The institute laser-focused on finding anti-aging compounds
Every longevity nerd should know something about the Interventions Testing Program (ITP). This is one of the largest and most rigorous longevity-based intervention trial programs around.
The ITP was developed at the NIH’s National Institute of Aging so that the aging research community could have easier access to a platform for testing potential interventions to reverse or slow down the hallmarks of aging,
The ITP is led by Dr. Richard Miller, a pioneering aging researcher who in 2002 created a stir in the scientific community by proposing that aging processes have common controlling factors that could be slowed down or reversed. Since then, Miller has dedicated his research to better understanding what controls the aging process and developing interventions based on those findings. What makes Miller an interesting leader of the ITP is his somewhat divergent philosophy on aging research: rather than obsessing on discovering what causes aging, he is focused on identifying what slows it down. That’s exactly what the ITP is meant to do.
A unique design
The ITP was designed with some very unique features meant to accelerate the discovery of agents that can slow aging. These include:
- Scale: the research platform is designed to test 4-5 interventions per year
- Replicability: the trials of the interventions selected are done simultaneously in three different sites (Jackson Laboratories, the University of Michigan, and the University of Texas Health Sciences Center at San Antonio). Simultaneously replicating results in three independent tests can save a lot of time in consolidating results
- Open access: the program is open to the aging research community and each year the ITP encourages scientists to submit proposals for agents they believe are worth including in the study.
- Collaborative: scientists who submit interventions for testing are not subject to the usual peer-review process, but are instead consulted and treated as collaborators on the ITP study with rights to all of the data generated by the intervention study for use in their own professional endeavors going forward The final selection is made by the ITP Access Committee
- Statistical rigor: the size of the studies is determined to have sufficient statistical power to detect 10% changes in lifespan
Another noteworthy feature of the ITP trials is the type of mice they use. Rather than relying on commercially available mice, which undergo high levels of inbreeding, the ITP uses genetically heterogeneous mice (using four-way crossing). This means the research is less likely to produce false positives (e.g., an agent that only works on one type of mouse) as well as false negatives (e.g., an agent that didn’t work in one type of mouse, but might work in others) that occasionally crop up in other longevity studies.
All these features in the design of the ITP make it a very unique research platform. Screening and choosing the 4-5 agents with the strongest clinical evidence for research across 3 labs means that not only are we getting information about the strongest contenders, but that we’re also getting valid, replicable results.
The rigor in this approach makes the ITP one of the key programs to follow if you want to stay on the cutting edge of longevity protocols.
What interventions are tested?
The ITP requires that the longevity agents submitted for testing can be categorized as one of the following:
- Food, diet, supplements, or nutraceuticals (e.g., phytochemicals)
- Amino acids
- Redox agents
- Other agents or mixtures of agents
Regardless of the type of compound being tested, the ITP committee holds a preference for agents that are cost-effective, easily obtainable, and can be delivered orally either through diet or water. Dive into the list of agents that have been tested since the beginning of the program.
Major findings to date
The ITP began its first intervention trials in 2004. Since then, it has tested agents in cohorts every year. Here are a few of the major findings of the ITP to date.
As a cohort 1 agent, aspirin was delivered to the treatment group of mice at 20ppm starting at age 4 months. Initial results suggested that aspirin was beneficial for male mice increasing lifespan by 8-10%. The 20ppm dose is low by clinical standards, and in subsequent studies lab scientists increased the dosage to 83ppm to mimic the dose of aspirin used to prevent heart attacks in humans. The increase in dosage didn’t result in any increase in lifespan for male or female mice and the agent.
A cohort 2 agent, rapamycin had previously shown promising anti-aging results in roundworms and fruit flies. It was given to the treatment group at a concentration of 14ppm starting at age 20 months after a year-long period of reformulation to make it easier to digest. Results of this phase 1 trial suggest that rapamycin increases lifespan in male and female mice 9 and 14%, respectively.
Rapamycin was examined again in cohort 3 in 2006, yielding similar though slightly more favorable results (increase lifespan by 11 and 16% in males and females, respectively). Rapamycin was later tested again as part of cohort 5, representing its phase 2 trials. The phase 2 trials tested low, medium, and high concentrations of rapamycin on mice starting at age 9 months. Again, rapamycin was shown to slow many aspects of aging in the treatment groups, although mice treated with rapamycin starting at 9 months also had higher incidence of testicular degeneration and cataracts when compared to control mice. Check out the full study here for more detailed results.
As a cohort 2 agent, acarbose originated as an antidiabetic drug used to block glucose absorption from the small intestine and has been used in subsequent longevity studies as a calorie-restriction mimetic. In the initial trial from 2009, the treatment group was given a dose of 1000ppm starting at age 4 months. Results from the trial suggest that extended lifespan preferentially in male mice.
Acarbose was tested again in 2012 as part of cohort 8. During this trial, treatment mice received 1000ppm starting at age 16 months; results suggested that although acarbose extended lifespan in male and female mice, late life treatment worked only about half as well as treatment beginning at age 4 months. The following year, phase 2 trials tested acarbose at 400, 1000, and 2500 ppm starting at age 8 months. The results showed that there were no significant differences among the three doses. The two highest doses produced a 16-17% increase in median lifespan among males and a 4-5% increase in females. Maximum lifespan was significantly increased in males at each dose (8-11%), but only increased in females by 3% at 1000 ppm.
Resveratrol has long been lauded as a longevity agent and the ITP set forth to examine it both as part of cohort 3 in 2006 and in cohort 4 in 2007. The cohort 3 trials tested treatments of resveratrol at 300ppm and 1200ppm starting at age 12 months. Results showed no significant difference in lifespan of mice treated with resveratrol when compared to controls. The following year in cohort 4, resveratrol was again tested this time using a concentration of 300ppm starting at age 4 months; results of this trial mirrored those of the one conducted in 2006, once again showing no significant difference in lifespan of mice treated with resveratrol when compared with controls.
Go Deeper: Check out these additional studies from the ITP to see how less common agents stack up:
- Evaluation of Resveratrol, Green Tea Extract, Curcumin, Oxaloacetic Acid, and Medium-Chain Triglyceride Oil on Life Span of Genetically Heterogeneous Mice
- Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α‐glucosidase inhibitor or a Nrf2‐inducer
Here is the full list of ITP publications.
Applying The Findings
When scientists test an agent or treatment in an intervention trial with controls and randomization, they enact the “gold standard” for research--a RCT. The results from the ITP trials are at this level and can help point to causality, giving scientists a better idea of which interventions are worth pursuing as strategies in human subjects.
For all these reasons the ITP is a unique barometer for surfacing the most effective compounds you could consider including in your longevity protocol. The ITP results also raise the level of scrutiny on compounds such as resveratrol which in the ITP showed no statistically significant impact on lifespan in two different cohorts. One unintended benefit of the ITP is that its results put the onus on the researchers and companies promoting these anti-aging compounds to replicate their claims at the same level of rigor.
Hear the full story of how the ITP was formed, how it operates and its most surprising findings in this fascinating conversation between Richard Miller and Peter Attia.
What compounds would you nominate for research by the ITP? Share with us your idea at firstname.lastname@example.org
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