Clearing Senescent Cells from the Neural Stem Cell Niche Rapidly Improves Neurogenesis in Old Mice
Neurogenesis is the generation of new neurons in the brain, and their integration into existing neural circuits. It is essential to learning and recovery from injury. Neurogenesis is most studied in the hippocampus, connected to memory, and in mice. In humans the debate continues over the degree to which neurogenesis takes place in adult life, and where in the brain it does take place, but the pendulum leans towards this being a significant process over much of the life span. Importantly, neurogenesis appears to decline with age, while increasing neurogenesis produces benefits to cognitive function.
This context is why today's open research materials make for an interesting expansion of the known benefits of senolytic drugs. Senolytic therapies are those capable of selectively destroying senescent cells. Cells become senescent throughout life, usually upon reaching the Hayflick limit to cell replication, but also as a result of damage and stress. Senescent cells enter a state in which they cease replication and actively secrete pro-growth, pro-inflammation signals. The immune system clears senescent cells efficiently in youth, but with age and declining immune function these cells grow in number. Their secretions cause considerable harm to surrounding cell and tissue function. Removing these lingering senescent cells produces rapid rejuvenation in many tissue types. As today's paper illustrates, that includes a reversal of declining neurogenesis.
Old neurons can block neurogenesis in mice
In the new study, researchers tested 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. 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.
Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on central nervous system (CNS) neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs.
This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.