Alteration of Immune Metabolism Restores Memory at Old Age

What is a scary but perpetual process that every living organism goes through? Ageing! We become aware of it from a very young age– looking at people growing older, having reduced quality of life, and forgetting things. We have always flirted with the idea of youth till death through works of art, whether it is mythology, literature, or films. Scientists have been working towards understanding the aging process and increasing the longevity of human life since the dawn of medicine. And they have succeeded to a large extent! Today, the average world life expectancy is almost double of what it used to be in a century ago.

When we talk about increasing the years of a human’s life, we barely give attention to immune cells. Today we are going to look at how aging affects the immune metabolism of brain cells leading to their reduced function, and the potentiality of circumventing it.

By this point, researchers have shown that immune cells are present almost everywhere in our body and are essential for homeostasis. As we grow older, our immune cells reduce in quantity and quality, making old people more vulnerable to infections, strokes, and cancers compared to healthy younger people. And the brain is not spared either!

The brain is an immune-privileged organ consisting of specialized macrophages called microglia that are involved in protection and maintenance of the neurons. With age, the ability of microglia to carry out its function starts waning, leading to reduced clearance of pro-inflammatory factors after an infection.

Minhas and colleagues from Stanford University explored the role of Prostaglandin E₂  (PGE₂) on macrophages and microglia. PGE₂ is a hormone-like messenger that increases in the bloodstream as we age. The authors found that PGE₂ binds to its receptor EP2 on ageing macrophages and directly affects the glucose metabolism. Glucose in aged macrophages is increasingly converted into glycogen for storage and not used directly. These aged macrophages could not utilize any alternate pathways to generate energy either. Glucose is the fundamental source of energy in a cell and glucose scarcity throws the cells into a starved state- adversely affecting macrophage functioning like glucose flux and mitochondrial respiration.

Poor functioning cause severe implications in the macrophages like abnormal shape and density of mitochondria, transition to a pro-inflammatory state, and a drop in phagocytosis. All these factors are signs of an aged immune system. However, when the researchers blocked the EP2 receptors using drugs or made EP2 absent in macrophages, the normal functioning of these macrophages was restored to almost youthful levels.

Immune metabolism of the brain was restored too as the absence or blockage of EP2 receptor had positive effects on the brain, especially the hippocampus. The hippocampus was emphasized in this study because it is involved in memory and learning, two things that deteriorate rapidly with aging. Ageing induces loss of synapses and the synaptic proteins thus reducing brain functioning. But when old mice were treated with EP2 blocker for a month, their hippocampal synapses and proteins were restored to levels comparable to young mice along with improved hippocampal health and plasticity. This recovery also reversed memory defects and improved cognition.

Hence, by investigating the correlation of high levels of PGE₂ in blood with aging homeostatic immune cells like macrophages and microglia, Minhas et al uncovered an important metabolic pathway. By learning the mechanism behind microglial immune dysfunction and blocking EP2, they could reverse hippocampal aging and make the brain functioning youthful again. The recovery studies were performed on aging mice, but would it improve the human brain functioning too? The researchers predicted that the therapeutic effect of EP2 on macrophages could also improve the state of the cardiovascular system and rest of the brain which should definitely be supported by follow up studies in the future. 

No doubt, the idea of reversing lost cognition and memory to youthful levels sounds like something straight out of a science fiction movie, but hopefully, it would not take long to translate it to real life.

Loved learning about the role of immune cells in the process of ageing and want more of it? We will be talking to one of the authors of another fascinating study on aged immune cells and their effect on solid organs this July! Follow us on Social Media to keep track!

Source: Minhas, P.S., Latif-Hernandez, A., McReynolds, M.R. et al. Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 590, 122–128 (2021). https://doi.org/10.1038/s41586-020-03160-0

Check out Antibuddies’ blog post “Alteration of Immune Metabolism Restores Memory at Old Age”.

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