Lifespan increases in mice when specific brain cells are activated, study finds

In recent years, research has begun to reveal that communication pathways between the body’s organs are key regulators of aging. When these lines are open, the body’s organs and systems work well together. But with age, communication lines deteriorate and organs no longer receive the molecular and electrical messages they need to function properly.

A new study from Washington University School of Medicine in St. Louis identifies a critical communication pathway in mice linking the brain and the body’s fatty tissues in a feedback loop that appears central to the production of energy throughout the body. Research suggests that the gradual deterioration of this feedback loop contributes to the increase in health problems typical of natural aging.

The study, published in the journal Cellular metabolism– has implications for the development of future interventions that could maintain the feedback loop longer and slow the effects of aging.

Researchers have identified a specific set of neurons in the brain’s hypothalamus that, when active, send signals to the body’s fatty tissues to release energy. Using genetic and molecular methods, researchers studied mice programmed so that this communication pathway was constantly open after reaching a certain age. The scientists found that these mice were more physically active, showed signs of delayed aging, and lived longer than mice in which this same communication pathway gradually slowed down as part of normal aging.

“We demonstrated a way to delay aging and extend healthy lifespan in mice by manipulating a significant portion of the brain,” said lead author Shin-ichiro Imai, MD, Ph.D., professor emeritus. Theodore and Bertha Bryan in Environmental Medicine and Professor in the Department of Developmental Biology at the University of Washington. “Showing this effect in a mammal is an important contribution to the field; previous work demonstrating lifespan extension has been carried out in less complex organisms, such as worms and fruit flies.”

These specific neurons, in a part of the brain called the dorsomedial hypothalamus, produce an important protein: Ppp1r17. When this protein is present in the nucleus, neurons are active and stimulate the sympathetic nervous system, which governs the body’s fight-or-flight response.

The fight-or-flight response is well known to have widespread effects throughout the body, including causing an increased heart rate and slowed digestion. As part of this response, researchers discovered that neurons in the hypothalamus trigger a chain of events that fire neurons that govern white adipose tissue – a type of fatty tissue – stored under the skin and in the abdominal region .

Activated adipose tissue releases fatty acids into the bloodstream that can be used to fuel physical activity. Activated adipose 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 essential for fueling the body and brain, but it slows down over time. With age, researchers have found that the Ppp1r17 protein tends to leave the nucleus of neurons, and when this happens, neurons in the hypothalamus send weaker signals.

With less use, the wiring of the nervous system through white adipose tissue gradually retracts and what was once a dense network of interconnected nerves becomes sparse. Adipose tissues no longer receive as many signals to release fatty acids and eNAMPT, leading to fat accumulation, weight gain, and less energy to fuel the brain and other tissues.

The researchers, including first author Kyohei Tokizane, Ph.D., a scientist and former postdoctoral researcher in Imai’s lab, found that when they used genetic methods in old mice to retain Ppp1r17 in the nucleus of neurons of the hypothalamus, the mice were more physically active – with increased wheel running – and lived longer than control mice. They also used a technique to directly activate these specific neurons in the hypothalamus of old mice, and observed similar anti-aging effects.

On average, the maximum lifespan of a typical laboratory mouse is about 900 to 1,000 days, or about 2.5 years. In this study, all control mice that had aged normally died by the age of 1,000 days. Those who underwent interventions aimed at maintaining the brain-adipose tissue feedback loop lived 60 to 70 days longer than control mice.

This results in an increase in service life of approximately 7%. In humans, a 7% increase over a 75-year lifespan translates to about five additional years. The mice receiving the interventions were also more active and appeared younger – with thicker, shinier coats – at older ages, also suggesting more weather and better health.

Imai and his team continue to look for ways to maintain the feedback loop between the hypothalamus and adipose tissue. One avenue they are investigating involves supplementing mice with eNAMPT, the enzyme produced by adipose tissue that returns to the brain and supplies the hypothalamus, among other tissues. When released from adipose tissue into the bloodstream, the enzyme is packaged into compartments called extracellular vesicles, which can be collected and isolated from the blood.

“We can consider a possible anti-aging therapy that would involve administering eNAMPT in different ways,” Imai said. “We have previously shown that delivering eNAMPT into extracellular vesicles increases cellular energy levels in the hypothalamus and extends the lifespan of mice. We look forward to continuing our work investigating ways to maintain this central feedback loop between the brain and the body’s fatty tissues in ways that we hope will prolong health and lifespan.