This short, interesting interview is with one of the Buck Institute neuroscience researchers with an interest in cellular senescence as a component of degenerative aging. Exhibited here is perhaps the most optimism that I recall seeing in public comments from any of the Buck Institute faculty - but if I were involved in cellular senescence research, I'd be fairly optimistic as well. This part of the field is progressing rapidly, producing solid evidence of the association of cellular senescence with the development of age-related disease, and of the benefits that can be obtained by removing these unwanted cells.
The field seems to have agreed upon nine hallmarks of aging, do you believe it is feasible for us to one day be able to treat all of them?
Ten years ago I would have wondered how feasible this was, but based on the progress that has been made in the last few years I do think it is plausible that we will be able to address each of those pillars of aging and that by addressing these underlying mechanisms that drive aging we are going to be able to treat age-related disease. I think we have a tendency to view age-related diseases in silos but many of these disorders have a lot in common. I think we are on the brink of solutions to these problems, not in the next decades, but within years.
Could you briefly describe senescence and its impact on neurodegenerative diseases?
Senescence is a process in cells that stops cells from dividing, it gets activated when certain types of damage occurs. From an evolutionary perspective, cellular senescence is there to prevent damaged cells from undergoing the kind of rapid division that leads to tumors. This is great in the short term, but if they persist they give off toxic pro-inflammatory factors which can damage neighboring tissues. A lot of research in the field goes into understanding this process and what we can do to prevent this toxic effect.
For a long time the field of neuroscience ignored senescence because everyone just looked at the neurons, which don't divide. However we also started looking at the other cell types in the brain that do divide, namely astrocytes. They are a major support cell in the brain that also secrete growth factors that help neurons grow and communicate, they are also much more abundant than neurons. We then discovered that these cells do undergo senescence by looking at post-mortem tissue from Parkinson's disease brains and found astrocytes that had become senescent. We showed in animal models that if we could remove aggregations of these cells we could slow some of the disease process. This is very exciting because it means we can push this strategy forward into human clinical trials as it is a possible therapeutic strategy that has not been explored before. We were one of the first labs to look into this but now a lot of other labs around the world are jumping into cellular senescence to try and tackle age-related disorders.
You also explore the protein TFEB to boost lysosomal function and autophagy?
We were looking at a young-onset model of Parkinson's disease that has a mutation in the Parkin gene which marks damaged mitochondria for disposal via autophagy. We then learned that one of the major factors in that process is this transcription factor called TFEB, which is a master regulator of autophagy. This has now become a potential target for treating Parkinson's and Alzheimer's because these diseases are the result of protein build ups and dysfunctional mitochondria. It is thought that if we boost TFEB then cells will be able to better dispose of these protein build ups. We screened a number of compounds that boosts TFEB in the brains of these animals are now trying to move this forward to clinical trial.