Dr. Julie K. Andersen is a professor at the Buck Institute in Novato, CA. Her main research interests include the role of biological aging in Parkinson’s disease and the identification of novel therapeutic targets for the disease. She is a Fellow of the Society for Free Radical Biology and Medicine and has been the recipient of scholarly awards from the Glenn Research in Aging, Brookdale Institute on Aging, the World Congress on Parkinson’s disease and the National Parkinson’s Foundation.
Dr. Andersen is pursuing a wide array of leads toward treatments for complex disorders including Alzheimer’s and Parkinson’s disease. Recently, the laboratory has joined efforts with the Lithgow laboratory at the Buck institute as part of a collaborative project aimed at identifying novel drugs that eliminate neurotoxic protein deposits in patients diagnosed with these devastating disorders.
In a recent collaborative effort with the Campisi lab, the Andersen lab has shown that a process known as cellular senescence, previously associated primarily with aging in peripheral tissues, may also play an important role in age-related brain pathologies. The laboratory is working to identify novel ‘senolytics’, compounds which prevent age-related brain senescence, as a novel potential cure. The Andersen lab is also involved in identifying potential biomarkers for Parkinson’s that may allow early interventional therapy.
The following has been paraphrased from an interview with Dr. Julie K. Andersen on March 12th, 2018
(Click here for the full audio version)
The field seems to have agreed upon 9 hallmarks of aging, do you believe it is feasible for us to one day be able to treat all of them? If so, any guesses on what the timeline would be and do you believe that would bring an end to aging?
10 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.
When we talk about aging, the emphasis previously was on longevity or length of life, now most of the emphasis is on quality of life and the notion that we can live healthy lives that are relatively disease free. As we say here at the Buck Institute, it is about living longer, better lives.
Much of your work is in cellular senescence, 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 Parkinsonian 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, could you talk about where that is in development?
We were looking at a young-onset model of PD that has a mutation in the Parkin gene which marks damaged mitochondria (energy producers of the cell) for disposal. This disposal process is called autophagy, it uses lysosomes (recycling centers of the cell) to break down and dispose of damaged components in the cell. We fed these mice a compound called rapamycin, which is believed to boost autophagy, in the hope that it might lead to less dopamine cell loss in the mid-brain and better motor function, which turned out to be true.
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 and lysosomal function. This has now become a potential target for treating Parkinson’s and Alzheimers 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 and it does seem to lead to less cell loss and improved motor symptoms. We are now trying to move this forward to clinical trial.
Have you done any research into fasting to similarly boost autophagy? Is this something being looked at in neurodegenerative diseases?
When we observe animal models undergoing a fast cycle we do see more expression of TFEB so theoretically this could be a natural way to potentially boost autophagy. Though my concern in Parkinson’s would be that people already experience weight loss so any fast would have to be carefully monitored.
What is the state of research into lithium to treat neurodegeneration?
One of the effects of lithium is also to boost autophagy, but there are concerns that need to be looked at because it has off-target effects so patients need to be carefully monitored. We have found that giving low levels of lithium in mouse models does help treat some of the pathology and motor behavour associated with PD. However because lithium is something that you can buy over the counter it is difficult getting money to fund a clinical trial for it. Also, because it has multiple effects beyond just autophagy it makes it difficult to design a trial around it.
If everyone lived long enough, roughly when would ‘healthy’ people get Parkinson’s Disease?
That is very hard to answer because I think of PD as something that involves genetic susceptibility and environmental exposures as well as normal aging. With aging, everyone does lose those neurons, just at a slower rate than people with PD. It seems that if people lived longer than the rates of disease would go up, but we are learning more about the genetic components of the disease and that will hopefully lead to new therapeutic targets. These days I see things moving fairly rapidly so I have a lot of hope that the more we learn the more we will soon be able to get these therapies into the clinic.
Click here for more information on the work going on at Dr. Andersen’s lab at the Buck Institute and watch this lecture from Dr. Andersen to learn more about the connection between senescence and neurodegeneration.