In vivo studies headed by researchers at the Hospital for Sick Children (SickKids), Toronto, have demonstrated that destroying senescent cells in the aging stem cell niche enhances hippocampal neurogenesis and cognitive function in mice. “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,” said David Kaplan, PhD, senior scientist at SickKids. “Moreover, they identify stem cells as a key cellular target, potentially explaining the widespread effects of senescent cells on tissue decline.”
Kaplan, and colleagues at SickKids, together with researchers at the University of Toronto, and the University of British Columbia, describe their results in Stem Cell Reports, in a paper titled, “Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche,” in which they concluded, “Collectively, these results indicate that senescent cells directly contribute to neurogenic decline in the middle-aged hippocampus, and that clearance of these cells can partially restore hippocampal neurogenesis and function.”
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, the authors wrote. “ … senescent cells accumulate in the degenerating human brain, and clearance of these senescent cells in mouse models of neurodegeneration and obesity ameliorates some adverse sequelae.” However, 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. “Notably, in the hematopoietic system, stem cells are key targets for senescence-associated functional decline, suggesting that senescence of neural precursor cells (NPCs) and/or their surrounding niche cells may also negatively affect aging brain function,” the team commented. 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.
For the new study, focused on the middle-aged mouse brain, Kaplan teamed up with Freda Miller, PhD, a cell and molecular developmental neurobiologist, and Paul Frankland, PhD, senior scientist, both at SickKids, to test the idea that increased senescence within the neural stem cell niche negatively impacts adult neurogenesis. “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 explained. “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.”
The researchers observed an aging-dependent accumulation of senescent cells, largely senescent stem cells, within the hippocampal stem cell niche, coincident with declining adult neurogenesis. Importantly, they showed that pharmacological ablation of the senescent cells using a drug called ABT-263 caused a rapid increase in normal stem cell proliferation and neurogenesis, while genetic ablation of senescent cells similarly activated hippocampal stem cells.
“This acute burst of neurogenesis had long-term effects in middle-aged mice,” the authors noted. 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 five days,” Kaplan said. “The newly awakened stem cells continued to function well for the next 30 days.”
The study 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. The authors commented, “Notably, we show that a substantive proportion of NPCs become senescent, thereby making them unavailable to generate new neurons, and that these senescent NPCs likely adversely affect neurogenesis from their non-senescent neighbors. Thus, our findings establish senescence, including NPC senescence, as one potential cause of neurogenic decline during aging.”
“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 pointed out. “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 added. “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.
“Safe-in-human senolytics such as ABT-263 (Navitoclax), developed for the treatment of cancer, are therefore promising therapeutic agents to treat aging-associated conditions, with several in clinical trials to ablate senescent cells in osteoarthritis, diabetes complications, idiopathic pulmonary fibrosis, and chronic kidney disease. Our findings suggest that senolytics may also be considered for age-related cognitive decline.”
“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 stated. “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.”