Senescent Cells Outside the Brain Contribute to Dysfunction in the Brain

While rising numbers of senescent cells in the brain, particularly microglia, are thought to contribute to age-related neurodegeneration, researchers here report on data that strongly suggests senescent cells in the rest of the body collectively produce a larger harmful effect. Two senolytic treatments, one that can readily access the brain, and one that cannot, produce quite similar outcomes in an animal study of neurodegeneration. We might add this data to other indications that senescent cell pro-inflammatory signaling is a body-wide phenomenon, and thus removing senescent cells locally will likely be insufficient to help patients.

We examine similar and differential effects of two senolytic treatments, ABT-263 and dasatinib + quercetin (D + Q), in preserving cognition, markers of peripheral senescence, and markers of brain aging thought to underlie cognitive decline. Male F344 rats were treated from 12 to 18 months of age with D + Q, ABT-263, or vehicle, and were compared to young (6 months). Both senolytic treatments rescued memory, preserved the blood-brain barrier (BBB) integrity, and prevented the age-related decline in hippocampal N-methyl-D-aspartate receptor (NMDAR) function associated with impaired cognition.

Compared to older controls, senolytic treatments decreased transcription of dentate gyrus genes linked to oxidative stress and immune response, and increased the expression of synaptic genes. However, D + Q had a greater effect on brain transcription categories associated with cellular senescence, decreasing expression of genes linked to apoptosis, regulation of apoptosis, and microglial activation that were not significant for ABT-263 treatment. Dissimilarities associated with brain transcription indicate divergence in central mechanisms, possibly due to differential brain access. Previous work indicates that dasatinib enters the central nervous system to clear senescent cells. In contrast, ABT-263 does not cross the BBB, which may explain differential effects.