Metabolism is regulated by regions of the brain, as well as by other tissues, and alterations to metabolism can affect the pace of aging. The hypothalamus has been identified as one of the brain regions relevant to aging in this way. In recent years, researchers have managed to tie more specific aspects of the aging of the hypothalamus to age-related changes elsewhere in the body. For example, loss of neural stem cells and the signaling that they produce appears to induce dysfunction and accelerated aging. Along similar lines, researchers here find another population of neurons in the hypothalamus that quite indirectly improve energy metabolism and thereby slow the pace of aging.
Recent studies have shown that the hypothalamus functions as a control center of aging in mammals that counteracts age-associated physiological decline through inter-tissue communications. We have identified a key neuronal subpopulation in the dorsomedial hypothalamus (DMH), marked by Ppp1r17 expression (DMHPpp1r17 neurons), that regulates aging and longevity in mice. DMHPpp1r17 neurons regulate physical activity and white adipose tissue (WAT) function, including the secretion of extracellular nicotinamide phosphoribosyltransferase (eNAMPT), through sympathetic nervous stimulation.
Within DMHPpp1r17 neurons, the phosphorylation and subsequent nuclear-cytoplasmic translocation of Ppp1r17, regulated by cGMP-dependent protein kinase G (PKG; Prkg1), affect gene expression regulating synaptic function, causing synaptic transmission dysfunction and impaired WAT function. Both DMH-specific Prkg1 knockdown, which suppresses age-associated Ppp1r17 translocation, and the chemogenetic activation of DMHPpp1r17 neurons significantly ameliorate age-associated dysfunction in WAT, increase physical activity, and extend lifespan. Thus, these findings clearly demonstrate the importance of the inter-tissue communication between the hypothalamus and WAT in mammalian aging and longevity control.
Link: https://doi.org/10.1...met.2023.12.011
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