Why do we age? It’s a seemingly simple question that nonetheless scientists don’t have a great answer to. Some amount of aging seems to be controlled by our genetic makeup, while other evidence shows that our cells have an upper limit to how many times they can divide.
But a new study points to a different player: a special population of cells in a tiny region of the brain. Middle-aged mice that got an infusion of stem cells to the hypothalamus — the hormone-releasing center of the brain — had less memory loss and longer lives than normal mice, indicating that the hypothalamus plays a role in whole-body aging.
The findings open the tantalizing — though far off — possibility that these same changes could one day be slowed in humans.
“This is a really important study … in the field of aging research,” said Dr. Shin-Ichiro Imai, professor of developmental biology at Washington University in St. Louis, who was not involved in the study. “It’s getting clearer that a very tiny part of our brain — the hypothalamus — is playing a very important role in controlling age and longevity in mammals.”
The brain’s aging center
The main job of the hypothalamus has long been thought to be secreting hormones that govern our most basic desires: water, food, sleep, sex.
But in 2013, Imai and others came upon a surprising discovery: The hypothalamus plays a major role in controlling aging. Mice that lived longer also had unusually high levels of activity in their hypothalamus.
The finding led to an obvious follow-up question: How does it work?
The current study by Dongsheng Cai and colleagues at Albert Einstein College of Medicine provides an answer to that question: stem cells. Stem cells are found in certain regions of the adult brain, including the hypothalamus, where they replace cells that die off.
To determine the role of the stem cells, researchers did two parallel experiments: killing off hypothalamic stem cells in one group of middle-aged mice, and adding more stem cells to another.
Three months later, behavioral tests showed that mice with depleted stem cells had poorer memory, slower learning, and died sooner. The mice also had issues that went beyond their brains — like poor muscle endurance on a treadmill.
But those mice that got a boost to stem cells in the hypothalamus showed an opposite, rejuvenating effect. They were more curious, ran farther, and lived about 15 percent longer than normal mice.
But how exactly that was happening was still puzzling, since the effects were too quick to be the result of the stem cells transforming into new neurons. So Cai’s team tested the fluid around the stem cells, and found that the cells released tiny packets loaded with RNA, known as exosomes. So they isolated those exosomes and injected just those into a group of mice — and lo and behold, those mice also lived longer and showed better memory retention, indicating that some signal stem cells are releasing appears to be governing aging writ large. The results were published Wednesday in Nature.
A route to the clinic?
So, could such a finding point a way toward a human fountain of youth?
Grigori Enikolopov, professor of developmental genetics at Stony Brook University, said that they could — though any leap from mouse studies to human therapies comes with, “many, many disclaimers.”
Still, “if you take neural stem cells from a particular person … in principle, you could get them to secrete [exosomes], collect them, and introduce them back into the brain,” he said.
New methods make it possible for researchers to grow brain stem cells from a skin biopsy. Exosomes from these cells could then be administered to a patient. But Imai noted that it is unclear whether the exosomes could pass the blood-brain barrier — a barrier that protects the brain from infection, but also makes it difficult to get drugs into the brain. If the exosomes cross the barrier, scientists may be able to deliver them through a simple intravenous injection — instead of boring into the brain.
Cai’s group is now sifting through the dozens of RNAs released by hypothalamic stem cells to identify which have the strongest anti-aging effects. And they are also trying to figure out where these RNAs end up — in the hypothalamus, other parts of the brain, or far-flung regions of the body.
“[During] the next few years, we still want to understand the whole picture as completely as we can,” said Cai. “Then we can more seriously get to the therapeutic stage.”