HACKING AGING WITH COLD; HYPOTHALAMIC DMH<SUP>VGAT2</SUP> NEURON SILENCING REWIRES ENERGY METABOLISM IN THE AGED BRAIN

Aging is characterized by progressive changes in energy metabolism, impaired homeostasis, and disrupted survival signaling. Recent evidence suggests that hypothermia induced by exogenous cooling may revert age-related degeneration via involvement of a wide range of pathways, although lowering the body temperature causes multiple side effects which outweigh the hypothermia-mediated neuroprotection. Thermoregulatory mechanisms are governed by specific neuronal subpopulations and hypothalamic circuits that relay peripheral thermal cues. Considering the central regulation of hypothermia, we herein aimed to investigate the role of hypothermia induced by GABA-expressing dorsomedial hypothalamus (DMH^Vgat2) neuron silencing on modulating cellular energetics of aged mice. To do this, we intracranially administered rAAV-EF1a-DIO-hM4D(Gi)-mCherry (n=10) or rAAV-EF1a-DIO-mCherry (n=10) to the DMH of Vgat2-cre mice and chemogenetically silenced DMH^Vgat2 neurons of 18-month-old Vgat2-cre mice for 7 consecutive days. We further investigated the levels of key components of energy metabolism and detected high AMPK expression which is known to reduce in aging and subsequent increase in phosphorylation of Akt at Ser473 and GSK-3α/β at Ser21/Ser9 in hippocampus of aged brains (p<0.05). Our results suggest that AMPK serves as the key regulator of energy homeostasis to induce energy conservation in aged hippocampal neurons upon hypothermia induced by DMH^Vgat2 neuron silencing. Increased AMPK modulates activation of Akt, which then inactivates GSK-3α/β, to restore energy metabolism, induce cell survival, regulate autophagy and promote cellular growth. Hypothermia induced by inhibiting DMH^Vgat2 neurons may provide a potent target to restore energy metabolism and induce longevity not only in aging, but also in other neurodegenerative disorders.