Age may not be a state of mind, but the brain is definitely involved. That's the conclusion of a study published on Wednesday in the journal Nature, which provides compelling evidence that a specific structure in the brain, called the hypothalamus, plays a significant role in controlling the entire body's aging. The results suggest stem cells play a critical role, but only in part via their ability to generate new neurons.

The results come from researchers at the Bronx's Albert Einstein College of Medicine. They, along with several other labs, have generated evidence that suggests the hypothalamus plays a key role in aging. That makes a certain amount of sense: aging is a systemic process, and the hypothalamus contains structures like the pituitary that release hormones that influence the entire body. And there have already been some indications that factors that control the dynamics of aging end up circulating through the blood.

Aging and stem cells

But what controls the timing of aging? One intriguing possibility is that neural stem cells are involved. These stem cells continue to divide and produce new neurons even after the brain is fully developed, but their numbers appear to go down over time (possibly because more of them produce new neurons than are replaced by cell divisions). If the key factors are produced by neural stem cells, then their levels should go down over time, allowing aging to proceed.

A number of labs have recently identified neural stem cells in the hypothalamus, so the researchers decided to take a look at those in mice. They found a suggestive correlation: as mice age, the number of stem cells in the area tends to decline. By the time mice were what we'd consider old, the stem cells were pretty much gone. But this didn't tell us whether the loss of stem cells contributes to aging or whether aging causes the stem cells to go away.

So, the researchers decided to kill them early. The stem cells lined the surface of a small, open chamber, and the researchers injected a virus into that chamber so that it primarily infected these cells. The virus was engineered to make the cells sensitive to a chemical that's non-toxic to most cells; injection of this chemical would then kill the stem cells. The researchers determined they could kill 70 percent of the stem cells in the hypothalamus with this technique.

And, when those stem cells were gone, the mice seemed to age faster: their muscles tended to tire out earlier, their coordination got worse, they became less social, and they didn't respond as strongly to new experiences. On average, their lives ended about 10 percent sooner. Clearly, 10 percent isn't the entire aging process, but the effects were definitely significant.

The researchers then confirmed this by killing off the same cells using a different method. That worked, too, showing it wasn't anything unusual about the virus. And they placed non-neural stem cells into the brain and confirmed that these didn't have the same effect.

It’s not what you are, it’s what you do

The obvious explanation for this would be that the stem cells were replacing a critical population of neurons. But the timing was all wrong. The turnover of neural cells is very slow, while the effects of these experiments could be seen after just a couple of months. So, the researchers suspected the stem cells themselves were making something that inhibits the aging process.

To search for that, they looked at things called "exosomes," which are bundles of proteins and RNA that are packaged and shipped outside of cells. They blocked a gene that's needed to get the exosomes out of cells and found that signs of aging accelerated a bit, but not to the same extent as when they eliminated the stem cells entirely. If they killed the stem cells and injected these exosomes back into the brain, they slowed down the accelerated aging a bit.

These results are strongly suggestive that stem cells in the hypothalamus play a key role in modulating the aging process. But we should recognize that many other things—from diet to hormones that circulate in the blood to the metabolism of individual cells—also seem to play roles in modulating the aging process. So, while figuring out more precisely what these cells are doing, the end result from that won't be a formula for youth. It'll just be one part of the picture.

Nature, 2017. DOI: 10.1038/nature23282 (About DOIs).