TY - JOUR
T1 - Restoring metabolism of myeloid cells reverses cognitive decline in ageing
AU - Minhas, Paras S.
AU - Latif-Hernandez, Amira
AU - McReynolds, Melanie R.
AU - Durairaj, Aarooran S.
AU - Wang, Qian
AU - Rubin, Amanda
AU - Joshi, Amit U.
AU - He, Joy Q.
AU - Gauba, Esha
AU - Liu, Ling
AU - Wang, Congcong
AU - Linde, Miles
AU - Sugiura, Yuki
AU - Moon, Peter K.
AU - Majeti, Ravi
AU - Suematsu, Makoto
AU - Mochly-Rosen, Daria
AU - Weissman, Irving L.
AU - Longo, Frank M.
AU - Rabinowitz, Joshua D.
AU - Andreasson, Katrin I.
N1 - Funding Information:
Acknowledgements This work was supported by RO1AG048232 (K.I.A.), RF1AG058047 (K.I.A.), R21NS087639 (K.I.A.), American Heart Association 19PABH134580007 (K.I.A.), 1P50 AG047366 (K.I.A.), 1P30 AG066515 (K.I.A.), Bright Focus (K.I.A.), the Paul and Daisy Soros Fellowship for New Americans (P.S.M.), the Gerald J. Lieberman Fellowship (P.S.M.), DP1DK113643 (M.R.M., L.L. and J.D.R.), the HHMI Hanna H. Gray Fellows Program (M.R.M.), the Burroughs Wellcome Fund PDEP (M.R.M.), the Stanford Innovation Fund (A.U.J. and D.M.-R.), the Takeda Pharmaceuticals Science Frontier Fund (D.M.-R.), the Ludwig Cancer Foundation (I.L.W.), NIH/NCI F30 CA228215 (J.Q.H), NIH/NCI R35CA220434 (I.L.W.), the Japan Science and Technology Agency’s Exploratory Research for Advanced Technology (JST-ERATO) Suematsu Gas Biology Project (Y.S. and M.S.), the Scully Family Initiative (F.M.L.), the Taube Family Foundation (F.M.L.) and the Jean Perkins Foundation (F.M.L.). The authors thank J. Perrino at the Stanford Cell Sciences Imaging Facility (supported by NIH 1S10RR02678001) and the Stanford Human Immune Monitoring Center.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/2/4
Y1 - 2021/2/4
N2 - Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1–3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease4–6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. 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 E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling 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.
AB - Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty1–3. The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease4–6. Systemically, circulating pro-inflammatory factors can promote cognitive decline7,8, and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration9,10. 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 E2 (PGE2), a major modulator of inflammation11. In ageing macrophages and microglia, PGE2 signalling 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85100141552&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-03160-0
DO - 10.1038/s41586-020-03160-0
M3 - Article
C2 - 33473210
AN - SCOPUS:85100141552
SN - 0028-0836
VL - 590
SP - 122
EP - 128
JO - Nature
JF - Nature
IS - 7844
ER -