Key Points:
- Each type of brain cell ages differently; our neurons age the least.
- Accessible interventions for protecting against brain aging include diet, exercise, senolytics, and mTOR inhibitors.
- Less accessible or future interventions include young blood transfusion and cellular reprogramming.
Our brain cells work together to form thoughts, initiate actions, and remember past experiences. With age, this ability to think declines. However, scientists are finding that the pace of this decline may be controllable. That is, recent breakthroughs in single-cell technology, as reviewed by researchers from Stanford University, are beginning to unravel which brain cells are most vulnerable to aging. Moreover, single-cell resolution studies are paving the way for revolutionary interventions that may rejuvenate the brain, one cell at a time.
Seeing Aging with Single-Cell Resolution
Until recently, it has been exceptionally difficult to analyze the genes of single brain cells. The analysis of bulk brain tissue (the traditional method for examining the brain) cannot pinpoint the specific changes that occur within each of the brain’s diverse cell types. In contrast, single-cell ‘omics’ technologies act as powerful microscopes that allow researchers to zoom in on the individual cells that make up the brain.
At the forefront of these cutting-edge techniques are single-cell RNA sequencing (scRNA-seq) and single-nuclei RNA-seq (snRNA-seq). RNA, in the form of messenger RNA (mRNA), determines which of our genes will be made into proteins — the proteins that form a complex network of interactions that ultimately determine the function of each of our cells.
By sequencing the mRNA from individual cells, scientists can get a snapshot of their activity and identify how these instructions change with age. While scRNA-seq provides a comprehensive view, snRNA-seq is particularly useful for delicate cells like neurons, which are difficult to isolate intact, and can even be used on frozen brain tissue, opening up new avenues for research on human brain samples.
The Brain is a Cellular Mosaic
One of the most striking revelations from single-cell studies is that aging is not a uniform process across all brain cells. Instead, it’s a complex mosaic of changes, with different cell types exhibiting unique vulnerabilities and responses to the passage of time.
- Neurons are responsible for transmitting information throughout the brain and nervous system. Interestingly, changes to neurons are generally of a lower magnitude compared to other brain cells.
- Glial cells include astrocytes, which provide metabolic support to neurons; oligodendrocytes, which produce the myelin sheath that insulates nerve fibers for rapid signal transmission; and microglia, the brain’s resident immune cells. Single-cell studies have found a striking increase in immune and inflammatory gene expression in glial cells with age.
- Neural stem cells (NSCs) can generate new neurons (a process called neurogenesis) and other brain cells throughout life. Single-cell studies have revealed that the decline in neurogenesis with age is linked to a decrease in NSCs.
Rejuvenation: Turning Back the Brain’s Clock
The ultimate goal of understanding brain aging is to develop strategies to slow, halt, or even reverse its detrimental effects. Single-cell omics is proving to be an invaluable tool in evaluating the impact of various rejuvenation interventions, providing a cell-by-cell view of their efficacy.
Diet
Studies on calorie restriction — consuming fewer calories per day — have shown remarkable effects. In aged rats, it can restore populations of endothelial cells (which line blood vessels) and inhibitory neurons to more youthful levels. It also appears to rescue the expression of genes involved in DNA damage response, suggesting a protective effect against age-related cellular damage. Interestingly, dietary restriction primarily impacts glial cells, highlighting their sensitivity to nutritional cues.
Exercise
Single-cell studies have shown that exercise rejuvenates the nervous system and brain more than other organs. Moreover, exercise has demonstrable rejuvenating effects on several brain regions. Remarkably, exercise increases the proportion of active NSCs, which may account for neurogenesis. It can also rejuvenate microglia, reducing their inflammatory state, which may mediate improvements in memory. This underscores the power of lifestyle interventions in promoting brain health.
Young Blood
Perhaps one of the most fascinating areas of research involves circulating blood factors. Experiments using heterochronic parabiosis (surgically connecting an old and a young animal to share blood circulation) have shown that exposure to young blood can rejuvenate the aged brain. This effect is particularly pronounced in neural stem cells and microglia, suggesting that factors present in young blood can directly influence the health and function of these critical brain cell populations.
Partial Reprogramming
Cellular reprogramming involves transiently expressing a set of genes called Yamanaka factors, which reset a cell’s developmental clock. In the brain, partial reprogramming has been shown to restore the proportion of neuroblasts (immature neurons) and rejuvenate gene signatures in certain cell types, including NSCs. However, this approach is still in its early stages and may have unintended detrimental effects on other cell types, such as microglia, astrocytes, and quiescent neural stem cells.
GLP-1 Receptor Agonists
Perhaps unexpectedly, drugs typically used for diabetes and weight loss, known as GLP-1 receptor agonists, are emerging as potential anti-aging therapies for the brain. Single-cell transcriptomic studies have revealed that GLP-1 receptor agonists can reverse aging signatures in glial and neurovascular cells, with the most significant impact observed in astrocytes and oligodendrocyte precursor cells. This opens up exciting possibilities for repurposing existing medications to combat brain aging.
Other Strategies
The Stanford scientists mention that single-cell omics could help evaluate the known rejuvenating effects of established interventions:
- Senescent Cell Clearance: Compounds that remove age-promoting senescent cells, called senolytics, have been shown to reduce brain inflammation and microglia activation. Importantly, clearing senescent cells has been shown to improve the cognition of aged mice.
- Inhibition of mTOR (mechanistic target of rapamycin): A repurposed drug called rapamycin, which inhibits our master nutrient-sensing molecule mTOR, has been shown to rejuvenate neural stem cells in aged mice. Other studies have shown that inhibiting mTOR also improves cognition and prolongs the lifespan of mice.
- Klotho Administration: A single-dose injection of the naturally occurring protein klotho has been shown to improve the cognition of aged monkeys.
- Inhibition of IL-11: Inhibiting IL-11, a pro-inflammatory molecule, has been shown to prolong the lifespan of mice and may reduce brain inflammation.
Combining Interventions
One critical direction is to explore the synergistic effects of combined interventions. If different rejuvenation strategies impact distinct cell types or pathways, combining them could lead to more potent and comprehensive anti-aging effects. For instance, if exercise rejuvenates one set of cells and a specific drug or supplement targets another, their combined application might yield superior results than either alone. Another example is the combination of senolytics and mTOR inhibition, which could reduce senescent cells while improving the brain’s regenerative capacity.
Maximizing the Mind Now
Some of the interventions listed above are out of the question for those wishing to act now on their aging brain. Namely, cellular reprogramming accelerates the aging of some brain cells, which is concerning. Additionally, an intervention that appears to be safe but may be less accessible to most individuals is young blood transfusion. Meanwhile, therapies involving klotho administration and IL-11 inhibition are in the works and may be readily available within the coming years.
The safest and accessible interventions are caloric restriction and exercise. Chronic aerobic exercise, in particular, has been shown to enhance neurogenesis. Senolytics are also relatively safe and accessible and can be found in fruits and vegetables, but also in supplement form. Furthermore, FDA-approved drugs like GLP-1 receptor agonists and rapamycin can be obtained from a doctor willing to prescribe off-label. Combining caloric restriction, exercise, and potentially other interventions may provide beneficial additive or synergistic effects on brain health and longevity.
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