Restoring metabolism of myeloid cells reverses cognitive decline in ageing

Jan 21, 2021Nature

Fixing energy use in immune cells may reverse age-related thinking decline

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Abstract

Inhibition of myeloid EP2 signaling in ageing mice rejuvenates cellular energy and cognitive functions.

Ageing is linked to persistent inflammation that contributes to cognitive decline and neurodegenerative diseases.
In ageing mice, the lipid messenger prostaglandin E (PGE) suppresses myeloid cell energy production.
This suppression leads to reduced glucose use and mitochondrial respiration in macrophages and microglia.
Energy deficiency in these cells drives maladaptive pro-inflammatory responses associated with ageing.
Blocking myeloid EP2 signaling restores energy metabolism, reduces systemic inflammation, and improves spatial memory.
Cognitive decline in aged mice may be reversible through reprogramming myeloid glucose metabolism.

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Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer's disease. Systemically, circulating pro-inflammatory factors can promote cognitive decline, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration. However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E(PGE), a major modulator of inflammation. In ageing macrophages and microglia, PGEsignalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions. 1-3 4-6 7,8 9,10 11 2 2 2

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Restoring metabolism of myeloid cells reverses cognitive decline in ageing

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