TORC1 inhibition enhances immune function and reduces infections in the elderly

Abstract

Inhibition of the mechanistic target of rapamycin (mTOR) protein kinase extends life span and ameliorates aging-related pathologies including declining immune function in model organisms. The objective of this phase 2a randomized, placebo-controlled clinical trial was to determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks. A low-dose combination of a catalytic (BEZ235) plus an allosteric (RAD001) mTOR inhibitor that selectively inhibits target of rapamycin complex 1 (TORC1) downstream of mTOR was safe and was associated with a significant ( = 0.001) decrease in the rate of infections reported by elderly subjects for a year after study drug initiation. In addition, we observed an up-regulation of antiviral gene expression and an improvement in the response to influenza vaccination in this treatment group. Thus, selective TORC1 inhibition has the potential to improve immune function and reduce infections in the elderly.

The clock is ticking: the impact of ageing on T cell metabolism

“…In two studies, low‐dose mTOR inhibitors were administered to elderly individuals for 6 weeks and prior to influenza vaccination. This led to a markedly fewer infections and a reduction in PD‐1 expression on circulating CD4 and CD8 T cells . It is not clear whether this is mediated by direct inhibition of mTOR in T cells, but this finding is supported by mouse and non‐human primate models.…”

“…Such interventions can be administered concurrently with vaccines to augment vaccine‐induced responses, but there was some concern that long‐term administration of mTOR inhibitors could inhibit infection‐induced responses . Reassuringly, a recent study suggests that extended treatment with rapamycin analogues provides anti‐ageing effects as well as enhanced protection against infections . This approach highlights that, during future development of interventions for age‐related T cell metabolic dysfunction, it will be important to define both direct and indirect impacts of interventions on the T cells themselves.…”

mTORC Inhibitors as Broad-Spectrum Therapeutics for Age-Related Diseases

“…Furthermore, a placebo-controlled, randomized, double-blind human clinical trial of over 200 elderly volunteers has shown similar results [110]. Volunteers were assigned to one of three regimes of the mTORC1 inhibitor RAD001 (everolimus—low: 0.5 mg daily or 5 mg weekly; high: 20 mg weekly) for a six-week period, followed by a two-week drug-free interval.…”

“…The studies of immunosenescence from Mannick et al [110,111] may provide critical insights into side effect profiles of low-dose mTOR inhibition in ageing humans. These studies showed that everolimus and BEZ235 were generally well tolerated, although with an increased incidence of mouth ulceration.…”

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

“…Moreover, rapamycin in mouse models has been shown to delay, or even reverse, the progression of multiple age-related pathologies including cardiac dysfunction, neurodegeneration, kidney disease and periodontitis (An et al, 2017; Dai et al, 2014; Shavlakadze et al, 2018; Tang et al, 2013). While there is evidence that rapamycin might improve some off-target age-related conditions in humans when provided as a short-term therapeutic (Kraig et al, 2018; Mannick et al, 2014; Mannick et al, 2018), it is unclear whether this may similarly delay aging in humans as in rodent subjects.…”