Long‐term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle‐aged marmosets

Abstract

Interventions to extend lifespan and improve health with increasing age would have significant impact on a growing aged population. There are now several pharmaceutical interventions that extend lifespan in laboratory rodent models with rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) being the most well studied. In this study, we report on the hematological effects on a cohort of middle-aged common marmosets (Callithrix jacchus) that were enrolled in a study to test the effects of daily rapamycin treatment on aging in this species. In addition, we assessed whether sex was a significant factor in either baseline assessment or as an interaction with rapamycin treatment. Among our cohort at baseline, we found few differences in either basic morphology or hematological markers of blood cell counts, metabolism or inflammation between male and female marmosets. After dosing with rapamycin, surprisingly we found trough blood concentrations of rapamycin were significantly lower in female compared to male marmosets. Despite this pharmacological difference, both sexes had only minor changes in cellular blood counts after 9 months of rapamycin. These data then suggest that the potential clinical hematological side effects of rapamycin are not likely outcomes of long-term rapamycin in relatively healthy, middle-aged marmosets.

Effect of rapamycin on aging and age-related diseases—past and future

“…Currently, there are ongoing studies on the effect of rapamycin on companion dogs (by Matt Kaeberlein and Daniel Promislow at the University of Washington) and the non-human primate, the common marmoset (by Adam Salmon at the University of Texas Health Science Center at San Antonio). Salmon’s group recently reported that 9 months of rapamycin treatment had minor effects on clinical laboratory markers (e.g., plasma levels of glucose, cholesterol, triglycerides, and C-reactive protein did not change significantly) in middle-aged male or female marmosets [ 114 ]. Therefore, we are at a point when the aging community should began seriously considering clinical trials to test the anti-aging properties of rapamycin in humans as has been argued by Kaeberlein and Galvan [ 115 ] and Blagosklonny [ 87 ].…”

The potential of rapalogs to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19

“…Indeed, no clinically significant adverse events were noted in either of the phase 2 mTOR inhibitor trials, 56,57 and there is growing evidence that low-dose rapalog monotherapy has minimal side-effects in healthy older adults. 64,65 These findings are further supported by the absence of observed side-effects in non-human primate marmosets 66 and in older companion dogs 67,68 treated with lower doses of rapamycin.…”

DNA methylation age analysis of rapamycin in common marmosets

“…Rapamycin (an inhibitor of mechanistic target of rapamycin, mTOR) is a promising anti-aging intervention because it has been observed to extend lifespan in laboratory rodent models. As a bridge towards clinical translation, we previously developed a cohort of aging marmosets at UT Health San Antonio (UTHSA) in which animals are treated daily with rapamycin with a primary aim of addressing the effect of this intervention on marmoset lifespan [ 38 ]. We have leveraged the existence of this cohort to address what effect rapamycin intervention has on the epigenetic clock.…”