Scientists at the Allen Institute have identified specific cell types in the brains of mice that undergo major changes as they age, as well as a specific hotspot where many of these changes occur. The discoveries, published in the journal Nature, could pave the way for future therapies to slow or control the ageing process in the brain.
The Most Important Findings
- Sensitive cells: The scientists discovered dozens of specific cell types, mainly glial cells known as brain support cells, in which gene expression changed significantly with age. The severely affected cells included microglia and marginal macrophages, oligodendrocytes, tanycytes and ependymal cells.
- Inflammation and neuronal protection: In aging brains, the activities of genes related to inflammation increased, while the activities of genes related to neuronal structure and function decreased.
- Aging hotspot: Scientists discovered a specific hotspot that combines both the decrease in neuronal function and the increase in inflammation in the hypothalamus. The most significant changes in gene expression were found in cell types near the third ventricle of the hypothalamus, including tanycytes, ependymal cells and neurons, which are known for their role in food intake, energy homeostasis, metabolism and the way our bodies use nutrients. This suggests a possible link between diet, lifestyle factors, brain aging and changes that may influence our susceptibility to age-related brain diseases.
Detailed Map Shows Which Brain Cells May be Most Affected by Ageing
“Our hypothesis is that these cell types are becoming less efficient at integrating signals from our environment or from things we consume,” said Kelly Jin, Ph.D., a scientist at the Allen Institute for Brain Science and lead author of the study. And this loss of efficiency somehow contributes to what we know as aging in the rest of our bodies, according to the researchers. To conduct the study, which was funded by the National Institutes of Health (NIH), the researchers used state-of-the-art single-cell RNA sequencing and advanced brain-mapping tools developed through the NIH’s BRAIN Initiative® to map more than 1.2 million brain cells from young (two-month-old) and old (18-month-old) mice in 16 broad brain regions.
According to the scientists, the old mice are equivalent to late middle-aged humans. Mouse brains show many similarities to human brains in terms of structure, function, genes and cell types. “Ageing is the most important risk factor for Alzheimer’s disease and many other devastating brain diseases. These findings provide a very detailed map of which brain cells may be most affected by aging,” said Richard J. Hodes, M.D., director of the NIH’s National Institute on Aging. This new map could fundamentally change the way scientists think about the effects of aging on the brain and also provides a guide for developing new treatments for age-related brain diseases.
A Path to New Therapies
Understanding this hotspot in the hypothalamus makes it a focus for future studies. Together with the knowledge of which cells need to be targeted, this could lead to the development of age-related therapeutics that help to preserve function and prevent neurodegenerative diseases. The researchers intend to develop tools that can target these cell types. According to Dr. Hongkui Zeng, executive vice president and director of the Allen Institute for Brain Science, the question is whether the aging process can be delayed by improving the function of these cells. The latest findings are also consistent with previous studies linking aging to metabolic changes, as well as research suggesting that intermittent fasting, a balanced diet or calorie restriction can influence or perhaps even extend lifespan. Previous research has shown, among other things, that the brain may benefit from a ketogenic diet as it improves memory performance.
This study lays the groundwork for new dietary strategies and therapeutic approaches aimed at maintaining brain health into old age, as well as further research into the complexities of advanced aging in the brain. As scientists continue to explore these connections, research could unlock more specific dietary or drug interventions to combat or slow aging at the cellular level. “The most important thing about our study is that we have found the key players – the real key players – and the biological substrates for this process,” Zeng said. “When you put the pieces of this puzzle together, you have to find the right players. It’s a nice example of why you need to study the brain and the body at this kind of cell type-specific level. Otherwise, if you mix different cell types together, changes that take place in certain cell types could be averaged out and undetected.”