Interventions Testing Program Results for Rapamycin and Arcabose in Combination

The Interventions Testing Program (ITP) at the National Institute on Aging (NIA) performs rigorous, expensive assessments of the ability of various (usually pharmaceutical) interventions to slow aging in mice. Conducting a study with rigor in this context means the use of large numbers of mice spread across multiple facilities, with careful control of the environment in order to minimize both known and unknown confounding factors in life span studies. Most of the interventions tested over the past twenty years of the ITP, on the basis of earlier studies suggesting that they may slow aging, in fact fail to extend life in mice once put under this degree of scrutiny. This outcome says something about the difficulty of robustly determining whether or not any given approach actually slows aging to a great enough degree to be useful. We should be suspicious of any single study in mice.

Today's open access paper is an update from the ITP, outlining the results from some of their recent work. It is interesting to note that the ITP is starting, slowly, to test combinations of interventions. There is far too little work taking place in the scientific community when it comes to assessing combinations of treatments that impact aging. Yet since degenerative aging comprises many distinct, very different processes, any effective approach must necessarily combine different interventions targeting different mechanisms.

The ITP has not yet branched out from dietary supplements and pharmaceuticals to test many of what I would consider to be interesting approaches. There is the potentially senolytic fisetin (which showed no effect on mouse life span at the dose used), but beyond that, the portfolio of interventions tested consists of line items that we should not expect to have meaningfully large impacts on human life span. The best and most reliable of these interventions is rapamycin, which, like most other approaches shown to extend life in mice, mimics aspects of the metabolic response to calorie restriction. We know that calorie restriction, while producing benefits to health, certainly doesn't extend life span by anywhere near as much in humans as it does in mice.

Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice

Eight of the 35 agents tested by the ITP have significantly increased lifespan in one or both sexes. None has shortened lifespan. Five of the 8, that is, nordihydroguaiaretic acid (NDGA), aspirin, 17-α-estradiol (17E2), Protandim, and canagliflozin have increased lifespan only in males. None of the agents tested to date has increased lifespan only in females. Three agents led to significant lifespan increased in both sexes, but with varying degrees of sex-specificity. Glycine, for example, led to small but similar increases, significant in both sexes. Acarbose effects were more dramatic in males than in females at any of the three tested doses, and if started later in life, that is, at 20 months of age. Rapamycin, over a range of doses and at two starting ages, has had strong positive effects in both sexes, but at a given dose in chow typically leads to a larger percentage increase in female than in male mice, Five of the agents that increase lifespan (NDGA, aspirin, rapamycin, 17E2, and acarbose) have been re-examined in later cohorts with different dosages and treatment durations. Of these, only aspirin did not replicate, although it was only tested at higher doses.

The ITP has also begun to test combinations of lifespan-extending agents for potential additive effects. Metformin and rapamycin were tested in combination based on the hypothesis that the insulin-sensitizing action of metformin might compensate for the potentially deleterious insulin desensitizing effect of rapamycin and potentially different mechanisms of action of the two agents might have additive effects on survival. The results were not entirely clear-cut because in both sexes the combination of metformin and rapamycin led to a larger percentage benefit compared with simultaneous controls than had been seen in previous studies of rapamycin alone, but the benefit of the combination over rapamycin-only historical controls was not statistically significant. Here, we extend this strategy, testing rapamycin and acarbose in combination, starting at 9 or 16 months of age, based on a similar rationale to that used for the metformin/rapamycin trial.

In male mice, the combination of rapamycin and acarbose produced a larger absolute and percentage change in survival than that seen in mice that had, in previous years, received the same dose (14 ppm) of rapamycin alone. Rapamycin-treated males in the previous C2006 cohort lived, on average, 10% longer than simultaneous controls (average of values at each site), and in the previous C2009 cohort males lived an average of 5% longer than controls. The males in the current study dosed with rapamycin and acarbose lived 19% longer, more than twice the percent change seen in either of the two earlier studies.


What I found most interesting and least talked about in this latest ITP release, was the Leucine result. Nothing. Yes no life extension, but more importantly no lifespan reduction. Why is that interesting and important?
Leucine is always referred to as an anabolic amino acid, one that promotes IGF, suppresses MTOR etc. When those of us that use BCAA's or just Leucine mention it, some people interject that Leucine is potentially lifespan shortening.
As an older adult that uses BCAA's as part of my exercise supplement routine, I no longer fear that it's interfering with my longevity protocol.
Not all healthspan promoting protocols extend lifespan, which is fine…as long as they don't inhibit it.

Posted by: Jonathon Mills at October 10th, 2022 6:57 PM

Acarbose does not work by reducing sugar uptake (and thus downregulating Mtor, etc.) but by increasing undigested sugar in the intestines which increases butyrate and thereby influencing the gut microbiome and gut permeability. Which results in less inflammation/inflammaging.

You will find the studies if you google. It is common mistake aging researchers make for many plant compounds, for example; pine bark, red wine, grape seed extract, pomenegrate extract, etc. have similair working mechanism. Why? Because they evolved to resist digestion.


Posted by: JP at October 13th, 2022 7:30 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.