Old neurons can block neurogenesis in mice

Date:
January 20, 2022
Source:
Cell Press
Summary:
Destroying senescent cells in the aging stem cell niche enhances
hippocampal neurogenesis and cognitive function in mice, researchers
report.



FULL STORY ========================================================================== Destroying senescent cells in the aging stem cell niche enhances
hippocampal neurogenesis and cognitive function in mice, researchers
report January 20 in the journal Stem Cell Reports.


==========================================================================
"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.



==========================================================================
This burst of neurogenesis had long-term effects in middle-aged mice. One
month after treatment with ABT-263, adult-born hippocampal neurons
increased and hippocampus-dependent spatial memory was enhanced. "The
surprise for us is that only one injection of the drug was sufficient to mobilize the normal stem cells in the hippocampus, and it did so after
only 5 days," Kaplan says. "The newly awakened stem cells continued to
function well for the next 30 days." These results support the idea that
the aging-dependent accumulation of senescent cells, including senescent
stem cells in the hippocampal niche, negatively affects normal stem
cell function and adult neurogenesis, contributing to an aging-related
decline in hippocampus-dependent cognition.

Moreover, the results provide a potential explanation for the
previously observed age-related decreases in hippocampal stem cells and neurogenesis. A large proportion of stem cells becomes senescent, making
them unavailable to generate new neurons, and these senescent stem cells
likely adversely affect neurogenesis from their non-senescent neighbors.

"When we improve the neighborhood by getting rid of deleterious cells in
the stem cell niche, we begin to mobilize and wake up the dormant stem
cells, enabling them to generate new neurons for spatial learning and
memory," Kaplan says. "We think that it is the senescent stem cells we
removed that were responsible for improving the function of the normal non-senescent stem cells in the niche." While the findings implicate
the senescence of stem cells in age-related decline, the stem cells are
clearly not the only important cellular substrates for senescence in the nervous system. A potential role for cellular senescence in the brain
has been most widely studied within the context of neurodegenerative
disorders. In particular, senescent microglia, astrocytes, and
oligodendrocyte progenitor cells accumulate in the aged degenerating
human brain, and clearance of these senescent cells in mouse models
can ameliorate some of the adverse consequences of neurodegeneration
and obesity. But these studies focused on senescent microglia and glial
cells in neuropathological conditions rather than normal aging.

"In addition, most studies on waking up dormant stem cells have focused
on mobilizing the cells themselves," Kaplan says. "A key question when
we age, however, is whether it is something intrinsic in stem cells that
causes them to become dormant or if it is the environment that they reside
in that elicits this dormant state. It is well known that the stem cell
niche, or neighborhood, deteriorates with age. Waking up dormant stem
cells themselves may not be useful if, when they do so, their neighborhood
does not allow them to function optimally." According to the authors,
one study limitation was the use of middle-aged mice and not older mice
that might have more relevance to potential therapeutic strategies for
the loss of cognitive abilities in older adults. Nonetheless, the findings
may have implications for the treatment of age-related conditions.

"A remaining question is whether reducing the number of senescent
stem cells alone will improve normal stem cell function and cognition
or if removing other senescent cell types is also important," Kaplan
says. "While our conditions are more specific for removing senescent
stem cells, it is likely that treatments that reduce the amounts of all deleterious senescent cells in the brain will produce the best outcomes."
This work was supported by the Canadian Institutes of Health Research
and the Canada First Research Excellence Fund.

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========================================================================== Journal Reference:
1. Michael P. Fatt, Lina M. Tran, Gisella Vetere, Mekayla A. Storer,
Jaclin
V. Simonetta, Freda D. Miller, Paul W. Frankland, David R. Kaplan.

Restoration of hippocampal neural precursor function by ablation
of senescent cells in the aging stem cell niche. Stem Cell Reports,
2022; DOI: 10.1016/j.stemcr.2021.12.010 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220120125404.htm

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