It’s easy to vilify body fat as just a layer of unwanted padding sitting silently beneath the skin. But these cells are surprisingly active. Beyond being storage containers for energy, they pump out a wide range of hormones that interact with multiple organs to control metabolism, immune responses, and even reproduction.
They could also regulate longevity with an unexpected partner: the brain.
A new study in mice found a “phone line” between fatty tissues and a group of neurons inside the hypothalamus—a region at the bottom of the brain that controls basic bodily functions such as temperature regulation and breathing.
When young, these neurons signal fatty tissues to release energy fueling the brain. With age, the line breaks down. Fat cells can no longer orchestrate their many roles, and neurons struggle to pass information along their networks.
Using genetic and chemical methods, the team found a marker for these neurons—a protein called Ppp1r17 (catchy, I know). Changing the protein’s behavior in aged mice with genetic engineering extended their life span by roughly seven percent. For an average 76-year life span in humans, the increase translates to over five years.
The treatment also altered the mice’s health. Mice love to run, but their vigor plummets with age. Reactivating the neurons in elderly mice revived their motivation, transforming them from couch potatoes into impressive joggers.
“We demonstrated a way to delay aging and extend healthy life spans in mice by manipulating an important part of the brain,” said study author Dr. Shin-ichiro Imai at Washington University.
The Brain-Body Internet
Longevity is complicated. Multiple factors influence how fast our tissues and organs age, such as genetic typos, inflammation, epigenetic changes, and metabolic problems.
But there is a throughline: Decades of work in multiple species have found that cutting calories and increasing exercise keeps multiple organ functions young as we age. Many of the benefits come from interactions between the brain and body.
The brain doesn’t exist in a vat. Although protected by a very selective barrier that only lets certain molecules in, neurons react to blood components which bypass the barrier to alter their functions—for example, retaining learning and memory functions in old age.
Recent studies have increasingly pinpointed multiple communication channels between the brain and muscles, skeleton, and liver. After exercise, for example, proteins released by the body alter brain functions, boosting learning and memory in aging mice and, in some cases, elderly humans. When these communication channels break down, it triggers health problems associated with aging and limits life span and health span (the number of healthy years).
The brain-body connection works both ways. Tucked deep in the base of the brain, the hypothalamus regulates myriad hormones to modify bodily functions. With its hormonal secretions, the brain region sends directions to a wide range of organs including the liver, muscle, intestines, and fatty tissue, changing their behavior with age.
Often dubbed the “control center of aging,” the hypothalamus has long been a target for longevity researchers.
Back in 2013, one team found that reprogramming immune responses in the brain region could increase life span. In the same year, Imai’s team found activating the brain region turned back the clock in elderly mice. Like younger peers, they exercised more, had a healthier metabolism, and maintained their body temperatures more easily in environments outside their usual comfort zone. They also slept better, and their brains sent faithful directions to their muscles, letting them parkour around their environments.
Yet a question gnawed at the team: Why did it work?
The new study hunted down neurons in the hypothalamus that link fatty tissues to the brain and longevity.
They first zeroed in on a subset of neurons within the hypothalamus from a pool previously known to regulate aging. These cells have a high level of a protein called Ppp1r17—basically, a marker differentiating them from all other cell types in the hypothalamus—and reach far across the brain and into the body.
The neurons “may signal to a specific tissue and regulate its function,” wrote the team. In other words, they could potentially establish a brain-body connection.
To test the theory, the team genetically eliminated Ppp1r17 in the hypothalamus of three-month-old mice—roughly the age of a teenager. Within two months, the critters blew up in size. They began feasting during sleep time and no longer felt the urge to run in their running wheel—a previous favorite pastime.
The changes caught the team’s eye. Reducing calories and exercise is known to increase health span in lab mice and perhaps in humans.
With molecular analysis, the team found that neurons with Ppp1r17 changed how fat cells behave. The protein floats around both the nucleus—the walnut-like structure that encapsulates our DNA—and other parts of the cell.
In young mice, it sits inside the nucleus and activates a nerve highway regulating fatty tissues. It directs fat cells to release energy stores during exercise, for example, and to pump out a protein that provides energy in the brain. With age, the entire loop breaks down. The protein drifts from the nucleus into other parts of the neuron, kneecapping communications with fat cells.
In an attempt to restore the system in aging mice, the team genetically altered a “shuttle” protein to transport Ppp1r17 back into the nucleus. This trick slowed the signs of aging.
Meanwhile, the mice’s fat cells were also rejuvenated. They readily pumped out a hormone critical to keeping the hypothalamus healthy. Rather than languishing on the couch, the mice opted for a run on their wheel. Compared to similarly aged peers, they had fluffy and shiny fur, a sign of youth and health.
The results suggest that moving Ppp1r17 back into the nucleus keeps a mouse healthy even in old age. And “remarkably,” wrote the team, the engineered mice lived longer than their littermates by roughly seven percent.
Using another technology that specifically kept the protein inside the nucleus, the team recapitulated the results. These elderly mice also ran like the wind, kept their fatty tissues in working order, and experienced increased life span compared to their peers.
The study is the latest to map highways between the body and brain in pursuit of longevity. The team is further exploring ways to optimize the fat-to-brain feedback loop as we grow older.