• Senescent neurons build up in the brain structure associated with learning and memory  – the hippocampus.
  • Senescent neuron accumulation in the hippocampus correlates with declining production of new brain cells (neurogenesis).
  • Injecting the senolytic agent navitoclax into aged mouse brains eliminates senescent neurons, improves neurogenesis, and revamps memory performance.

As we grow older, we typically experience a decline in our ability to learn and remember. We may forget where we placed our keys or find learning a new language difficult. For some of us, this deterioration of learning and memory will reach pathological levels, as older adults are often diagnosed with mild cognitive impairment (MCI), or worse, Alzheimer’s disease. To treat these age-related brain pathologies, researchers have repurposed the chemotherapeutic navitoclax to kill off aged neurons and possibly enhance brain performance.

Published in Stem Cell Reports, Kaplan and colleagues from the Hospital for Sick Children in Toronto, Canada found that by eliminating senescent neurons by injecting 50 ng of navitoclax into the brain of middle-aged mice, neurogenesis was improved. Moreover, ablating senescent neurons with navitoclax significantly improved hippocampus-dependent performance on a learning and spatial memory task.

“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 neurogenesis and function,” stated Kaplan and colleagues in their publication.

(Fatt et al., 2022 | Stem Cell Reports) The senolytic agent navitoclax revamps hippocampal neurogenesis and learning and memory in middle-aged mice. The top image shows the location of the mouse hippocampus with a line pointing to the dentate gyrus subgranular zone, where neurogenesis, paramount to spatial learning and memory, takes place. The bottom image on the left shows that without the navitoclax senolytic, precursor neuron (green cells) proliferation declines with age, along with neurogenesis and subsequent learning and memory. As shown in the bottom right image, navitoclax treatment enhances precursor neuron proliferation through neurogenesis to substantially enhance learning and memory.

Navitoclax Improves Spatial Learning and Memory

To see what effects navitoclax has on spatial memory in mice, Kaplan and colleagues tested hippocampus-dependent memory. Following navitoclax treatment, the researchers trained mice to find an underwater platform in a swim test called the Morris water maze. The platform was then removed and the amount of time the mice spent swimming in the previous location of the platform was used as a measure of spatial learning and memory. The researchers found that navitoclax-treated mice spent significantly more time in this target region than non-treated mice, indicating that navitoclax enhances hippocampus-dependent learning and memory.

(Fatt et al., 2022 | Stem Cell Reports) Treating middle-aged mice with navitoclax significantly enhances their ability to learn and remember spatial locations. The Morris water maze test, where mice learn the location of an underwater platform to take a break from swimming, showed that navitoclax (ABT263) enhanced spatial learning and memory. The graph shows that trained mice given navitoclax spent a markedly higher amount of time in the zone of the underwater platform compared to trained mice without navitoclax (Figure B). A visualization of the Morris water maze shows that navitoclax significantly increased the average number of visits to the underwater platform area compared to non-treated mice (Figure C). These results provide functional evidence that navitoclax improves learning and memory in middle-aged mice.

Age-Related Decline in Hippocampal Neurogenesis

To recapitulate that neurogenesis declines with age, Kaplan and colleagues measured the number of immature hippocampus neurons from young (6 weeks), adult (3 months), and middle-aged (12 months) mice. The researchers found that immature neurons decreased a remarkable 50% from young to adult and 90% from adult to middle age. These findings indicate that neurogenesis markedly diminishes as mice grow older.

(Fatt et al., 2022 | Stem Cell Reports) Neurogenesis dramatically declines in middle-aged mice as indicated by dramatic reductions in the number of newly produced, immature neurons. The immature-neuron label doublecortin (DCX) showed remarkably greater numbers of immature neurons in the dentate gyrus of the mouse hippocampus at six weeks of age compared to 12 months (A). Quantification of these immature neurons shows a dramatic reduction in neurogenesis with age (B).  

Chemotherapeutic Navitoclax Dramatically Enhances Neurogenesis

During aging, senescent cells accumulate throughout the brain and release inflammatory factors, which are thought to impair neurogenesis. Senescent cells are usually killed by the immune system, but with aging, the immune system can’t keep up. Senolytics, like navitoclax, are a class of drugs that can kill senescent cells and stop the spread of inflammatory factors. 

To determine the effect of eliminating senescent neurons on neurogenesis, the Canadian researchers treated mice with navitoclax. They found that treating adult mice increased immature neurons by about 50% in the hippocampus. What’s more, mature (fully differentiated) neurons increased by a whopping 48% after 30 days. These results demonstrate that treating adult mice with navitoclax dramatically revamps neurogenesis in adult mice.

To see whether these findings apply to older mice, Kaplan and colleagues treated the middle-aged mice. The researchers found that five days after treating the mice with navitoclax, senescent hippocampus cells diminished by about 40%. Moreover, navitoclax treatment induced an increase in neurogenesis, a colossal 2.6-fold  five days after treatment, as shown by a dramatic increase in the number of immature neurons. These findings show that not only does navitoclax recapitulate its neurogenesis-driving effects in older, middle-aged mice but that they are magnified in comparison to younger adult mice.

(Fatt et al., 2022 | Stem Cell Reports) Treating middle-aged mice with navitoclax significantly reduces senescent cell abundance and boosts neurogenesis 2.6-fold. As shown by the  senescence-associated β-galactosidase protein marker, senescent hippocampal neurons were reduced by about 40% with navitoclax (ABT263) treatment. (black dots, Figure A; quantification shown in the graph of Figure B). Immature neurons (DCX), an indicator of neurogenesis, increased a whopping 2.6-fold after five days of navitoclax treatment in 12-month-old mice. These results show that not only does navitoclax prune away dead neurons but that it dramatically improves neurogenesis.

“We show that ABT-263 [navitoclax] administration in middle-aged mice improves spatial learning and memory,” stated Kaplan and colleagues in their publication. This improvement in learning was correlated with reduced senescent cell buildup, which putatively inhibits neurogenesis, and subsequently enhances neuron production in aged mice. This finding suggests that navitoclax may be repurposed from use as a chemotherapeutic against cancer to a cognition-enhancing pharmaceutical to combat age-related cognitive decline.

Elucidating How Navitoclax Eliminates Senescent Cells

The exact cellular mechanism by which the age-related accumulation of senescent neurons and reduced neurogenesis occurs remains unexplained. Multiple potential explanations exist, such as senescent neurons excreting inflammatory factors termed the senescence-associated secretory phenotype (SASP). Other factors exerted by senescent brain cells on surrounding cells that abate neurogenesis may be cell stress, mitochondrial damage, and/or erosion of the ends of chromosomes (telomere decay). By eliminating these senescent cells, navitoclax may then allay such cell stressors. At any rate, once navitoclax has been shown to enhance cognition in aged mice, further research will be required to figure out whether this chemotherapeutic agent can be used in humans to combat age-related cognitive decline.

The findings presented in the study highlight that instead of treating individual, age-related diseases, research is becoming more geared toward treating processes of aging itself, like declining cognition. Utilizing senolytics like navitoclax, dasatinib, or quercetin may pave the way toward eliminating aged, non-proliferating senescent cells that lead to the deterioration of organs like the brain. In doing so, new brain cells can form, leading to brain tissue rejuvenation and ultimately, enhanced learning and memory, as demonstrated by the spatial memory experimentation in this study. Perhaps senolytics developed in the future will be able to ablate senescent cells throughout the body instead of eliminating these cells in a tissue-specific manner. At any rate, the future of treating aging as a disease looks bright, and the research presented here on the senolytic navitoclax may only be the tip of the iceberg for improving physiological function during aging.

Most Senolytics Currently Require a Prescription

Most senolytics, like navitoclax, require a prescription since many of them are currently listed as chemotherapeutic pharmaceuticals. However, one promising senolytic called quercetin is available as a supplement, and it has been shown in mouse models to increase lean muscle mass and even heal intervertebral discs as they deteriorate with age. Although quercetin is the only supplemental senolytic available, perhaps future studies showing the efficacy of senolytics against aging will pave the way to making them available over-the-counter.

What is Navitoclax?

Navitoclax, owned by the pharmaceutical company AbbVie, is an experimental drug designed for use against solid tumors. Clinical studies of navitoclax are currently in phase III trials, meaning that the safety and efficacy phases of testing are mostly complete and a confirmation of its clinical effects against cancer need further testing.

The clinical studies for Navitoclax started in 2009 and current trials of the drug will continue for at least a few more years. Once clinical trials are completed, it typically takes the FDA six to 12 months to approve a drug, so navitoclax may not receive approval for another two to four years.

Navitoclax is mostly considered well-tolerated; however, some patients who take the drug experience diarrhea, vomiting, nausea and fatigue. Navitoclax also presents affordability issues for many patients as a typical 50 g dose of the drug costs nearly $280. Given the potential side effects of navitoclax with its cost, substantial clinical testing on its benefits against age-related cognitive impairment would take at least another 10 years.