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

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.

Rapamycin treatment early in life reprograms aging: hyperfunction theory and clinical practice

“…However, this result should not be overgeneralized, as the result may depend on specific conditions, mouse strains and doses. In fact, this was challenged by additional experiments (rapamycin plus acarbose) by the same authors [43]. Also, adaptation to rapamycin may explain the result.…”

Deciphering the Timing and Impact of Life-extending Interventions: Temporal Efficacy Profiler Distinguishes Early, Midlife, and Senescence Phase Efficacies

“…Footnotes: # New Compounds that significantly affect mortality (i.e., not identified by the log-rank test) are also noted in bold font. $ PB125 is a mixture of luteolin, withaferin A, and carnosol, dosages refer to publication 23 . Interventions that significantly modified mortality hazard using the time-varying hazard analytic tool, which is ranked by the cessation age of beneficial effects in females.…”

“…Footnotes: # New Compounds that significantly affect mortality (i.e., not identified by the log-rank test) are also noted in bold font. $ PB125 is a mixture of luteolin, withaferin A, and carnosol, dosages refer to publication 23 .…”

The Gehan test identifies life-extending compounds overlooked by the log-rank test in the NIA Interventions Testing Program: Metformin, Enalapril, caffeic acid phenethyl ester, green tea extract, and 17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride

“…To determine the life-extending effect of a compound, the ITP uses the log-rank test, which assumes an effect on mortality hazard independent of age [2], combined with the Allison-Wang test to assess effects on maximum lifespan [3]. Using these tests, twelve of the forty-eight drugs tested, including notable examples like rapamycin and acarbose, have had positive impacts on lifespan [4][5][6][7][8][9][10][11][12][13][14][15][16].…”