Destroying senescent cells in the aging stem cell niche enhances hippocampal neurogenesis and cognitive function in mice, researchers report.
«Our results provide further support for the notion that excessive senescence is a driving factor behind aging, and even late-life reduction of these cells can rejuvenate and restore the function of the stem cell niche,» says senior author David Kaplan of The Hospital for Sick Children (SickKids) in Toronto, Canada. «Moreover, they identify stem cells as a key cellular target, potentially explaining the widespread effects of senescent cells on tissue decline.»
Senescent cells, which are permanently arrested because of chronic stress, are partly responsible for tissue decline during aging. Several studies indicate that senescent cells also play a negative role in age-related neurodegenerative disorders. But the cellular mechanisms responsible for tissue failure during aging are still not entirely clear.
Some research has pointed to stem cells as targets for aging and senescence-associated functional decline. The adult mammalian brain contains stem cells that continuously generate new neurons that are important for cognition. The generation of new neurons in the hippocampus declines rapidly with age, and this decline is associated with reduced stem cell activity. This raises the possibility that age-dependent senescent cell accumulation may deregulate neural stem cells and thereby negatively impact brain function.
«Stem cells last throughout life and, like us, are subjected to the ravages of aging, environmental stressors, and deterioration of the machinery that enables them to function optimally,» Kaplan explains. «To survive, many stem cells revert to a dormant, unresponsive, and inactive state. Our goal was to wake up these dormant cells and, in doing so, enable them to carry out their biological functions that facilitate learning, memory, and brain repair.»
In the new study, Kaplan teamed up with Freda Miller and Paul Frankland (@Franklandlab) of SickKids to test the idea that increased senescence within the neural stem cell niche negatively impacts adult neurogenesis, focusing on the middle-aged mouse brain. They observed an aging-dependent accumulation of senescent cells, largely senescent stem cells, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of the senescent cells via a drug called ABT-263 caused a rapid increase in normal stem cell proliferation and neurogenesis, and genetic ablation of senescent cells similarly activated hippocampal stem cells.
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