M(o)TOR of pseudo-hypoxic state in aging: rapamycin to the rescue.

ABSTRACT

A groundbreaking publication by Sinclair and coworkers has illuminated the pseudo-hypoxic state in aging and its reversibility. Remarkably, these data also fit the mTOR-centered model of aging. Here we discuss that the mTOR pathway can cause cellular pseudo-hypoxic state, manifested by HIF-1 expression and lactate production under normoxia. We found that rapamycin decreased HIF-1 and lactate levels in proliferating and senescent cells in vitro. This reduction was independent from mitochondrial respiration rapamycin decreased lactate production in normoxia, hypoxia, and in the presence of the OXPHOS inhibitor oligomycin. We suggest that pseudo-hypoxic state is not necessarily caused by mitochondrial dysfunction, but instead mitochondrial dysfunction may be secondary to mTOR-driven hyperfunctions. Clinical applications of rapamycin for reversing pseudo-hypoxic state and lactate acidosis are discussed.