Transfusion of Plasma from Young Exercise mice ameliorates Aging-associated Cognitive Impairments on Learning and Memory through activation of Autophagy

Abstract

The brain’s cognitive skills gradually decline with aging. In old animals, damaged proteins accumulate in neurons since autophagy, a catabolic process responsible for organelle and protein degradation, decreases. Physical exercise is a known lifestyle factor that promotes learning and memory formation in the hippocampus. The beneficial effects of exercise are mediated through the induction of the brain derived neurotrophic factor (BDNF). Previous work identified that exercise promotes cognition by inducing autophagy. In this study, we report that voluntary exercise increases autophagic activity in the hippocampus of adult C57BL/6 mice. This increase in autophagy is correlated with enhanced spatial learning and memory formation in the Morris water maze. Inhibition of autophagy in adult exercise mice with chloroquine phosphate (CQ) during the behavioral test showed impaired learning and memory formation, as well as decreased BDNF levels in the hippocampus as compared to the control exercise group. Activation of BDNF signaling in mice treated with CQ did not rescue learning and memory deficits. Hence, our results suggest that BDNF signaling is upstream of autophagy in the hippocampus. The same exercise paradigm did not promote learning and memory formation in middle aged and old male mice. Interestingly, we show that systemic administration of adult exercise plasma into middle-aged mice rejuvenates learning and memory in an autophagy dependent manner. Our results are consistent with autophagy playing central roles in promoting exercise-induced effects on cognition. Among the plasma factors, we identified β-hydroxybutyrate, a liver-derived molecule, as an exercise-induced factor that promotes learning and memory in an autophagy-dependent manner. The results reveal the potential therapeutic benefits of plasma factors released in response to exercise in an autophagy dependent manner.