An important part of the process of aging is a dysregulation of all of the finely tuned control and feedback systems that connect the different organs of the body. As one organ falters, there are indirect harmful effects on other organs. For example, distinct portions of the brain actively modulate the operation of metabolism elsewhere in the body in many different ways. The degenerative aging of brain tissue affects these communications, and that gives rise to issues outside the brain – just as aging of organs outside the brain can cause harm to the brain itself. Everything is connected.
Many studies have shown that longevity is regulated through cell non-autonomous signaling mechanisms by pathways originating in central nervous system neurons. These signaling pathways, which affect peripheral tissues, can significantly influence organismal health and longevity. Enhancement or suppression of these signaling pathways in central nervous system neurons leads to functional changes within the neurons (cell autonomous process) and transmits signals to the periphery to modulate its functions (cell non-autonomous process). For instance, in the nematode worm Caenorhabditis elegans, ASI amphid chemosensory neurons are important to maintain proper metabolic status, and possibly longevity. Ablation of ASI neurons completely suppresses the effect of lifespan extension induced by dietary restriction, suggesting that ASI neurons are required for the longevity effect of dietary restriction.
In the fly Drosophila melanogaster, neuronal activation of AMPK or Atg1, an autophagy-specific protein kinase, induces autophagy in the brain to slow aging and improves various parameters of healthspan. Drosophila insulin-like peptides are implicated in mediating the inter-tissue responses between the nervous system and the intestines. Furthermore, modifying mitochondrial function in neurons that influence aging and fly longevity also affects cells through cell non-autonomous mechanisms. A recent study demonstrated that the overexpression of hedgehog signaling, which is present in the glial cells of an adult fly, rescues proteostasis defects and the reduced lifespan in the glia of hedgehog mutant flies.
In mammals, increasing evidence highlights the role of the brain in the regulation of aging and longevity through cell non-autonomous signaling mechanisms. Specifically, the hypothalamus stands out as one of the most active regions involved in these signaling processes related to aging and longevity. In this review, we summarize the multiple signaling pathways in the hypothalamus that convey signals from the brain to peripheral organs and modulate aging and mammalian longevity. We describe how the structure and function of the hypothalamus are conserved across species and how these aspects are altered with age. Finally, we discuss some future perspectives on aging research that focus on the hypothalamus.
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