Interventions Testing Program: revision 1 to 2

Revision 1

Revision 2

categories: ["organizations", "longevity"]

tags: ["aging", "biogerontology", "lifespan", "mice", "drug testing", "replication"]

summary: "A National Institute on Aging programme that tests whether candidate anti-aging compounds extend lifespan in genetically heterogeneous mice, run in parallel at three sites."

summary: "A National Institute on Aging programme that tests whether candidate anti-aging compounds extend lifespan in genetically heterogeneous mice, run in parallel at three sites."

updated: "2026-08-23"

updated: "2026-10-29"

---

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```

**The Interventions Testing Program** (ITP) is a programme of the US National Institute on

**The Interventions Testing Program** (ITP) is a programme of the US National Institute on Aging

Aging that tests whether candidate compounds extend the lifespan of mice, running every

that tests whether candidate compounds extend the lifespan of mice, running every test in parallel

test in parallel at three independent sites under an identical protocol. Since its first

at three independent sites under an identical protocol. Since its first cohorts in 2004 it has

cohorts in 2004 it has become the closest thing biogerontology has to a benchmark: a

become the closest thing biogerontology has to a benchmark. A lifespan claim that survives the ITP

lifespan claim that survives the ITP is taken seriously, and one that fails there is

is taken seriously, and one that fails there is substantially weakened however striking the original

substantially weakened however striking the original report. Its most consequential

report. Its most consequential outputs include the 2009 demonstration that [[rapamycin]] extends

outputs include the 2009 demonstration that [[rapamycin]] extends mouse lifespan when

mouse lifespan when begun late in life, and a long list of famous candidates that did nothing.

begun late in life, and a long list of famous candidates that did nothing.

## Overview

The ITP exists because the mouse-longevity literature it inherited was unreliable. A

The ITP exists because the mouse-longevity literature it inherited was unreliable. A lifespan result

lifespan result from one laboratory, in one inbred strain, on one diet, frequently failed

from one laboratory, in one inbred strain, on one diet, frequently failed to reproduce anywhere

to reproduce anywhere else; a compound could look life-extending simply because it

else, and a compound could look life-extending simply because it corrected a quirk of a single

corrected a quirk of a single genotype. The programme's design answers each failure mode

genotype. The programme's design addresses each of these failure modes. Every compound is tested

directly. Every compound is tested simultaneously at the Jackson Laboratory, the

simultaneously at the Jackson Laboratory, the University of Michigan, and the University of Texas

University of Michigan, and the University of Texas Health Science Center at San Antonio.

Health Science Center at San Antonio. The mice are genetically heterogeneous UM-HET3 animals, bred

The mice are genetically heterogeneous UM-HET3 animals, bred as a four-way cross so that

as a four-way cross so that every mouse is a genetically distinct sibling of every other, which

every mouse is a genetically distinct sibling of every other, which prevents any result

prevents any result from being an artifact of one inbred genome. Both sexes are tested, doses are

from being an artifact of one inbred genome. Both sexes are tested, doses are verified in

verified in blood, and survival is pooled across the three sites before analysis.[^miller2007]

blood, and survival is pooled across the three sites before analysis.[^miller2007]

```keyfacts

[

  { "value": "3", "label": "Sites running identical protocols", "note": "The Jackson Laboratory, University of Michigan, UT Health San Antonio" },

  { "value": "3", "label": "Sites running identical protocols", "note": "The Jackson Laboratory, University of Michigan, UT Health San Antonio" },

{ "value": "2004", "label": "First cohorts enrolled" },

  { "value": "9–14%", "label": "Rapamycin gain in age at 90% mortality", "note": "males and females, treatment begun at 600 days" }

  { "value": "9-14%", "label": "Rapamycin gain in age at 90% mortality", "note": "males and females, treatment begun at 600 days" }

]

```

Anyone may propose a compound. The programme runs an annual open call, and nominations

Anyone may propose a compound. The programme runs an annual open call, and nominations have come

have come from academic laboratories, companies, and independent researchers; the sponsor

from academic laboratories, companies and independent researchers; the sponsor of a compound is

of a compound is typically involved in designing the dose and interpreting the result.

typically involved in designing the dose and interpreting the result. The openness is deliberate,

This openness is deliberate. The ITP is a public filter for the field's hypotheses,

and it makes the ITP a public filter for the field's hypotheses, including the ones its own

including the ones its own investigators doubt.

investigators doubt.

## History

The National Institute on Aging launched the programme in 2004, after several years of

The National Institute on Aging launched the programme in 2004, after several years of planning

planning among investigators who had watched single-laboratory lifespan claims collapse

among investigators who had watched single-laboratory lifespan claims collapse on replication.

on replication. The founding design — three sites, heterogeneous mice, pooled analysis,

Richard Miller, David Harrison, Randy Strong and colleagues described the founding design (three

pre-specified statistics — was described by Richard Miller, David Harrison, Randy Strong

sites, heterogeneous mice, pooled analysis, pre-specified statistics) in a 2007 interim report that

and colleagues in a 2007 interim report that remains the reference for how the programme

remains the reference for how the programme works.[^miller2007] The

works.[^miller2007] The [[methuselah-foundation|Methuselah Foundation's]] Mprize, created

[[methuselah-foundation|Methuselah Foundation's]] Mprize, created around the same period, approached

around the same period, approached the same problem from the opposite direction, rewarding

the same problem from the opposite direction, rewarding record lifespans rather than standardising

record lifespans rather than standardising their measurement.

their measurement.

The programme's defining moment came in 2009, when it reported in *Nature* that rapamycin

The programme's defining result came in 2009, when it reported in *Nature* that rapamycin fed to

fed to mice from 600 days of age — roughly equivalent to a human in their early sixties —

mice from 600 days of age, roughly equivalent to a human in their early sixties, extended lifespan

extended lifespan in both sexes at all three sites.[^harrison2009] It was the first drug

in both sexes at all three sites.[^harrison2009] It was the first drug shown to extend mouse

shown to extend mouse lifespan robustly when started that late, and the result, an

lifespan robustly when started that late. The late start was itself an accident, caused by a

accident of a formulation delay that pushed the start date back, did more than any other

formulation delay that pushed the start date back. The finding did more than any other single result

single finding to make aging look pharmacologically tractable. It is a core exhibit for

to make aging look pharmacologically tractable. It is a core exhibit for the

the [[geroscience-hypothesis]], and it launched the wave of interest in mTOR inhibition

[[geroscience-hypothesis]], and it launched the wave of interest in mTOR inhibition and

and [[autophagy]] that continues today.

[[autophagy]] that continues today.

## How a compound is tested

UM-HET3 mice are the offspring of two F1 hybrid parents, drawing on four inbred

UM-HET3 mice are the offspring of two F1 hybrid parents, drawing on four inbred grandparental

grandparental strains. Compounds are almost always delivered in food, at a dose negotiated

strains. Compounds are almost always delivered in food, at a dose negotiated with the sponsor and

with the sponsor and confirmed by measuring blood levels; treatment usually begins in

confirmed by measuring blood levels. Treatment usually begins in early adulthood, though some agents

early adulthood, though some agents are deliberately started late to model treatment of

are deliberately started late to model treatment of already-aged animals. The primary endpoint is

already-aged animals. The primary endpoint is survival, pooled across sites and analysed

survival, pooled across sites and analysed separately by sex, with secondary studies of

separately by sex, with secondary studies of [[healthspan]] measures and pathology in

[[healthspan]] measures and pathology in parallel cohorts.[^miller2007] The design trades breadth

parallel cohorts.[^miller2007] The design trades breadth for rigour: a compound is

for rigour. A compound is typically tested at one or a few doses, so a null result is a statement

typically tested at one or a few doses, and a null result is a statement about those

about those doses and that schedule, and says nothing about the molecule in every possible regimen.

doses and that schedule, not about the molecule in every possible regimen.

## Results

]

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Two decades of testing have produced a short list of validated life-extending drugs and a

Two decades of testing have produced a short list of validated life-extending drugs and a much

much longer list of failures. After rapamycin, the diabetes drug acarbose extended

longer list of failures. After rapamycin, the diabetes drug acarbose extended lifespan in both

lifespan in both sexes, though far more strongly in males.[^harrison2014] A striking

sexes, though far more strongly in males.[^harrison2014] A striking pattern emerged and has

pattern emerged and persisted: 17-α-estradiol, a weakly feminising estrogen isomer,

persisted. 17-α-estradiol, a weakly feminising estrogen isomer, extends lifespan only in

extends lifespan only in males,[^harrison2021] and the same male-only pattern holds for

males,[^harrison2021] and the same male-only pattern holds for canagliflozin,[^miller2020]

canagliflozin,[^miller2020] nordihydroguaiaretic acid, and the 2024 additions astaxanthin

nordihydroguaiaretic acid, and the 2024 additions astaxanthin and meclizine.[^harrison2024] Why most

and meclizine.[^harrison2024] Why most ITP-positive drugs work better in males is an open

ITP-positive drugs work better in males is an open question in the field; proposed explanations

question in the field, with proposed explanations running from sex differences in drug

range from sex differences in drug metabolism to interactions with growth signalling. In 2026 the

metabolism to interactions with growth signalling. In 2026 the programme reported that

programme reported that astaxanthin, meclizine and mitoglitazone failed to repeat their benefits

astaxanthin, meclizine, and mitoglitazone failed to repeat their benefits when given at

when given at different doses or starting ages, which shows that even within mice, dose and timing

different doses or starting ages, a reminder that even within mice, dose and timing can

can make or unmake a longevity drug.[^korstanje2026]

make or unmake a longevity drug.[^korstanje2026]

## The null results

The negatives are arguably the programme's most valuable product. Resveratrol, the

The negatives are arguably the programme's most valuable product. Resveratrol, the sirtuin activator

sirtuin activator whose promise [[david-sinclair]]'s work had made famous, did not extend

whose promise [[david-sinclair]]'s work had made famous, did not extend lifespan at the doses the

lifespan at the doses the ITP tested.[^miller2011] [[metformin|Metformin]] alone did not

ITP tested.[^miller2011] [[metformin|Metformin]] alone did not significantly extend lifespan in

significantly extend lifespan in either sex — a result that sits awkwardly beneath the

either sex. That result sits awkwardly beneath the TAME trial proposed by [[nir-barzilai]], which

TAME trial proposed by [[nir-barzilai]], which rests substantially on human observational

rests substantially on human observational data rather than mouse survival.[^strong2016]

data rather than mouse survival.[^strong2016] Nicotinamide riboside, the most-studied of

Nicotinamide riboside, the most-studied of the [[nad-precursors]], had no effect on lifespan in

the [[nad-precursors]], had no effect on lifespan in either sex.[^harrison2021] Fisetin,

either sex.[^harrison2021] Fisetin, widely sold as a senolytic supplement, joined the null list in

widely sold as a senolytic supplement, joined the null list in 2024 at the dose and

2024 at the dose and schedule used.[^harrison2024] The result matters for how [[senolytics]] claims

schedule used[^harrison2024] — a result that matters for how [[senolytics]] claims are

are graded, even though other senolytic agents and regimens remain untested there. Dozens of other

graded, even though other senolytic agents and regimens remain untested there. Dozens of

agents, including green tea extract, curcumin and methylene blue, have likewise shown nothing.

other agents, from green tea extract to curcumin to methylene blue, have likewise shown

nothing.

> [!stat] The base rate

> The large majority of compounds tested since 2004 have produced no significant lifespan

> The large majority of compounds tested since 2004 have produced no significant lifespan extension

> extension in either sex. Several of the failures — resveratrol, metformin, nicotinamide

> in either sex. Several of the failures (resveratrol, metformin, nicotinamide riboside, fisetin)

> riboside, fisetin — are among the best-selling ingredients of the longevity supplement

> are among the best-selling ingredients of the longevity supplement market.

> market.

The nulls carry a caveat the programme itself states: a compound tested at one dose, one

The nulls carry a caveat the programme itself states: a compound tested at one dose, one formulation

formulation, and one starting age has not been tested exhaustively. Metformin's advocates

and one starting age has not been tested exhaustively. Metformin's advocates note that the ITP dose

note that the ITP dose produced blood levels below those of treated diabetic humans. But

produced blood levels below those of treated diabetic humans. The asymmetry still stands. Under

the asymmetry is the point. Under identical conditions rapamycin worked and these agents

identical conditions rapamycin worked and these agents did not, and a marketplace of

did not, and a marketplace of [[dietary-supplements]] sold against aging has produced few

[[dietary-supplements]] sold against aging has produced few molecules that clear the same bar.

molecules that clear the same bar.

## Reception and limits

Within biogerontology the ITP is routinely described as the field's most rigorous test of

Within biogerontology the ITP is routinely described as the field's most rigorous test of longevity

longevity interventions, and its three-site replication in heterogeneous animals is the

interventions, and its three-site replication in heterogeneous animals is the standard against which

standard against which single-laboratory claims are discounted. Regulators have no

single-laboratory claims are discounted. Regulators have no approval pathway for aging, so the

approval pathway for aging, so the programme functions as the de facto arbiter of which

programme acts as the de facto arbiter of which compounds deserve human study, informing trial

compounds deserve human study, informing trial design from TAME to the veterinary trials

design from TAME to the veterinary trials run by [[loyal]]. Its data are public, its statistics are

run by [[loyal]]. Its data are public, its statistics are pre-specified, and its failures

pre-specified, and its failures are published as prominently as its successes, practices that remain

are published as prominently as its successes — practices that remain rare in the

rare in the surrounding literature.

surrounding literature.

Its limits are equally plain. Mice in specific-pathogen-free housing, fed one diet and

Its limits are equally plain. Mice in specific-pathogen-free housing, fed one diet and dying largely

dying largely of cancer, are an imperfect model of human aging; effect sizes are

of cancer, are an imperfect model of human aging. Effect sizes are percentages of a

percentages of a two-to-three-year lifespan, not steps toward

two-to-three-year lifespan, not steps toward [[maximum-human-lifespan|record human lifespans]]. And

[[maximum-human-lifespan|record human lifespans]]; and lifespan itself is a blunt

lifespan itself is a blunt endpoint that can miss what a compound does to function. The programme

endpoint that can miss what a compound does to function. The programme measures survival

measures survival superbly and mechanism not at all, which is why its results are read alongside the

superbly and mechanism not at all, which is why its results are read alongside the

[[hallmarks-of-aging]] framework and validated [[aging-biomarkers]] rather than in place of them.

[[hallmarks-of-aging]] framework and validated [[aging-biomarkers]] rather than in place

of them.

> [!key] The best mouse evidence is still mouse evidence

> The ITP is what makes the rule "animal results are not human results" enforceable with

> The ITP makes the rule "animal results are not human results" enforceable with data, because it

> data: it defines what a real mouse result looks like. No ITP finding, positive or

> defines what a real mouse result looks like. No ITP finding, positive or negative, establishes

> negative, establishes anything about human aging, and no compound the programme has

> anything about human aging, and no compound the programme has validated has been shown to slow

> validated has been shown to slow aging in people.

> aging in people.

## Outlook

The programme's current direction is toward combinations and refinements: rapamycin plus

The programme is now moving toward combinations and refinements. In results reported in 2022,

acarbose outperformed either drug alone in males, and the ACE inhibitor captopril

rapamycin plus acarbose outperformed either drug alone in males, and the ACE inhibitor captopril

produced a modest extension, in results reported in 2022.[^strong2022] A companion NIA

produced a modest extension.[^strong2022] A companion NIA effort applies the same multi-site logic

effort applies the same multi-site logic to *Caenorhabditis* worms, and proposals keep

to *Caenorhabditis* worms, and proposals keep arriving faster than the three sites can test them.

arriving faster than the three sites can test them. The unresolved question is the one

The unresolved question is one the ITP was never designed to answer.

the ITP was never designed to answer. [[caloric-restriction|Caloric restriction]],

[[caloric-restriction|Caloric restriction]], rapamycin and acarbose all extend mouse lifespan under

rapamycin, and acarbose all extend mouse lifespan under its protocol, yet no human trial

its protocol, yet no human trial has demonstrated that any drug slows human aging, and none of the

has demonstrated that any drug slows human aging, and none of the programme's male-only

programme's male-only results has an accepted explanation. Much of the longevity field, from

results has an accepted explanation. Whether the ITP's short list of validated compounds

companies and trials to off-label use, currently rides on the wager that the ITP's short list of

translates into human healthspan is the wager on which much of the longevity field —

validated compounds translates into human healthspan.

companies, trials, and off-label use alike — currently rides.

## See also