#148 - Richard Miller, M.D., Ph.D.: The gold standard for testing longevity drugs: the ITP

A class of drugs including canagliflozin, used for type 2 diabetes, which block glucose reuptake in the kidney. ITP results show it extends lifespan in male mice, possibly by reducing peak glucose levels.

An initial ITP candidate drug that showed a small lifespan extension in male mice at a very low dose, but did not replicate the effect at higher doses.

A coenzyme central to metabolism and DNA repair, whose levels are often linked to aging, and is targeted by many supplements.

A popular NAD+ precursor supplement tested in the ITP, which did not extend lifespan in mice at the tested dose, and did not consistently show increased NAD+ levels in tissues.

A compound popularized for alleged anti-aging benefits, especially in relation to red wine. ITP studies (at high doses on normal diets) found no significant lifespan extension, debunking earlier findings in mice poisoned with high-fat diets.

A popular supplement believed to be healthful; tested in the ITP, but did not extend lifespan in mice.

A popular supplement that was tested in the ITP and failed to show longevity benefits.

A compound suggested to the ITP, potentially related to bile acids and retinoid receptor activation, but Dr. Miller isn't certain about its rationale. It was mentioned as being not orally bioavailable in a human supplement context.

An FDA-approved diabetes drug that blocks starch digestion and glucose absorption. In ITP, it extends lifespan in both sexes, especially males, likely by reducing glucose peaks, and is effective even when started in middle age.

A compound that caught Dr. Miller's eye on the list of ITP-failed compounds.

An amino acid that, when tested in the ITP, showed significant but tiny lifespan effects in both males and females.

A dietary intervention known to extend lifespan across many species, serving as early proof that aging is malleable, though it typically needs to be initiated early in life.

A gene mutation in C. elegans, an analog of the IGF-1 receptor, shown to extend lifespan, a foundational discovery in aging.

One of two protein complexes containing mTOR; its inhibition by Rapamycin is believed to be the primary driver of longevity benefits.

The concept that normal human cells divide a limited number of times in culture before stopping (replicative senescence), which Hayflick incorrectly linked to organismal aging.

Protective caps at the ends of chromosomes whose shortening limits cell division; a fundamental biological discovery, but its role as a central cause or biomarker of aging is often overemphasized.

A genetic mutation in mice that extends longevity by 30% and is associated with reduced mTORC1 activity and elevated mTORC2 activity.

A gene mutation in C. elegans, an analog of FoxO3a/3b, which blocks the lifespan-extending effect of Daf-2 mutations when combined, indicating interaction.

A family of proteins believed to play a role in cellular health and aging, and targeted by Resveratrol. Research on their importance in aging remains controversial.

A clinically useful measure indicating average glucose levels over weeks; observed to decrease with Acarbose and SGLT2 inhibitors in humans, but not consistently in ITP mice.

One of two protein complexes containing mTOR; its inhibition by Rapamycin is associated with negative consequences, and its elevation in some dwarf mice is linked to longevity.

A genetic mutation in mice that extends longevity by 30% and is associated with reduced mTORC1 activity and elevated mTORC2 activity.

One of the classical estrogen receptors, for which 17-alpha Estradiol has a much lower affinity than 17-beta Estradiol.

A nematode worm, commonly used model organism in aging research, where Daf mutants were first shown to extend lifespan.

A genetic mutation in mice shown to extend lifespan by about 40%, serving as critical evidence that aging can be slowed in mammals.

Mammalian target of Rapamycin, a protein kinase that regulates cell growth, proliferation, and survival, and is inhibited by Rapamycin.

One of the classical estrogen receptors, for which 17-alpha Estradiol has a much lower affinity than 17-beta Estradiol.

A neurodegenerative disease that does not ordinarily occur in mice but can be studied in engineered mouse models, where anti-aging drugs have shown postponement of the disease.

A gas that some researchers hypothesize is an important controlling element in the aging process; a drug designed to produce it is being re-tested in the ITP after an initial methodological error.

A scientist who initially argued against the possibility of single gene mutations extending lifespan, then modified her stance to exclude C. elegans.

A researcher who demonstrated that caloric restriction works best when initiated at a younger age in mice, failing when started later in life.

A scientist in Dr. Miller's lab who has studied the activity of mTORC1 and mTORC2 in long-lived mutant mice and ITP-treated mice.

A scientist at the University of Rochester who has done work on how different species with varying body sizes and lifespans differ in their anti-cancer mechanisms, including telomere reliance.

A mathematical biodemographer who carefully compared the survival curves of early-start vs. late-start Rapamycin-treated mice, finding them statistically indistinguishable.

A researcher who, with Daniel Smith, initially suggested Acarbose for ITP testing based on its caloric restriction-mimicking effects.

A close friend and colleague of David Sinclair, who also provided advice on Resveratrol dosing for the ITP research.

A researcher whose early work in C. elegans demonstrated that single gene mutations (Daf-2 and Daf-16) could dramatically extend lifespan, challenging prevailing scientific beliefs.

A researcher who, with J.L. Shansky, estimated the impact of abolishing specific diseases on human lifespan.

A colleague of Randy Strong and an expert on mTOR, who suggested Rapamycin as an ITP candidate based on invertebrate data.

A scientist interested in hydrogen sulfide as a controlling element in aging, who suggested a hydrogen sulfide-producing drug (SG1002) for ITP testing.

A friend of Dr. Miller, conducting an important study giving Rapamycin to dogs.

Chair of Pathology at New York University and a colleague of Hayflick, who shared an anecdote about the origins of the Hayflick Hypothesis.

A colleague of Dr. Miller at Texas (now Oklahoma) who collaborated on sketching out the initial plan for the ITP.

A friend and colleague of Dr. Miller, who held a differing view on whether aging is a unitary process at a Gordon Research Conference.

A colleague of Randy Strong at the University of Texas who conducted studies on Rapamycin blood levels in male and female mice.

A colleague of David Allison, who collaborated on the Acarbose suggestion for the ITP.

A collaborator in the ITP, leading one of the three testing labs at UT San Antonio.

A Nobel Prize-winning scientist known for her foundational work on telomeres.

Deputy to Huber Warner in the NIA's Division of Aging Biology, involved in the early discussions about the ITP.

A colleague of Andre Bartke, co-author on the paper demonstrating Ames dwarf mutation extends mouse lifespan.

An Australian scientist who continued to argue against the possibility of single gene mutations affecting longevity, even after evidence to the contrary emerged.

A colleague of Mike Garrett, co-author on the paper showing beneficial effects of 17-alpha Estradiol.

A visionary guy who headed NIA's Division of Aging Biology and conceived the idea of a program to test interventions, which evolved into the ITP.

Leader of one of the three ITP labs at The Jackson Laboratory, a collaborator with Dr. Miller and Randy Strong.

A Harvard researcher whose lab published early work on Resveratrol, showing longevity benefits in metabolically ill, overfed mice.

A science journalist who wrote a book about the Resveratrol story, 'The Youth Pill'.

A researcher who, with Holly Brown-Borg and colleagues, showed that the Ames dwarf mutation could extend lifespan in mice, providing "second shoe" to C. elegans findings.

The director of the NIA, who Dr. Miller and his colleagues were trying to convince to carry genetically heterogeneous mice, and who later directly ordered the ITP to test Resveratrol.

A pharmacologist interested in estrogen receptors who synthesized 17-alpha Estradiol and proposed it for ITP testing.

A colleague of Mike Garrett, co-author on the paper showing beneficial effects of 17-alpha Estradiol.

A former student of Dr. Miller and independent researcher who, with colleagues, published a paper showing beneficial effects of 17-alpha Estradiol on muscle strength, glucose tolerance, and muscle structure in mice, even with late initiation.

A researcher who made claims about retinoid receptor activation and bile acids in long-lived Ames dwarf mice, possibly relating to the suggestion of ursolic acid.

A well-known figure in anti-aging research, whose views on rapid solutions to aging were satirized by Dr. Miller in an MIT Technology Review article about 'flying pigs'.

A major funder of biomedical research in the US, mentioned in the context of hypothetical funding for expanded longevity research.

Academic institution where Dr. Richard Miller is a professor of pathology and director of the Paul F. Glenn Center for Aging Research.

A component of the NIH that funds research on aging, including the Interventions Testing Programs (ITPs).

A set of rigorous, multi-site studies funded by the NIA to test potential longevity-extending molecules in genetically heterogeneous mice, considered the 'gold standard' for longevity drug testing.

Academic institution where Randy Strong runs one of the three ITP testing labs.

An organization for which Dr. Miller served in editorial and advisory positions, supporting aging research.

The institution that funds the ITP, initially through a Nathan Shock center where Dr. Miller conducted early drug testing.

The institution where Dr. Miller did a postdoc after Yale, referred to as Memorial Sloan Kettering (MSK).

The institution where Dr. Miller set up his first independent lab, focusing on immunology and aging.

A prominent scientific journal that published early papers discussing why single gene mutations couldn't extend lifespan, and then later, papers showing that they could.

A research center at the University of Michigan directed by Dr. Richard Miller, focusing on aging research.

A scientific journal where a subsequent paper on Resveratrol from David Sinclair's lab revealed the cause of death for the mice in the original study.

A primate species often used in aging research, but deemed less ideal than marmosets due to longer lifespan.

A primate species suggested as a more suitable model for aging research than rhesus monkeys, due to its shorter lifespan while still mimicking human biology.

A diabetes drug that, despite epidemiological evidence for longevity benefits in diabetic humans, has largely failed to extend lifespan in ITP mice when tested alone.

A rapalog (Rapamycin analog) used in humans, with studies favoring intermittent dosing strategies to selectively inhibit mTORC1 without long-term mTORC2 inhibition.

An SGLT2 inhibitor used for diabetes that blocks peak glucose in mice and humans, extending lifespan preferentially in male mice, with mechanisms potentially beyond direct glucose control.

An ITP candidate drug that demonstrated lifespan extension consistently three times, but only in male mice.

An mTOR inhibitor that has shown consistent and significant lifespan extension in ITP mice, even when started in middle age, with a stronger effect often seen in females due to higher blood levels.

A synthetic estrogen compound, proposed to extend male lifespan without feminizing effects. ITP studies showed a dramatic lifespan extension in male mice, even when started in middle age, with no effect in females.

The 'classical estrogen' hormone, which 17-alpha Estradiol was designed to resemble but with lower receptor affinity and non-feminizing effects.

A drug designed to break down and produce hydrogen sulfide, suggested by Jay Mitchell for ITP testing.

A book by David Stipp about the Resveratrol story.

A scientific journal where Dr. Miller and Huber Warner published a formal plan for the ITP.

A scientific journal where Dr. Miller served as editor-in-chief, focusing on the biology of aging.

Often mistakenly associated with Resveratrol benefits; contains negligible amounts of Resveratrol, requiring impractical daily consumption to match research doses.

Highlighted as a natural source containing significant amounts of Resveratrol.

A publication where Dr. Miller wrote a satirical piece about the unrealistic expectations for solving the aging problem, comparing it to making pigs fly.

Targeting Aging with Metformin, a proposed human clinical trial to investigate Metformin's longevity benefits in non-diabetic individuals, inspired by epidemiological data.

Institution where Dr. Miller had an unproductive postdoc experience and where his wife was denied tenure in English.

A company that suggested Nicotinamide Riboside (NR) to the ITP for testing, providing the compound and dose recommendations.