© Roger Harris/Science
"It's a pretty stunning paper," says Charles Mobbs, a neuroendocrinologist at the Icahn School of Medicine at Mount Sinai in New York City. The new aging mechanism "is totally novel and quite unexpected," adds neuroendocrinologist Marianna Sadagurski of Wayne State University in Detroit, Michigan.
Tucked away deep in the brain, the hypothalamus monitors and maintains our blood concentration, our body temperature, and other physiological variables. Researchers have also suspected that it plays a role in aging. The hypothalamus becomes inflamed as we get older, and 4 years ago a team led by neurodendocrinologist Dongsheng Cai of Albert Einstein College of Medicine in New York City showed that quelling this inflammation delays physical deterioration and boosts life span in mice.
In the new study, the team turned its attention to the hypothalamus's stem cells, which in young animals divide to produce replacements for dead and damaged cells. As mice get older, the scientists found, the number of stem cells in the hypothalamus plunges. By later ages they are "basically all gone," Cai says.
To determine whether this loss promotes aging, researchers tried to speed up the process, genetically altering mice so that stem cells in the hypothalamus died when the animals were dosed with an antiviral drug. Knocking off some 70% of the cells shortened the mice's lives by about 8%, the team reports today in Nature. The mice's memory, coordination, and endurance also suffered. Behaviorally, they were like grumpy grandparents, less social and curious than youthful rodents. For example, when researchers put a new object into their cages, control mice spent about twice as long exploring it than did their modified counterparts.
Next, the team tried to reverse this deterioration by injecting stem cells into the hypothalami of middle-aged animals. Mice that received the stem cells outlived mice injected with a different type of brain cell by more than 10%, and they retained more of their physical and mental capabilities. In humans, the extra boost could mean a few more years of healthy life, Mobbs notes.
Researchers assume the loss of stem cells causes organs and tissues to wear out gradually because they can't replenish their lost cells. But because injecting stem cells into the mice produced benefits quickly, Cai and his colleagues concluded a faster-acting mechanism was at work.
Their suspicions fell on RNA molecules known as microRNAs, which stem cells manufacture and release. These microRNAs ferry messages to other cells, altering which proteins they produce. The researchers found that stem cells from the hypothalamus pump out huge amounts of microRNAs, packaged in tiny containers called exosomes. They also found that injecting mice with microRNA-rich exosomes isolated from cultures of young hypothalamus stem cells slowed the animals' physical and cognitive breakdown almost as much as injections of stem cells.
"The big question is how those microRNAs influence function," Mobbs says. The molecules could spur other cells to curb inflammation or stress, Cai says, though he isn't certain how they work. Where the microRNAs exert their effects is also a mystery. Their targets may be other cells in the brain or the spinal cord, but they might also slip into the bloodstream and prod cells elsewhere in the body.
The work suggests that protecting or replacing the hypothalamus's stem cells-or replicating the effects of the microRNAs-could slow aging in humans. It might also be possible to suppress the inflammation that provokes the stem cell die-off, Sadagurski says. She says some current drugs, including the diabetes treatment acarbose, curb inflammation in the hypothalamus and may be worth testing.
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