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.

Restoration of hippocampal neural precursor function by ablation of senescent cells in the aging stem cell niche

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.


so, if one were interested in self experimentation, it looks like the drug they used (ABT-263) can be easily attained here:

Anyone familiar with

Posted by: GREGORY S SCHULTE at January 27th, 2022 9:31 PM

At GS, have you ordered from them successfully without being forced to jump through hoops? My experience with research chemical companies is that most will do some searches to access the veracity of your research organization, e.g. they will not ship to a residential address.

This the compound Unity Biotech has been researching. Not sure of the extent of their rights to this compound.

Posted by: JohnD at January 27th, 2022 11:03 PM

@ Reason. Hi Reason and everybody.
I'm just wondering why some recent scientific breakthroughs were not publish on here?
I was excited to read about a pig heart transplant operation performed on 7 January 2022.
As I remember Reason published an article on this topic a few years ago.

Second breakthrough is regeneration of a frog leg.

I wanted to see these news on here in order to know your opinion about these scientific achievements. Are these topics still relevant to aging research?

Thank you


Posted by: Alek Ales at January 28th, 2022 4:21 AM

Hopefully we don't learn that senescent cells prevent cancer by using some sort of tip the scales Network effect.

Well I guess they would have seen this by now with all of this research?


Posted by: Matt at January 28th, 2022 5:26 AM

#1 Bassia arabica
As per earlier reports, Navitoclax (ABT263) has limited ability to cross the blood-brain barrier {PMID: 22071632 and PMID: 31222722}. So senescent cell "ablation" in the hippocampus by the direct action of ABT-263 is doubtful without much pharmacological evidence. However, ABT263 mediated systemic reduction of SASP factors with neuroregulatory functions is also a possibility that might indirectly help restore hippocampal neural precursor function.
#2 David R. Kaplan
ABT-263 has indeed been reported to be very inefficient at accumulating in brain tissue after peripheral injection. This is why we performed intraventricular injection of ABT-263, obtaining the same results as with peripheral injection, and confirmed our findings with the genetic p16-3MR senescent cell ablation model. Whether small amounts of ABT-263 can cross the BBB in sufficient amounts to ablate senescent neural precursors is not known, or if the ablation of senescent neural precursors following peripheral injection is due to direct or indirect effects of the drug. Please note that ABT-263 administered peripherally (by gavage) to ablate senescent CNS glia in a murine tau-dependent neurodegeneration model was published by Bussian et al., Nature 2018.

Posted by: Jones at February 3rd, 2022 4:00 AM
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