Two popular senolytic compounds, dasatinib plus quercetin (D + Q) and ABT-263, similarly improve memory and positively rewire the brain in middle-aged rats.
The latest aging biology research has revealed that damaged cells called senescent cells accumulate with age and promote widespread inflammation, making them a hallmark of aging. This is why senolytics — therapies that selectively eliminate senescent cells — have become a promising new class of anti-aging compounds. Now, researchers from the University of Florida compare the effect of two well-studied senolytics on neuroplasticity and memory.
Budamagunta and colleagues compare D + Q, which can cross the blood-brain barrier (BBB), to ABT-263, which does not normally cross the BBB. In the journal Aging Cell, the researchers report that both senolytics improve the memory of middle-aged rats. These findings indicate that targeting senescent cells outside of the brain can improve brain aging, suggesting that the secretions of senescent cells are the larger problem.
The researchers divided middle-aged rats (12 months) into three groups. The D + Q group received 1.2 mg/kg of dasatinib and 12 mg/kg of quercetin (ADQ), the ABT-263 group received 12 mg/kg of ABT-263 (AA), and the third group received no senolytic treatment (AV). These three groups were compared to young rats (YNG).
Spatial memory was assessed using the gold standard of memory tests, the water maze. The water maze test showed that both D + Q and ABT-263 improved the learning and memory of middle-aged rats. Additionally, episodic memory — memories of previous experiences — was assessed using inhibitory avoidance.
For the inhibitory avoidance test, the rats were placed next to a dark chamber. Upon entering the dark chamber, the rats were afflicted with an electrical shock. The next day, the rats were again placed next to the dark chamber. It was found that over 38% of the rats from the untreated group re-entered the dark chamber while none of the young rats entered. In contrast, only about 10% of the senolytic-treated rats entered the chamber, suggesting improved memory of the painful shock. Futrmore, of the rats that re-entered, both senolytics reduced the time it took before re-entering.
Senescent cells secrete what are called SASP factors, which include inflammatory molecules. Sometimes referred to as the bystander effect, SASP factors spread senescence to neighboring cells. Furthermore, SASP factors that gain access to the bloodstream can act on distant organs like the brain. For example, senescent cells in the liver could cause inflammation in the brain.
To determine the levels of senescent cells in different organs, Budamagunta and colleagues measured mRNA for a gene called Cdkn2a, a widely-used marker for senescent cells that encodes for the cell-cycle arrest protein P16ink4a. They found an increase in Cdkn2a in the lung, liver, bone marrow, and spleen of untreated middle-aged rats. However, Cdkn2a mRNA was decreased in the senolytic-treated rats, suggesting both senolytics reduce senescent cells in these organs.
Age-related impairment in episodic memory is linked to a decline in the brain’s N-methyl-D-aspartate receptor (NMDAR). NMDAR influences the strength of synaptic connections between neurons and is associated with neuroplasticity. Therefore, Budamagunta and colleagues examined synaptic strength in middle-aged rats. They found that untreated rats exhibited decreased synaptic strength compared to the senolytic-treated rats, suggesting that both senolytics improve neuroplasticity, which could explain improved memory.
While both D + Q and ABT-263 improved learning and memory, and reduced senescent cells in multiple organs, gene analysis showed that D + Q prevented age-related increases in neuroinflammation genes better than ABT-263. This could be due to the inability of ABT-263 to cross the BBB and act on neurons within the brain. Notably, both senolytics showed a protective effect on the BBB, which was damaged in the untreated middle-aged rats.
While D + Q and ABT-263 are not often studied together in the same experiments, they have been compared previously. One study showed that D + Q, but not ABT-263 (Navitoclax) reversed the biological aging of brain organoids. The same study showed that D + Q, but not ABT-263 increased the lifespan of SARS-CoV-2-infected mice. In another study, D + Q, but not ABT-263 was shown to improve grip strength and physical performance in young mice transfused with old blood. Therefore, based on these studies directly comparing the two senolytics, it would seem that D + Q has more robust effects than ABT-263.
Model: Male Fischer rats (12 months)
Dose (oral): 1.2 mg/kg dasatinib + 12 mg/kg quercetin, or 12 mg/kg ABT-263