We all know that the brain's favorite source of energy is glucose. We also know the body will do anything to make sure the brain has adequate glucose, which serves a myriad of functions in the central nervous system. Can too much of a good thing become a bad thing? A recent Stanford Medicine study published in Nature a few days ago delves into the role of elevated glucose levels in neural stem cell inactivation.
Although it was initially believed that adult brains cannot undergo neurogenesis, the growth of new neurons, neural stem cells continue to produce neurons well into old age. This process, however, declines as we age, proving to be detrimental to preserving memory and recovering from neurological injuries such as strokes. Further, it seems likely that inactive neural stem cell populations contribute to neurodegenerative diseases like Alzheimer’s Disease or Parkinson’s Disease. Elevated glucose levels have been found around inactive neural stem cell populations, leading researchers to examine the link between elevated glucose and decreased neurogenesis.
Anne Brunet, PhD and her team used CRISPR to knock out a GLUT4 gene and observe its effects on living mice. What they found is nothing short of ground-breaking. By reducing glucose intake, they observed neurogenesis in relevant areas of the brain via activation and proliferation of neural stem cells. Their results even showed over a 2-fold increase in “newborn” neurons in old mice. Why is it significant that they used old mice and not young mice? It’s significant because it has a more direct clinical application in age-related neurodegenerative diseases. This is rightfully classified as a massive win for patients suffering from the detrimental and life-altering effects of these diseases. We can use this finding to inform development of genetic therapy drugs that can turn off glucose transporters in patients with neurodegenerative disease and thus promote neurogenesis, exemplifying the principle of beneficence. With the knowledge and resources, we have at our disposal, we are using them for the good of patients. We teeter on the cutting edge of scientific advancement that will hopefully create avenues for better clinical outcomes.
Ruetz, T.J., Pogson, A.N., Kashiwagi, C.M. et al. CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells. Nature (2024). https://doi.org/10.1038/s41586-024-07972-2
This is such a fascinating topic to write about! It is super cool that there was an increase in new neurons in old mice, especially because of the impacts it could have on clinical outcomes in patients with Alzheimer's and Dementia! It is also very interesting that there is increased glucose levels around the inactive neural stem cells. Did the researchers mention any further research they will be performing in the future? Or suggestions for further research on this? This seems like a very promising advancement with addressing neurodegenerative diseases!
ReplyDeleteHi Rylee, yes! They are already talking about further research involving glucose restriction as opposed to knocking out genes for glucose transport as a potential route for therapy that they want to explore. I am excited to see how this lab pursues this branch of research and have included a link to their lab page in case you are interested about their work, most of which is focused around the biology of aging.
Deletehttps://web.stanford.edu/group/brunet/
This study truly is fascinating and one step closer to understanding neurodegenerative diseases! What really interested me about this study was the fact that reducing glucose intake, a vital source of energy for our brain to function, actually helped promote neurogenesis?! One would think the opposite, right? This then led me to this study which says that dysfunctional metabolism of glucose disrupts the regular functioning of neurons, an occurrence commonly found in neurodegenerative diseases. The dysfunction also results in lower energy supply to the neurons. So how can decreasing glucose intake actually help promote neurogenesis if another root problem is a dysfunction in the metabolism of glucose? As your post said, "Elevated glucose levels have been found around inactive neural stem cell populations, leading researchers to examine the link between elevated glucose and decreased neurogenesis." So maybe this big increase in glucose levels is what causes the disfunction in metabolizing glucose as an older brain cant keep up with so much glucose. Thus, maybe reducing glucose intake prevents the progression of this metabolic disfunction and keeps glucose at the perfect level an older brain can handle.
ReplyDeleteHan, R., Liang, J., & Zhou, B. (2021). Glucose metabolic dysfunction in neurodegenerative diseases—new mechanistic insights and the potential of hypoxia as a prospective therapy targeting metabolic reprogramming. International Journal of Molecular Sciences, 22(11), 5887. https://doi.org/10.3390/ijms22115887
Hi Josh, I'm glad that this research article prompted you to delve into this topic further. I can imagine that any problems in this vital glucose pathway could result in the pathogenesis of neurodegenerative disease. And you bring up a very valid point about elevated glucose levels causing dysfunctional glucose metabolism. Thank you for including that article, I am excited to look into it!
DeleteI wonder what glucose is doing to the brain to make it not undergo neurogenesis with age, could glucose have unobserved properties on cell creation and regulation that we are unaware of yet? I think the best way to further this study would be to find exactly as to why taking out the GLUT4 gene promotes neurogenesis and then start clinical trials on more long-lived species. However it is always a question as to whether it would be ethical to prolong life and memory to such a degree since it could prolong suffering to those that have stable memory at old age but who are too weak to obtain enough stimulus in their day to day life.
ReplyDeleteHi Andrew, I agree with your idea to further the study. Under the section "Knocking out GLUT4 boosts neurogenesis" they state that they do not know the exact role of glucose metabolism in neural stem cells. They did also find that the gene responsible for GLUT 4 is upregulated in older mice, expressing more GLUT 4 transporters and thus increasing overall glucose intake. I'm curious to see where these insights lead the research team. You also bring up a great point about ethics and quality of life, specifically relating to the principle of non-maleficence. Can too much medical care actually hurt the patient? When does it become too much?
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