Life Extending Drugs from the NIH's Intervention Testing Program (ITP)

The Interventions Testing Program (ITP) trials are a systematic effort by the National Institute on Aging (NIA) to evaluate drugs and compounds for their potential to extend longevity and healthspan in mammals.

Initiated by Richard Miller and colleagues in early 2000s, the ITP trials test substances in genetically heterogeneous mice* across three independent study sites.

Prof. Richard Miller, Director of the Intervention Testing Program

The premise is that if a drug-induced lifespan extension effect is replicated at all three sites, which have slightly varied environmental conditions, then the benefit is likely real and not merely an artifact.

The multi-site design helps mitigate individual site biases and provides built-in study replication without needing new cohorts of mice.

So far, several ITP discoveries have substantially impacted aging research. They keep a log of all the molecule outcomes here.

By systematically testing agents in a uniform model system, the ITP trials help the aging biology community determine what interventions are truly promising for translational efforts.

The trials also provide tissue samples from mice exposed to longevity treatments for other researchers to explore anti-aging mechanisms.

Even drugs that fail to slow aging teach us something in the process about biological regulation of longevity and health.

With new cohorts initiated each year, the ITP trials remain an engine of discovery in aging science.

In this article, we will:

Look at the major successes from the ITP trials, including drugs that extended lifespan
Examine some of the more interesting and notable failures – compounds that did not increase longevity as hoped
Finally, we’ll explore future developments and discoveries that may emerge from the ITP trials as new cohorts are initiated each year

*The ITP trials test substances in genetically heterogeneous mice, which means the mice have a diverse genetic makeup.

This is important because results from narrowly bred mouse models may not generalize well to a more varied population with a range of genomes.

Successful Life-Extending Drugs

Rapamycin

Rapamycin is an FDA-approved immunosuppressant drug and known mTOR inhibitor that can mimic some aspects of calorie restriction.

It has produced the largest effects on longevity to date in the ITP trials.

Mice treated with rapamycin starting at either 600 days old or, as young adults, have shown significant lifespan benefits in multiple independent reports:

Median* lifespan increased 14-26% in females, 9-23% in males
90th percentile maximum lifespan increased as well¹

*The median is the middle value in a dataset – so for lifespan, the median represents the age at which half the mice live longer and half live shorter.

More recently, another ITP trial found that starting rapamycin at 600 days old extended lifespan in both male and female mice.²

The mice were either given rapamycin continuously for life, in intermittent cycles, or for just 3 months.

All three rapamycin protocols produced similar 9-11% increases in male and 4-15% increases in female median lifespan.

Rapamycin likely works by inhibiting the mTOR protein complex, which when overactive can accelerate aging.

Rapamycin has also been found to protect against cancer, age-related cognitive decline,, and multiple organ system pathologies in mice.³

Synergistic Combinations with Rapamycin

The ITP trials have not only tested substances individually but also in tandem to probe potential synergies between compounds.

Rapamycin deserves particular attention as combining it with other agents has yielded lifespan benefits surpassing either alone.

Co-administering rapamycin plus acarbose increased median longevity in male mice further than prior rapamycin or acarbose only regimens.⁴

This supports the premise that simultaneously blunting mTOR signaling and glucose spikes is more potent than targeting either process individually.

Furthermore, a combination of low-dose metformin and rapamycin was tested.

In one trial, the combination resulted in robust survival gains than historical rapamycin-only controls, suggestive of synergy.⁵

However, in another study, the advantages of pairing metformin with rapamycin were not statistically greater than rapamycin alone.⁶

So the jury remains out on whether this specific combination is additive or simply recapitulates rapamycin’s benefits.

Contrasting outcomes highlight that anticipating synergies between compounds is not straightforward, but optimized pairing may yet unlock additional anti-aging activity.

Acarbose

Acarbose is an FDA-approved prescription drug for diabetes that inhibits an intestinal enzyme needed to digest starches and carbohydrates.

It was found to increase median lifespan by 16-20% and maximum lifespan by 8-11% in male mice. Smaller but significant 4-5% improvements occurred in females.⁷

In another trial, it was also shown to positively shift the gut microbiome and thus resulted in increased SCFA* levels which are correlated with increased lifespan.⁸

*SCFAs (short chain fatty acids) are compounds produced by gut bacteria that provide energy to cells and have been associated with various health benefits.

Glycine

Glycine is a common, naturally occurring amino acid involved in biosynthesis and antioxidant defenses.

In ITP trials, it has been found to increase median and maximum lifespan 4-6% when added to mouse chow. Glycine-fed mice also had reduced late-life death rates from lung cancer.⁹

Glycine is involved in methionine metabolism and may counter aging effects of dietary methionine, which is linked to elevated homocysteine levels that adversely impact vasculature.¹⁰

Low methionine diets were also shown to extend lifespan in rodents.¹¹ This offers a potential explanation for the longevity boost, though more research is needed.

NDGA

Nordihydroguaiaretic acid (NDGA) is an antioxidant compound derived from the creosote bush.

It was found to increase lifespan specifically in male genetically heterogeneous mice. When given lifelong starting at 4 months of age, NDGA led to an 8-10% increase in median lifespan compared to controls.¹²

The effects were dose-dependent and not seen in females, even at doses leading to similar blood levels as the lifespan-extending dose in males.

Canagliflozin

Canagliflozin is an FDA-approved diabetes medication that causes blood glucose loss through the urine.

It increased median lifespan 14% and maximum lifespan 9% when given to male mice starting from 7 months of age.¹³

However, no lifespan gains occurred in female mice despite similar metabolic improvements in both sexes.

This pattern mirrors effects of acarbose in the ITP although through distinct mechanisms, providing convergent evidence that minimizing glucose fluctuations over life positively impacts longevity, especially in male mammals.

17-α Estradiol

17-α estradiol is an endogenous estrogen-related steroid hormone and isomer of the sex hormone estradiol.

In multiple ITP trials, this estrogen-related steroid preferentially improved survival of male mice. For example:

In a 2014 ITP trial, the median longevity increased 12% and initially higher doses boosted this to 18%, but only in males.

In a 2016 ITP trial, adding 17-alpha estradiol to the diet of young mice extended their median lifespan by 19%. No such benefits were observed in female mice.

In a 2021 ITP trial, it extended the median lifespan in male mice by 19% when started at the equivalent of 50 years in human age and 11% at a 60-year equivalent.

Effects again likely owe to sex differences in how 17-α estradiol is metabolized intracellularly to other active or inactive products.

Regardless of mechanism, it represents another pharmacological tool to probe sex influences in mammalian aging.

Protandim

Protandim is a patented dietary supplement consisting of five herbal ingredients reported to activate the transcription factor NRF2. Specifically:

Milk thistle
Bacopa
Ashwagandha
Green tea
Turmeric

In an ITP trial, mice were fed chow containing Protandim starting from 10 months of age.

It significantly increased median lifespan by 7% in male but not female mice (source).

However, the maximum lifespan assessed by the age at 90% mortality was not affected in either sex. The median longevity benefits were only significant at one of the three independent test sites.

Astaxanthine & Meclizine

Astaxanthin is a naturally occurring carotenoid pigment and popular nutritional supplement promoted for antioxidant effects.

Meclizine is an over-the-counter antihistamine drug commonly used to treat nausea, vomiting, and dizziness from motion sickness.

In the ITP trials, astaxanthin supplement increased median lifespan 12% in males but not females.

And meclizine increased median lifespan 8% in males but not females. It was thought to act as a TOR inhibitor (source).

Failures & Non-Successes

While the ITP has uncovered success stories like rapamycin and acarbose, most agents tested to date have shown no lifespan benefit.

But failures remain scientifically useful by indicating which pathways probably do not offer easy anti-aging shortcuts.

They also help benchmark efficacy of emerging candidates against validated life extending interventions.

Here I highlight a few substances that failed to extend lifespan in ITP trials despite the enthusiasm from the biohacking community surrounding their alleged anti-aging benefits:

Resveratrol

Resveratrol is a natural polyphenolic compound found in some plant species like grapes and Japanese knotweed that is believed to activate sirtuin proteins.

Early enthusiasm for the potential anti-aging effects of resveratrol diminished significantly when neither doses of 300 ppm nor 1200 ppm resulted in longevity improvements in ITP mice (source).

This signaled that sirtuin-activating compounds may only show modest effects in mammal models, contrasting positive results in simpler organisms (source).

Nevertheless, resveratrol remains under study for other therapeutic indications like protecting against metabolic disease.

Metformin

Metformin is widely prescribed to manage elevated blood sugar in type II diabetes and prediabetes.

Observational data also associated metformin use with lower cancer rates and mortality.

But metformin alone failed to slow aging in mice based on ITP testing (source).

However, it’s again important to mention that combining metformin with rapamycin increased longevity beyond rapamycin alone in some ITP trials but not in others, so these two drugs might synergistically target complementary longevity pathways or not.

Nicotinamide Riboside

Nicotinamide riboside is a NAD+ precursor supplement thought to boost NAD+ bioavailability.

It didn’t alter lifespan trajectories relative to control mice despite promising cellular data (source).

The ITP outcomes indicate boosting NAD+ bioavailability may not be sufficient as a standalone anti-aging intervention in mammals, at least not with the dosing regimen employed.

While interest continues in potential cognitive benefits of nicotinamide riboside, direct aging relevance remains uncertain absent further supportive data.

Fisetin

Fisetin is a flavonoid molecule found in some fruits and vegetables that is claimed to have senolytic activity.

It’s promoted as capable of eliminating senescent cells, which are proposed contributors to aging-related dysfunction.

However oral fisetin failed to remove senescent cell markers or provide any lifespan advantages in ITP mice at up to 263 mg/kg/day (source).

This indicates that alleged senolytic activity and oral bioavailability in mice may be insufficient for tangible impacts or that clearance of senescent cells is simply ineffective against aging processes.

Aspirin

In an early ITP trial, aspirin increased median lifespan by 8% and maximum lifespan by 4% in male but not female mice (source).

However, subsequent attempts by independent research groups to reproduce these longevity effects in mice have failed.

Given aspirin’s known impacts on inflammation, cardiovascular disease, and cancer risk in humans, there was interest in better understanding its potential effects on aging.

But with the initial positive ITP outcome now in question, aspirin has not been prioritized for further lifespan testing relative to more promising substances.

The early aspirin results remain an important reminder that promising initial findings do not always manifest as true biological signals upon replication.

Methylene Blue

I also wanted to mention methylene blue (MB) briefly because it has recently grown in popularity a lot.

MB is a small molecule with antioxidant properties.

In the same mouse study that evaluated NDGA, researchers also tested MB to see if it could extend lifespan.

However, MB did not alter the median lifespan in either male or female mice, although there was a small 6% increase in maximum lifespan seen in females (source).

Methylene Blue didn’t demonstrate significant longevity benefits in these mouse models and it wasn’t continued to be tested in the ITP trials.

What’s Next for ITP Trials?

With new cohorts initiated annually, the ITP trials continue their search for pharmacology to slow aging.

The goals remain to discover safe, scalable interventions that extend lifespan by targeting underlying biology rather than ameliorating single diseased states.

In a 2022 interview, Prof. Richard Miller said that drugs now under study include the combination of rapamycin and alpha-ketoglutarate.

Also, many agents from past cycles warrant re-examination at additional doses or alternative treatment schedules – one of which is canagliflozin.

Ultimately, translation to human trials remains paramount.

However, the ITP’s uniform platform aids efficient translation in a field historically fraught with reproducibility issues.

And the trials promise to keep delivering data to convince people of the viability of therapeutically targeting aging – which I think is appreciated by most of us.

References

1
Rapamycin fed late in life extends lifespan in genetically heterogeneous mice | Harrison et al. | 2009 | Aging Cell
2
Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects | Strong et al. | 2020 | Aging Cell
3
Rapamycin slows aging in mice | Miller et al. | 2012 | Aging Cell
4
Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice | Harrison et al. | 2022 | Aging Cell
5
Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer | Strong et al. | 2016 | Aging Cell
6
Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice | Strong et al. | 2022 | Aging Cell
7
Acarbose improves health and lifespan in aging HET3 mice | Harrison et al. | 2019 | Aging Cell
8
Changes in the gut microbiome and fermentation products concurrent with enhanced longevity in acarbose-treated mice | Smith et al. | 2019 | BMC Microbiology
9
Glycine supplementation extends lifespan of male and female mice | Miller et al. | 2019 | Aging Cell
10
The atherogenic effect of excess methionine intake | Troen et al. | 2003 | Proceedings of the National Academy of Sciences of the United States of America
11
Low methionine ingestion by rats extends life span | Orentreich et al. | 1993 | Journal of Nutrition
12
Acarbose, 17-α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males | Harrison et al. | 2014 | Aging Cell
13
Canagliflozin extends life span in genetically heterogeneous male but not female mice | Miller et al. | 2020 | JCI Insight

Life Extending Drugs from the NIH’s Intervention Testing Program (ITP)