Fight Aging!

Researchers here describe a specific issue in the aging of metabolism connected to the activity of Ppp1r17 in the hypothalamus in the brain. This affects the sympathetic nervous system, leading to reduced innervation of fat tissue, which in turn negatively affects many tissues via altered availability of circulating nutrients, signal molecules, and the like. The researchers note a few points at which they can intervene to stop this decline, either Ppp1r17 in the brain, or the circulating molecule eNAMPT released by fat cells. The effect size on life span in mice is modest, and there is the remaining question of why this decline led by the hypothalamus starts to occur in the first place, but it is an interesting insight into one specific facet of the broader aging of metabolism.

Neurons in the dorsomedial hypothalamus, produce an important protein - Ppp1r17. When this protein is present in the nucleus, the neurons are active and stimulate the sympathetic nervous system. The neurons in the hypothalamus set off a chain of events that triggers neurons that govern white adipose tissue - a type of fat tissue - stored under the skin and in the abdominal area. The activated fat tissue releases fatty acids into the bloodstream that can be used to fuel physical activity. The activated fat tissue also releases another important protein - an enzyme called eNAMPT - which returns to the hypothalamus and allows the brain to produce fuel for its functions.

This feedback loop is critical for fueling the body and the brain, but it slows down over time. With age, the researchers found that the protein Ppp1r17 tends to leave the nucleus of the neurons, and when that happens, the neurons in the hypothalamus send weaker signals. With less use, the nervous system wiring throughout the white adipose tissue gradually retracts, and what was once a dense network of interconnecting nerves becomes sparse. The fat tissues no longer receive as many signals to release fatty acids and eNAMPT, which leads to fat accumulation, weight gain and less energy to fuel the brain and other tissues. When researchers used genetic methods in old mice to keep Ppp1r17 in the nucleus of the neurons in the hypothalamus, the mice were more physically active - with increased wheel-running - and lived 7% longer than control mice. They also used a technique to directly activate these specific neurons in the hypothalamus of old mice, and they observed similar anti-aging effects.

Researchers are continuing to investigate ways to maintain the feedback loop between the hypothalamus and the fat tissue. One route they are studying involves supplementing mice with eNAMPT, the enzyme produced by the fat tissue that returns to the brain and fuels the hypothalamus, among other tissues. When released by the fat tissue into the bloodstream, the enzyme is packaged inside compartments called extracellular vesicles, which can be collected and isolated from blood. "We can envision a possible anti-aging therapy that involves delivering eNAMPT in various ways. We already have shown that administering eNAMPT in extracellular vesicles increases cellular energy levels in the hypothalamus and extends life span in mice."

Link: https://medicine.wustl.edu/news/life-span-increases-in-mice-when-specific-brain-cells-are-activated/