Scientists just discovered a new brain phase between 50 and 75. It may help explain cognitive decline

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Scientists just discovered a new brain phase between 50 and 75. It may help explain cognitive decline

A single-cell study of the hippocampus suggests brain aging is not a steady decline, but a coordinated immune, vascular, and neuronal overhaul.

Scientists at the University of California, San Diego School of Medicine just discovered a new brain phase.

A single-cell study identified a new biological phase the brain may enter between 50 and 75. The research offers new, important insights about brain aging and cognitive decline.

Between the ages of 50 and 75, the cellular landscape of the hippocampus, the brain’s memory region, begins to change. Immune cells get replaced, the genome’s physical structure loosens, and gene regulation is reshaped across multiple cell types. 

The study’s findings, which were published in the peer-reviewed journal Science, suggest that aging is not so much a gradual decline than an active biological overhaul—one that may eventually be a target for treatment.

The researchers looked at individual cells from human hippocampal tissue collected at various points across the adult lifespan. They then mapped gene regulation and three-dimensional genome architecture to produce what Sci Tech Daily called “one of the most detailed accounts yet of how these features change as the human brain ages.”

A changing immune system

One of the most significant shifts the scientists discovered appeared in the microglia—the immune cells that help maintain and protect that brain. In midlife, between the ages of 50 and 75, the microglia that formed during embryonic development declined sharply. The researchers found that cells with similar traits to blood immune cells replaced the missing microglia cells.

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Those replacements carried stronger inflammatory signatures, raising the possibility that they help drive the persistent inflammation tied to brain aging. At the same time, cell populations that maintain the blood-brain barrier dropped off substantially.

“Microglia are critical for maintaining brain homeostasis,” Bing Ren, PhD, a corresponding author of the study and scientific director and CEO of the New York Genome Center told Sci Tech Daily. “When these cells fail to perform their housekeeping duties, toxic materials accumulate that can trigger inflammatory processes that may contribute to neurodegenerative diseases.”

Nathan Zemke, PhD, lead author and a principal investigator at the UC San Diego Center for Epigenomics, told Inc. that the immune system shift is directly connected to memory. 

“Between roughly ages 50 and 80, many of the brain’s original immune cells appear to be replaced by immune cells that enter from the bloodstream,” he told Inc. 

Those cells are important for clearing debris and protecting the brain, he added, but the incoming ones carry stronger inflammatory signals, which may contribute to the chronic brain inflammation commonly associated with cognitive decline.

Across several brain cell types, the genome’s three-dimensional structure grew progressively less organized with age. DNA folds into a precise architecture that helps determine which genes a cell can use. As that folding erodes, so does the cell’s control over its own machinery. The researchers suggest it may be a basic feature of brain aging.

That breakdown is what makes the structural changes matter for the mind, Zemke said. “Every type of brain cell relies on a carefully organized set of genetic instructions to perform its specialized role,” he told Inc. “As we age, that organization begins to break down, which may disrupt the genes needed to maintain healthy brain function and cognition.”

Notably, the immune, vascular, and neuronal systems appeared to change together, in a coordinated way. 

“Importantly, this study reveals that aging is not simply a gradual decline, but involves coordinated and dynamic remodeling of immune, vascular, and neuronal systems,” said Xiangmin Xu, PhD, a co-corresponding author and director of the Center for Neural Circuit Mapping at UC Irvine told Sci Tech Daily.”These findings open the door to identifying new therapeutic targets aimed at preserving circuit integrity and brain function across the lifespan.”

Implications for the future of aging research

The findings should also change how professionals think about aging itself, Zemke told Inc. “Many biological changes associated with aging appear to accelerate around age 50, including increased inflammation and reduced cellular energy production,” he said. “However, the timing varies greatly from person to person. Understanding what drives that variation could help explain why some people age more successfully than others.”

The immune-cell shift may carry the greatest significance for Alzheimer’s research. The replacement of the brain’s original immune cells by blood-derived ones occurs during the same window when Alzheimer’s-related changes are thought to begin, Zemke said. The incoming cells show inflammatory features associated with the disease, suggesting the transition could be an important contributor to Alzheimer’s risk.

This post originally appeared at inc.com.

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Reversal of immune-cell shutdown protects the ageing brain

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Reversal of immune-cell shutdown protects the ageing brain

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Immune cells called macrophages are found in almost every tissue, and are crucial for maintaining organ health and providing a first line of defence against disease-causing organisms. The energy demands of macrophages increase drastically when they are activated, and so they rebalance or enhance their two main energy-producing metabolic pathways (glycolysis and oxidative phosphorylation) to quickly fuel an effective immune response¹. Writing in Nature, Minhas et al.² report that macrophages shut down these metabolic pathways during ageing, severely compromising macrophage function and, in turn, brain health. This work has implications not only for the preservation of brain health during ageing, but also for conditions such as Alzheimer’s disease or sepsis, in which similar maladaptive macrophage states could be common.

Read the paper: Restoring metabolism of myeloid cells reverses cognitive decline in ageing

As we age, chronic, low-grade inflammation develops in most people³. One inflammatory signalling protein whose levels rise not only during ageing⁴ but also during neurodegenerative disease⁵ is prostaglandin E₂ (PGE₂). Minhas et al. set out to investigate whether PGE₂ might cause age-associated changes in macrophages. Interestingly, the authors found increased production of PGE₂ in human and mouse macrophages themselves — both in the brain and elsewhere in the body (the periphery). This led to the activation of PGE₂’s receptor protein EP2 in the cells, which in turn resulted in suppression of oxidative phosphorylation and glycolysis. The resulting energy-deficient state both limited the beneficial functions of macrophages and increased inflammation.

To determine whether these changes could cause age-associated cognitive dysfunction, the authors examined a mouse strain in which EP2 receptor levels were reduced exclusively in macrophages in the body and brain, and treated mice with an EP2 inhibitor. Strikingly, EP2 inhibition restored macrophage metabolism to youthful levels in both settings, reducing inflammation in the periphery and brain, and alleviating cognitive decline (Fig. 1). These results indicate that (at least in mice) macrophage dysfunction during ageing affects brain health, and that normal cell function can be restored by reversing metabolic shutdown in the cells.

Figure 1 | Reversing metabolic shutdown in aged macrophages. Immune cells called macrophages are found throughout the body (the periphery) and in the brain, where they are called microglia. a, Minhas et al.² report, that during ageing, peripheral macrophages and microglia produce more of the protein prostaglandin E2 (PGE₂), which binds to EP2 receptors on the cells’ membranes. They demonstrate that activation of this signalling pathway leads to metabolic dysfunction in the cells, and so to systemic chronic inflammation and cognitive decline. b, The authors inhibited the EP2 receptor in two ways. First, they used a genetic approach to reduce levels of EP2 in both macrophages and microglia. Second, they inhibited the receptor pharmacologically — but only in the periphery. Under both conditions, EP2 inhibition improved metabolic function in peripheral macrophages and microglia, reducing inflammation and restoring cognitive ability. The mechanism by which peripheral inhibition of EP2 leads to changes in microglia is unknown (dashed arrow).

Minhas and colleagues went on to dive deeper into the metabolic rewiring of aged macrophages. They found that such macrophages favoured energy storage in the form of glycogen (a large glucose polymer) over the use of glucose for energy production through glycolysis or oxidative phosphorylation. Although glycogen normally serves as a fuel reserve, aged macrophages did not seem to use this reserve, despite their energy-deficient state.

It is unclear why aged macrophages store extra glycogen, but dendritic cells, a related cell type, use their glycogen stock to fuel their earliest inflammatory responses⁶. Therefore, it is conceivable that aged macrophages increase glycogen storage so that they can mount a stronger immune response during acute inflammatory activation. In line with this idea, aged microglia (brain macrophages) are well known to be primed — that is, to respond more strongly to inflammatory insults than do young microglia⁷. Minhas and co-workers did not directly analyse whether microglial priming is enabled by increased glycogen stores. However, this possibility would certainly be worth investigating, because some evidence suggests that exacerbated immune responses in the aged brain contribute to neurodegenerative disease⁷.

Commonality with cancer

Notably, there is also evidence for a role of microglial metabolic dysfunction in brain disease, particularly in Alzheimer’s disease. The risk of developing Alzheimer’s increases several-fold in people who carry mutations in the microglial receptor protein TREM2. In mice, TREM2 deficiency causes breakdown of microglial metabolism and exacerbation of Alzheimer’s pathology⁸. Furthermore, chronic exposure of microglia to aggregated amyloid-β protein, a hallmark of Alzheimer’s disease, leads to the breakdown of oxidative phosphorylation and glycolysis in these cells in mice⁹. In both cases, enhancing microglial metabolism leads to less-severe Alzheimer’s pathology in the mouse models.

In sepsis (a condition that results from excessive inflammation in response to infection), PGE₂ levels also increase⁹ and long-term cognitive deficits often develop⁷. Here, macrophages enter a state called immune paralysis, which is also characterized by suppression of both oxidative phosphorylation and glycolysis^1,10. Thus, the cellular shutdown of macrophages during sepsis or during ageing and neurodegenerative disease might be a response to excessive or chronic immune stimulation, respectively. This adaptation would be beneficial from an evolutionary perspective because it would protect an organism from a hyperactive immune response that could cause tissue damage. However, in the context of an ageing organism, it seems to predispose the brain to dysfunction or even degeneration. Whether macrophage immune states are indeed similar across these different conditions remains to be investigated.

Inflammation keeps old mice healthy

Another intriguing aspect of Minhas and colleagues’ study is the finding that, even when EP2 inhibition was limited to the periphery in aged mice (using a substance that cannot enter the brain), brain inflammation was reversed and cognitive function restored (Fig. 1). This corroborates previous findings that immune signals generated outside the brain can affect microglia11, and that stimulation of immune cells outside the brain can partially restore the metabolism and function of peripheral macrophages after sepsis¹⁰ and of microglia in mouse models of Alzheimer’s disease⁹. Thus, a growing body of evidence indicates that, in mice, macrophages remain responsive to immune stimulation even during disease and ageing.

The next challenges will be to demonstrate that this macrophage plasticity is also retained towards the end of the considerably longer human lifespan, and that the PGE₂–EP2 pathway is relevant for human brain ageing and disease. Moreover, the immune signals that induce initial microglial shutdown or restore microglia to a youthful state in aged animals remain unknown. Their identification could lead to therapeutic approaches to combat a range of diseases.

doi: https://doi.org/10.1038/d41586-021-00063-6