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Written by Thanmay Kumar ‘27
Edited by Matthew Lam ‘27
What if the key to solving age-related cognitive decline lies within our own DNA? In a revolutionary 2024 study, researchers at Stanford University may have uncovered part of this secret and their research may help unlock a future in which memory loss, Alzheimer’s disease, and other neurodegenerative diseases are not just treatable, but completely preventable [2].
In the early stages of life, the brain is constantly changing as neurogenesis—the formation and development of new neurons—occurs rapidly throughout the brain. However, as we begin to age, our brain’s ability to generate new neurons declines rapidly, potentially contributing to various forms of cognitive decline [3].
Decreased neurogenesis is implicated in a wide range of negative health outcomes for adults, including depression-like symptoms, anxiety, obesity, and a host of disorders including Alzheimer’s disease and certain forms of epilepsy.
The groundbreaking study, published in the journal Nature, explores ways to reverse this decline. The scientists started their research by using CRISPR-Cas9 technology to systematically disrupt a wide range of over 2,300 genes in aged mice. The researcher then measured the growth of each population of aged neuronal stem cells to isolate the effects that each ‘knockout’ gene had on cellular replication [4]. Through their measurements, they could identify roughly 300 genes that were linked to changes in the neurogenesis of the adult stem cells [5].
One of the genes producing the largest change in neurogenesis was a gene called SLC2a4, a DNA segment that encoded a glucose transporter protein [2]. The protein, GLUT4, helps transport glucose across the cell membrane and is released when insulin is present [6]. Glucose uptake is critical for energy production in the stem cells and often changes dramatically as stem cells age. By using CRISPR to knockout SLC2a4, the researchers were able to reduce glucose uptake in the aging stem cells which paradoxically increased their replication, effectively revitalizing their proliferation to resemble that of their younger selves [5].
The dramatic increase in glucose metabolism had cascading effects throughout the stem cells. Old neuronal stem cells, which typically struggle to survive, started behaving more like their younger counterparts: growing and dividing at a prodigious rate. Furthermore, this change did not impact the replication of younger stem cells which suggests that targeting glucose metabolism is a mechanism for therapies to selectively target age-related cognitive impairments [2].
These results have profound implications for the development of therapies to combat diseases associated with age-related cognitive decline, including Alzheimer’s and Parkinson’s. By enhancing the brain’s resilience to aging, treatments could not only preserve cognition at later stages of life, but may extend life expectancy as well [4].
The findings from the paper also open the door for further exciting research into the underlying mechanisms for cognitive decline. A greater understanding of genes that play a role in slowing metabolism and neurogenesis may help provide alternative routes for future treatments of age-related cognitive disorders. Additionally, the research paves the way for behavioral interventions, such as low-carbohydrate diets, for enhanced neurogenesis and cognitive resilience [7].
The future of cognitive resilience is not only a distant dream, it’s a science that is rapidly becoming a reality.
References
Verywell Health [Internet]. [cited 2024 Nov]. Types of Neurons: Parts, Structure, and Function. Available from: https://www.verywellhealth.com/types-of-neurons-5201172
Ruetz TJ, Pogson AN, Kashiwagi CM, Gagnon SD, Morton B, Sun ED, et al. CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells. Nature. 2024 Oct;634(8036):1150–9.
Sorrells SF, Paredes MF, Cebrian-Silla A, Sandoval K, Qi D, Kelley KW, et al. Human hippocampal neurogenesis drops sharply in children to undetectable levels in adults. Nature. 2018 Mar;555(7696):377–81.
Slack G. News Center. 2023 [cited 2024 Nov]. Stanford Medicine study hints at ways to generate new neurons in old brains. Available from: http://med.stanford.edu/news/all-news/2024/10/study-generating-neurons.html
Ledford H. CRISPR helps brain stem cells regain youth in mice. Nature [Internet]. 2024 Oct 2 [cited 2024 Nov]; Available from: https://www.nature.com/articles/d41586-024-03177-9
Vargas E, Podder V, Carrillo Sepulveda MA. Physiology, Glucose Transporter Type 4. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 [cited 2024 Nov]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK537322/
Kim L. Targeting Glucose May Spark Neurogenesis [Internet]. Neuroscience News. 2024 [cited 2024 Nov]. Available from: https://neurosciencenews.com/glut4-genetics-neurogenesis-27755/.
Schröter C. Glucose has a surprise role in directing cell fate and migration. Nature. 2024 Oct;634(8035):792–3.
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