Faulty communication between organs could make us old

Good news! The first article, a backgrounder, is very long, I did not read the entirety of it.

Are we getting closer to solve the riddle of aging! Are we coming closer to the proverbial fountain of youth?

"The tails were a clue. As some kinds of mice get old, their tails can stiffen and kink. But the aged rodents in the lab of molecular biologist Shin-Ichiro Imai at the Washington University School of Medicine in St. Louis sported tails that were limber and nearly straight. The genetically altered mice seemed to defy aging in other ways, too. They were more robust than control mice and spent more time scampering in their exercise wheels. Most dramatic, the animals lived about 7% longer than their normal counterparts, gaining an extra 58 days of life, Imai and colleagues reported earlier this year in Cell Metabolism.

The genetic modification the researchers had made boosted a key communication signal from the animals’ brain to their body. Thanks to the tweak, a specific group of neurons in the hypothalamus, a physiological control center deep in the brain, remained active as the animals got older. Imai’s team discovered that those neurons send signals to the animal’s fat stores via the sympathetic nervous system, a network of nerves carrying messages from the brain throughout the body. In response to the signal, the mouse fat burns lipids and secretes a long-distance signal known as NAMPT that forestalls aging-related damage in other parts of the body, including the hypothalamus itself.

The neurons that send the initial signal typically falter with age in mice ... “The bottom line,” he says, is that the fat stores “can’t get the proper stimulation,” and the animals accumulate fat, become sedentary, and produce less NAMPT. In other words, the communication breakdown promotes physical decline. Counteracting it seemed to keep the mice spry. ..."

From the highlights and abstract:

"Highlights

• DMHPpp1r17 neurons control WAT function, eNAMPT secretion, and physical activity

• Ppp1r17 is localized to cytoplasm by PKG with age, causing synaptic dysfunction

• DMH-specific Prkg1 knockdown counteracts aging and extends lifespan

• Chemogenetic activation of DMHPpp1r17 neurons delays aging and extends lifespan

Summary

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 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."

Faulty communication between organs could make us old | Science | AAAS

Life span increases in mice when specific brain cells are activated (original news release)

DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication (open access)

Graphical abstract

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 (left) becomes sparse (right).