Short-term fasting induces profound neuronal autophagy

TLDR

Autophagy disruption causes neurodegeneration, while up‑regulation is considered neuroprotective, yet the prevailing view is that food restriction does not induce brain autophagy despite its effect on other organs. The study aims to test whether short‑term fasting can induce neuronal autophagy by applying a novel in‑vivo autophagosome detection method. Using a validated in‑vivo imaging approach that identifies and characterizes autophagosomes, the authors quantified neuronal autophagy in cortical neurons and Purkinje cells, revealing a dramatic increase after short‑term fasting. Fasting markedly elevated autophagosome abundance and altered morphology, reduced phosphorylated S6 ribosomal protein in Purkinje cells, and was confirmed by electron microscopy, suggesting that intermittent fasting could safely enhance therapeutic neuronal autophagy.

Abstract

Disruption of autophagy—a key homeostatic process in which cytosolic components are degraded and recycled through lysosomes—can cause neurodegeneration in tissue culture and in vivo. Up-regulation of this pathway may be neuroprotective, and much effort is being invested in developing drugs that cross the blood brain barrier and increase neuronal autophagy. One well-recognized way of inducing autophagy is by food restriction, which up-regulates autophagy in many organs including the liver; but current dogma holds that the brain escapes this effect, perhaps because it is a metabolically-privileged site. Here, we have re-evaluated this tenet using a novel approach that allows us to detect, enumerate, and characterize autophagosomes in vivo. We first validate the approach by showing that it allows the identification and characterization of autophagosomes in the livers of food-restricted mice. We use the method to identify constitutive autophagosomes in cortical neurons and Purkinje cells, and we show that short-term fasting leads to a dramatic up-regulation in neuronal autophagy. The increased neuronal autophagy is revealed by changes in autophagosome abundance and characteristics, and by diminished neuronal mTOR activity in vivo, demonstrated by a reduction in levels of phosphorylated S6 ribosomal protein in Purkinje cells. The increased abundance of autophagosomes in Purkinje cells was confirmed using transmission electron microscopy. Our data lead us to speculate that sporadic fasting might represent a simple, safe and inexpensive means to promote this potentially-therapeutic neuronal response.