International Business Department           Liu Bojia           August 21, 2023

  Memory loss, poorer spatial awareness, slower learning of new things ...... As we get older, these signals often alert us to the fact that our brains are aging, and sometimes they are symptoms of neurodegenerative diseases such as Alzheimer's disease. And what changes are happening inside the brain and in brain cells behind cognitive decline? How can these molecular changes be slowed or even reversed?

  Recently, the research team of Prof. Tony Wyss-Coray, a renowned neuroscientist at Stanford University School of Medicine, published a paper in the top academic journal Cell, and got a rather surprising answer based on a mouse study. They found that the most pronounced changes in gene expression as the brain ages occur in the white matter. In addition, they tested how two highly publicized methods of life extension - caloric restriction, and transfusion of young blood - affect gene expression changes associated with aging.

  The brain is roughly divided into "gray matter" and "white matter" based on color, with much attention paid to gray matter, the area where neuronal bodies are concentrated and thought to be critical for higher brain functions. In contrast, the deeper white matter of the brain receives less attention. White matter consists primarily of nerve fibers wrapped in white myelin sheaths that act like undersea fiber optic cables and are responsible for transmitting neural signals throughout the brain. In the words of Prof. Wyss-Coray, white matter is an area that is often overlooked in the field of aging research.

  In this study, scientists analyzed nearly 60 mice ranging in age from 3 to 27 months, subdivided their brain hemispheres into 15 regions, and analyzed the cellular gene expression in each brain region using single-cell sequencing. In this way, the researchers identified a dozen genes that were most commonly and differentially expressed in these brain regions, and as a result developed an aging scoring system to assess how gene activity in each brain region changes with age.

  The results found that the white matter of the mouse brain was the earliest region to show changes in gene expression, showing significant gene expression changes in mice at 12 to 18 months of age (equivalent to about 50 years of age in humans). In contrast to this, glial cell populations in white matter regions showed more pronounced acceleration of aging, while neuronal populations in gray matter showed more regional specificity in gene expression changes.

  Although it is not known exactly how gene expression changes in white matter affect memory and cognition, the researchers hypothesize that it may be related to genes that regulate inflammation and immune responses being turned on, leading to disruption of myelin integrity. These speculations have yet to be verified in subsequent experiments.

  In previous studies, Prof. Wyss-Coray's team had conducted a classic set of experiments in which older mice were infused with plasma from younger mice, which was found to help rejuvenate the aging brain. This time, utilizing a new gene expression assessment method, the team once again verified the effects of this approach, and also compared it to another commonly used anti-aging strategy, dietary intervention.

  The researchers started the intervention when the mice were moving into old age for four weeks, and then focused on brain regions that undergo gene expression changes with aging. The results showed that caloric restriction led to the switching on of genes associated with circadian rhythms, while infusion of young blood turned on genes involved in stem cell differentiation and neuron maturation.

  Interestingly, they found that the two methods of intervening in aging seemed to act on completely different brain regions. The study authors concluded that this suggests that to improve cognitive abilities in old age, there may be multiple pathways in multiple regions of the brain.

  The team also looked at how the expression of genes associated with three neurodegenerative diseases - Alzheimer's disease, Parkinson's disease, and multiple sclerosis - which typically affect specific brain regions, changed with age. They observed that the distribution of expression of several disease-associated genes changed in the brains of older mice, yet was not limited to the typical brain regions typically affected by the disease. Indeed, a large number of patients with neurodegenerative diseases do not run in families, and these new findings may shed light on understanding and intervening in sporadic cases.