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Restoring Youthful Immune Function Through Metabolic Reprogramming Reverses Cognitive Aging

Review of "Restoring metabolism of myeloid cells reverses cognitive decline in ageing" from Nature by Stuart P. Atkinson

The development of persistent pro-inflammatory responses by immune cells during normal aging contributes to the development of a wide range of pathologies, including age-associated cognitive decline and Alzheimer's disease [1-3]. While studies have shown that circulating pro-inflammatory factors promote cognitive decline [4, 5], we do not currently possess a complete understanding of how age-related maladaptive inflammation initiates and sustains itself. Cellular energy metabolism can regulate the activation state and function of the immune system, with a recent study establishing a link between macrophage dysfunction and a decrease in glycolysis and mitochondrial oxidative phosphorylation [6]. In an exciting new advance in this research area [6], researchers led by Katrin I. Andreasson (Stanford University School of Medicine, Stanford, CA, USA) now report that restoring youthful immune function through metabolic reprogramming can reverse cognitive aging.

Minhas et al. focused on the role of prostaglandin E2 (PGE2) in age-associated maladaptive inflammation and cognitive decline due to a previously observed increase in the level of this inflammatory modulator [7] during aging and in neurodegenerative disease [8, 9]. Initial analysis in human macrophages suggested that the age-related increase in PGE2 levels prompted a decrease in glycolysis, mitochondrial oxidative phosphorylation, and energy production by signaling through the EP2 receptor, which displays an age-related increase in expression; however, EP2 inhibition reversed these age-related effects.

A similar analysis in vivo demonstrated that aged mice displayed abnormalities in the morphology, number, and density of macrophage mitochondria and decreased macrophage function. Furthermore, they observed increased plasma and brain PGE2 levels, macrophage EP2 levels, systemic and brain-localized levels of pro-inflammatory factors, and numbers of macrophages with a pro-inflammatory phenotype. Interestingly, aged macrophages derived from engineered mice expressing 50% less EP2 in myeloid cells remained remarkably similar to macrophages derived from young wild-type mice, and the reduction in PGE2-EP2 signaling also inhibited the loss of hippocampal plasticity and memory function typically observed in aged mice.

The subsequent exploration of how modulating EP2 signaling contributes to the reversal of these signs of aging found evidence for an important impact on glucose flux. Aging normally drives the sequestration of glucose into glycogen in macrophages – this reduces energy production, as these cells cannot use alternative energy sources to support mitochondrial respiration, which then drives pro-inflammatory immune responses; however, aged mice lacking normal EP2 levels possessed macrophages that metabolized glucose like younger wild-type macrophages. Furthermore, EP2 inhibition in human macrophages prompted similar metabolic alterations (increased glucose flux and improved bioenergetics), which the authors linked to the induction of an anti-inflammatory profile and increased phagocytic function.

Finally, the authors evaluated the in vivo pharmacological inhibition of EP2 signaling in aged wild-type mice via treatment with a brain-penetrant EP2 inhibitor, finding the restoration of pro- and anti-inflammatory factors in plasma and the hippocampus to youthful levels and the reduction in microglial activation. Furthermore, brain microglia and peritoneal macrophages displayed enhanced glucose flux and improved bioenergetics, hippocampal mitochondria had a more youthful appearance, and cognitive functions exhibited significant improvements. Notably, the authors also established that peripheral EP2 inhibition in wild-type aged mice also reversed age-associated systemic and hippocampal inflammation, returned hippocampal memory deficits to youthful levels, and induced youth-associated immune and metabolic signatures in peritoneal macrophages.

Overall, these findings suggest that the cognitive decline associated with maladaptive inflammation represents a reversible component of the aging process. For more on how inhibiting inflammatory PGE2 signaling through the myeloid EP2 receptor may aid in the battle against aging, stay tuned to the Stem Cells Portal!


  1. Cunningham C and Hennessy E, Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research. Alzheimer's Research & Therapy 2015;7:33.
  2. Brayne C, The elephant in the room — healthy brains in later life, epidemiology and public health. Nature Reviews Neuroscience 2007;8:233-239.
  3. Lindenberger U, Human cognitive aging: Corriger la fortune? Science 2014;346:572.
  4. Villeda SA, Plambeck KE, Middeldorp J, et al., Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nature Medicine 2014;20:659-663.
  5. Villeda SA, Luo J, Mosher KI, et al., The ageing systemic milieu negatively regulates neurogenesis and cognitive function. Nature 2011;477:90-94.
  6. Minhas PS, Latif-Hernandez A, McReynolds MR, et al., Restoring metabolism of myeloid cells reverses cognitive decline in ageing. Nature 2021;590:122-128.
  7. Ricciotti E and FitzGerald Garret A, Prostaglandins and Inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology 2011;31:986-1000.
  8. Montine TJ, Sidell KR, Crews BC, et al., Elevated CSF prostaglandin E2 levels in patients with probable AD. Neurology 1999;53:1495.
  9. Wu D and Meydani SN, Mechanism of age-associated up-regulation in macrophage PGE2 synthesis. Brain, Behavior, and Immunity 2004;18:487-494.