Over-the-hill cells may cause trouble in the aging brain

Killing senescent cells in the noggins of mice prevented memory loss

tau tangles in a nerve cell illustration

TANGLED UP  Senescent brain cells that no longer do their jobs properly may have a hand in creating tangles of tau (illustrated in blue inside a nerve cell) and, ultimately, dementia, a mouse study suggests.

UT Southwestern

Cells past their prime may have a role in dementia. Culling these cells protected the brains of mice that were otherwise destined for brain decline, a new study finds.

Senescent cells, which accumulate with age, are still alive but in a state of suspended animation — they stop doing their jobs and they stop dividing. Getting rid of these cells in the body extends the life spans of mice and improves their heart and kidney health, scientists have found (SN: 3/5/16, p. 8). The new research, published online September 19 in Nature, suggests that senescent cells also make mischief in the aging brain.

Molecular biologist Darren Baker of the Mayo Clinic in Rochester, Minn., and colleagues studied mice with mutations that led nerve cells in their brains to accumulate a toxic form of the protein tau. Damaging globs of this protein, called neurofibrillary tangles, are a hallmark of Alzheimer’s disease and other dementias.

In some of these mice, Baker and colleagues also engineered in a genetic trick — a “kill switch” that destroys cells as soon as they become senescent. In mutated mice with this switch, tau didn’t accumulate as fast. What’s more, these mice were better able to recognize new smells and objects than mice with more senescent cells in their brains. An anticancer drug called navitoclax that targets senescent cells also had protective effects in these mutated mice’s brains.  

two images of the brains of 8-month-old mice
CLUMPS BEGONE In the brains of 8-month-old mice designed to accumulate tau, senescent cells prodded the protein to clump (green, left). Tau tangles were sparser in the brains of mice with fewer senescent cells (right). T.J. Bussian et al/Nature 2018
Specifically, the senescent troublemakers in mice were glial cells — support cells that help nerve cells do their jobs. The researchers suspect that neurons in trouble, such as those with toxic tau, may prod glial cells to become senescent, and once senescent, those glial cells damage nerve cells by causing even more tau to accumulate. “It’s a back-and-forth kind of system,” Baker says.

The results are early evidence that senescent cells in the brain may have a role in aging, says neuroscientist Mark Mattson of the National Institute on Aging in Baltimore. But “there are a lot of open questions that are unanswered by this study,” he says, such as what signals cause glial cells to become senescent, and how those senescent cells harm nerve cells.

Baker and his colleagues plan to study whether destroying senescent cells in animals that already have signs of disease can slow or even reverse brain damage.

Laura Sanders is the neuroscience writer. She holds a Ph.D. in molecular biology from the University of Southern California.

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