortality than non-diabetics, motivating a human trial
- 1:48:48 – 1:55:32
Nicotinamide riboside results
Miller explains why NAD attracted attention and how a company suggested nicotinamide riboside for the ITP. At the dose used it did not extend lifespan, and the lab could not show consistent tissue NAD changes.
- •The company suggesting NR agreed to publication of positive or negative results
- •NR did not extend lifespan in the ITP at the dose tested
- •The team could not show consistent NAD changes in brain, muscle or heart, though NAD turns over rapidly
- •Only lifespan is measured in first tests, with health outcomes reserved for drugs that extend life
- •None of the tested drugs has significantly shortened lifespan
- 1:55:32 – 1:59:41
Three takeaways from the ITP
Attia proposes mTOR, glucose and sex hormones as key themes, and Miller offers his own three general lessons. His points are that drugs can slow aging, that they can work in middle age, and that effects are often sex-specific.
- •Miller's first point: drugs in food can extend healthy lifespan by far more than curing cancer would
- •Second: several drugs work when started in middle age
- •Third: effects are often sex-specific, with rapamycin and glycine working in both sexes
- •The molecular questions of TOR, glucose and sex-specific receptors are what he gives new lab members
- 1:59:41 – 2:08:11
Model organisms, cause of death, and starting early versus late
Miller says the mouse is the best single model organism but that the answer depends on the question, and he defends mice against Attia's concerns about diet and cancer-dominated mortality. They also revisit whether interventions must start early.
- •Different organisms suit different questions; Miller favors marmosets over rhesus among primates
- •Attia notes mice are herbivores and mostly die of cancer, whereas humans die with atherosclerosis
- •Rapamycin-treated mice euthanized at 22 months showed youthful tissues across many organs
- •Miller says late-start data on 17α-estradiol argue against needing to start early
- •Miller declines to say whether he takes any ITP drugs
- 2:08:11 – 2:14:25
Flying pigs and closing thoughts
Attia reads from Miller's satirical open letter to Aubrey de Grey listing seven reasons pigs cannot fly. He uses it to frame Miller's grounded view that a 10-25% extension of lifespan would be a major achievement, and the conversation ends with thanks.
- •Miller wrote the piece for MIT Technology Review in a mean mood at six in the morning
- •The satire lists seven reasons pigs cannot fly, ending with 'they do not tweet'
- •Attia says he shares Miller's skepticism about immortality
- •Attia sees a 10-15% gain in lifespan and healthspan as remarkable
