In a new study published in Aging Cell, researchers have tested several individual drugs and a combination of rapamycin plus acarbose as potential life extension agents in genetically heterogeneous mice [1].
Anti-aging agent testing
Identification of successful anti-aging interventions is arguably one of the most challenging research problems to date. In addition to the complexity of aging, researchers have to deal with the biological heterogeneity of animals even within the same species and research reproducibility issues due to different experimental designs and approaches.
The National Institute on Aging Interventions Testing Program (ITP) was launched in 2004 with these limitations in mind. It is a peer-reviewed multi-institutional study evaluating potential lifespan-extending agents. The experiments are run in parallel at the Jackson Laboratory; the University of Michigan; and the University of Texas Health Science Center at San Antonio on genetically heterogeneous mice of both sexes.
Several promising anti-aging agents have been already identified and tested by the ITP, including aspirin, glycine, acarbose, and rapamycin, with varying effects depending on the sex of the animals. The lifespan extension potential of drug combinations is also being studied, such as metformin plus rapamycin, which has recently shown promising results.
In this study, the researchers tested a drug combination of rapamycin and acarbose, another anti-diabetic medication. Previously, a drug cocktail containing these agents along with phenylbutyrate was shown to delay aging when administered to 20-month-old mice. In addition, this study investigated the effect of six other drugs not tested before.
Rapamycin plus acarbose
First, the researchers evaluated the effect of the rapamycin and acarbose combination given to mice starting from the age of either 9 or 16 months. The former regimen was most successful, increasing the medium lifespan of female and male mice by 28% and 34%, respectively. The latter regimen increased the medium lifespan of both female and male mice by 13%.
Importantly, in males, the combination was more effective at extending lifespan than rapamycin only, while in females, the effect was similar between the combination-treated and rapamycin-treated animals. This is in line with the previous research showing limited benefits of acarbose treatment for female mice.
Individual drugs
Next, the researchers examined the life extension effects of six individual agents when given to mice starting at the age of 5 months: captopril (ACE inhibitor used to treat hypertension), 1,3-Butanediol (a ketone), leucine (an amino acid), PB125 (a mixture of rosemary extract, ashwagandha extract, and luteolin), sulindac (a non-steroidal anti-inflammatory drug), and syringaresinol (a component of the ginseng berry). Of all the agents, only captopril showed a beneficial effect, increasing the median lifespan in both females and males by 6% and 13%, respectively. When treated with 1,3-butanediol, a 2% lifespan increase was shown only in the female group.
Unexpected complications
Besides the pooled data from all the three experimental sites, the researchers analyzed site-specific effects of the treatments. Apart from the intersite differences in the lifespan extension effects of the agents, they noticed that a specific cohort of mice used as controls was unusually short-lived at one of the sites. The researchers hypothesize that the short lifespan of these control mice was caused by an unknown environmental factor.
Interestingly, the lifespan of the drug-treated mice of the same cohort at the same site was not reduced. This means that the controls and the drug-treated mice of this cohort differed not only in their experimental group assignment but also in being exposed to an unknown factor influencing their lifespan.
Therefore, the researchers decided to do an additional set of analyses only using the data from the other two sites to avoid making misleading conclusions. The results from these data were similar to the initial three-site analysis for the rapamycin and acarbose combination treatment, but they differed for captopril and 1,3-Butanediol, with a more modest or absent effect on lifespan.
Abstract
Mice bred in 2017 and entered into the C2017 cohort were tested for possible lifespan benefits of (R/S)-1,3-butanediol (BD), captopril (Capt), leucine (Leu), the Nrf2-activating botanical mixture PB125, sulindac, syringaresinol, or the combination of rapamycin and acarbose started at 9 or 16 months of age (RaAc9, RaAc16). In male mice, the combination of Rapa and Aca started at 9 months and led to a longer lifespan than in either of the two prior cohorts of mice treated with Rapa only, suggesting that this drug combination was more potent than either of its components used alone. In females, lifespan in mice receiving both drugs was neither higher nor lower than that seen previously in Rapa only, perhaps reflecting the limited survival benefits seen in prior cohorts of females receiving Aca alone. Capt led to a significant, though small (4% or 5%), increase in female lifespan. Capt also showed some possible benefits in male mice, but the interpretation was complicated by the unusually low survival of controls at one of the three test sites. BD seemed to produce a small (2%) increase in females, but only if the analysis included data from the site with unusually short-lived controls. None of the other 4 tested agents led to any lifespan benefit. The C2017 ITP dataset shows that combinations of anti-aging drugs may have effects that surpass the benefits produced by either drug used alone, and that additional studies of captopril, over a wider range of doses, are likely to be rewarding.
Conclusion
This multi-centered study provides several insights regarding promising anti-aging drugs. First, it supports a combination-based approach to address aging, at least for male mice. Second, it highlights the response differences to various agents and treatment regimens between sexes. Third, it demonstrated the absence of survival benefits of several previously untested compounds. Finally, the researchers show the results of analyzing pooled three-site data (based on the initial design) and two-site data (ad hoc), which helps identify consistent findings.
Literature
[1] Strong, R. et al. Lifespan benefits for the combination of rapamycin plus acarbose and for captopril in genetically heterogeneous mice. Aging Cell e13724 (2022)
