ABOVE: A subset of neurons in the dorsomedial hypothalamus regulates the aging process in mice. © iStock, BlackJack3D

The brain is the body’s control center, with billions of neurons branching out in every direction to carry instructions to distant organs. These instructions tell muscles to contract, prompt the intestines to process digested food, and coordinate many other critical tasks. But the brain may also play an unexpected role in a universal phenomenon: aging.

Two mice with dark, shiny black fur alongside two mice with lighter, sparser fur.
At 25 months, mice with reduced PKG had shinier, thicker fur than unmodified elderly mice.
Kyohei Tokizane

In a study published in Cell Metabolism, researchers identified a subset of neurons in the brain that modulate not only aging, but also a slew of other metabolic processes.1 Using mouse models, the team showed that perturbing key genes in these neurons triggers a cascade of changes that start on the molecular scale and ultimately extend the mouse lifespan. Shin-Ichiro Imai, a developmental biologist at the Washington University School of Medicine and coauthor of this study, hopes that the findings will help scientists understand and intervene in human aging.

Aging is a complex multiorgan process. Imai first became interested in the brain’s contributions more than a decade ago, when he identified a population of sirtuin-expressing neurons in the dorsomedial hypothalamus (DMH) region of the brain, which regulates circadian rhythms and feeding, that was important for aging.“The brain must play a really important role in aging and longevity control in mammals,” Imai said.

In the current study, Imai’s team narrowed this key population down to a set of neurons expressing protein phosphatase 1 regulatory subunit 17 (Ppp1r17). The researchers didn’t know the function of this gene, but when they reduced its expression in the DMH neurons, they found that the mice became obese, less physically active, and less able to break down fat. When they looked closer, they saw that the neurons in the fat tissue had retracted and become less active.

“The significance lies in the realization that a neural population influencing both body weight and food intake also plays a crucial role in the aging process,” said Caner Çağlar, a molecular biologist at Bezmialem Vakıf University who was not involved in this study but has studied Ppp1r17 neurons’ role in eating behavior.3

While Ppp1r17 was interfering with the mouse metabolism, the scientists noticed that the molecule itself exhibited intriguing behavior. As mice grew older, Ppp1r17 moved from the nucleus to the cytoplasm of each cell. The researchers suspected that when Ppp1r17 moved to the cytoplasm, it stopped sending important longevity-promoting neuronal signals. This migration was controlled by another molecule called protein kinase G (PKG). When the researchers reduced PKG levels, they observed effects throughout the mice's bodies. Even for mice as old as 30 months (which some scientists equate with more than 70 human years), their fur didn’t gray, they maintained high levels of physical activity, and their tails remained free of typical age-related kinks and angles.4 The mice were also less likely to die, even at older ages, than their peers with normal Ppp1r17 activity.

The multifaceted effects of modulating Ppp1r17 in these neurons reflects their ability to coordinate the activities of many different organs, Imai said. Çağlar also noted that Ppp1r17 neurons signal to many different brain regions. “It would be more insightful to illustrate the specific impact of each of these projections on the aging process,” Çağlar said.

Imai's team also showed that chemogenetic activation of these neurons over the course of one to two years—independent of Ppp1r17 levels or location in the cells—had the same longevity-promoting effect, convincing him that this is the first example of neuronal control of aging in mammals. Scientists previously identified similar patterns in worms and flies, where modulating neurons that communicate with metabolic organs increased lifespans.5,6 But now, Imai is more confident that human aging also ties to this type of interorgan crosstalk. “Mice and humans are different, but I think it's very likely that we’ll see the same type of regulation in humans,” he said.

Imai is especially interested in a curious byproduct of Ppp1r17 neuronal activation: an increase in the number of small capsules in the blood containing the enzyme extracellular nicotinamide phosphoribosyltransferase (eNAMPT), which is involved in energy balance. These vesicles travel throughout the body and alter organ activity, often, improving their function and delaying their aging. “This is a really amazing interorgan communication system,” Imai said.

He and his team are now testing eNAMPT infusions as a treatment to counteract aging by restoring organ function. It’s still in the early phases of testing in mice and far from clinical trials in humans, but Imai is optimistic that the information will one day help people who are suffering from whole-body effects of aging.

References

  1. Tokizane K, et al. DMHPpp1r17 neurons regulate aging and lifespan in mice through hypothalamic-adipose inter-tissue communication. Cell Metab. 2024;36(2):377-392.
  2. Satoh A, et al. Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. Cell Metab. 2013;18(3):416-430.
  3. Caglar C, Friedman J. Restriction of food intake by PPP1R17-expressing neurons in the DMH. Proc Natl Acad Sci USA. 2021;118(13):e2100194118.
  4. Jackson SJ, et al. Does age matter? The impact of rodent age on study outcomes. Lab Anim. 2017; 51(2):160-169.
  5. Bishop NA, Guarente L. Two neurons mediate diet-restriction-induced longevity in C. elegans. Nature. 2007;447(7144):545-549.
  6. Hwangbo DS, et al. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature. 2004;429(6991):562-566.