A new study by a team of researchers, including Dr. Kirkland of Mayo Clinic, shows the effect of whole-body senolytic treatment on the health and function of the brain.
This follows up on previous Mayo Clinic research led by Dr. James Kirkland. That experiment treated mice with a combination of the cancer drug dasatinib and the dietary supplement quercetin, and the results suggested that this combination has a senolytic effect, meaning that it can destroy senescent cells.
To test if senolytics would have any influence on age-related cognitive decline, the researchers opted to work with INK-ATTAC mice, which are specially engineered to destroy populations of senescent cells (specifically p16Ink4a‐positive senescent cells) upon exposure to the drug AP20187. Having this chemical trigger to kill senescent cells allows researchers to reliably observe what happens when populations of senescent cells are destroyed.
Upon examining the hippocampi of young and old mice, they discovered there was an age-dependent increase in the numbers of p16Ink4a-expressing senescent cells, and microglia and oligodendrocyte progenitor cells were shown to have the highest p16Ink4a activity.
The researchers then treated the mice with either AP20187 or a combination of dasatinib and quercetin. They discovered that both forms of treatment decreased p16Ink4a-expressing microglial cells, resulting in reduced microglial activation and a reduction of the SASP, the cocktail of inflammatory signals secreted by senescent cells.
In addition, both treatments improved cognitive function in the aged mice.
Cellular senescence is characterized by an irreversible cell cycle arrest and a pro‐inflammatory senescence‐associated secretory phenotype (SASP), which is a major contributor to aging and age‐related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single‐nuclei and single‐cell RNA‐seq in the hippocampus from young and aged mice. We observed an age‐dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK‐ATTAC mice, in which p16Ink4a‐positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof‐of‐concept for senolytic interventions’ being a potential therapeutic avenue for alleviating age‐associated cognitive impairment.
These findings suggest that an effective senolytic treatment could improve brain health and reduce age-related cognitive decline. While this research was in mice, there are multiple senolytic drugs poised to enter human trials this year. Given that senescent cell accumulation is a likely reason why humans, mice and most other species age, there is reason to be optimistic that the benefits of removing these harmful cells may well translate to humans too.
2021 is primed to be an exciting year in aging research, especially given the number of therapies entering the clinic. We discuss some of the companies that we are watching closely this year here.