International Business Department           Liu Bojia           December 24, 2024

  As we grow older, our body's tissues and organs will gradually age, and our more intuitive feelings may be a loss of skin elasticity, a decline in muscle function, and a loss of physical strength. In addition, the brain will inevitably be affected by aging, such as memory loss and slower reaction time. Brain aging is also associated with the development of some neurodegenerative diseases, including Alzheimer's disease, the risk of many types of dementia will gradually increase with age.

  Neuroscientists are trying to identify the molecular or cellular changes that characterise the brain as it ages, as a way of finding targets for intervention. In the past, many studies have looked at the single-cell level to compare the differences between a particular type of cell when it is young and when it is old, to determine which molecules are potentially valuable to study. But this approach ignores the complex environment and spatial context of the brain, where cells of all kinds not only function on their own but also have a huge impact on neighbouring cells. Some may stress and damage neighbouring cells, while others may boost the resilience of others.

  In a recent paper published in Nature, a team of researchers from Stanford University found that brain cell interactions can have a profound effect on brain aging. For example, T-cells act as senescence promoters, with pro-inflammatory and damaging consequences for neighbouring cells, while neural stem cells do the opposite, boosting the ‘rejuvenation’ potential of neighbouring cells and slowing down the rate of localised ageing. Based on this, inhibiting pro-aging and activating anti-aging cellular interactions is expected to be a new direction for anti-aging in the brain.

  In order to ensure the temporal continuity of the study population and samples, the authors collected and analysed brain samples from mice throughout their adult life and generated a large-scale single-cell transcriptome atlas, which contains transcriptome data from approximately 4.2 million cells spanning 20 different age stages of mouse adulthood. During this time, the researchers will also rejuvenate the mice by allowing individuals to exercise or by means of local reprogramming to obtain even more diverse and rich data.

  Eighteen different cells are shown throughout the atlas, ranging from abundant cell types such as excitatory/inhibitory neurons, astrocytes and microglia, to rarer cells such as T cells, B cells, and immune cells such as neutrophils, which are usually less frequently mentioned.

  The authors then analysed the cell-specific transcriptome during aging with the help of a spatial aging clock and deep learning model training. On the one hand, they could identify which cell types have rejuvenating transcriptome expression changes by comparing control and post-exercise mouse brain data. The authors found that some cell types were ‘younger’ as a result of exercise, such as endothelial cells, pericytes, and vascular smooth muscle cells, and hypothesised that enhanced blood supply and exposure to blood factors as a result of exercise were responsible for the transcriptome changes in these cells.

  On the other hand, the researchers were able to observe the interactions between cells in the spatial environment. Of the 18 types of cells, the authors found two that could have a significant effect on neighbouring cells.

  The first were T-cells, which are uncommon in young brains and gradually infiltrate the brain with aging. When they reside in the microenvironment, they produce interferon gamma to promote inflammation levels in surrounding cells, thus exerting a pro-aging effect.

  Conversely, neural stem cells, which are also scarce in number, rejuvenate neighbouring cells and exist to resist ageing. The analysis showed that neural stem cells promote rejuvenation by boosting endocytosis pathways and lipid metabolism in neighbouring cells.

  The researchers note that these findings also shed new light on future anti-aging strategies: in addition to focusing on tissues that require direct intervention, specific cell types surrounding them in these tissues are also worthy targets. And for brain anti-aging, reducing the inflammatory factor secretion process of T cells is one possible direction.