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Implications for Age-Associated Neurodegenerative Diseases [Version 1; Peer Review: 2 Approved] Yiwei Wang *, Aarti Mishra *, Roberta Diaz Brinton

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Implications for Age-Associated Neurodegenerative Diseases [Version 1; Peer Review: 2 Approved] Yiwei Wang *, Aarti Mishra *, Roberta Diaz Brinton F1000Research 2020, 9(F1000 Faculty Rev):68 Last updated: 31 JAN 2020 REVIEW Transitions in metabolic and immune systems from pre-menopause to post-menopause: implications for age-associated neurodegenerative diseases [version 1; peer review: 2 approved] Yiwei Wang *, Aarti Mishra *, Roberta Diaz Brinton Center for Innovation in Brain Science, University of Arizona, Tucson, AZ, 85721, USA * Equal contributors First published: 30 Jan 2020, 9(F1000 Faculty Rev):68 ( Open Peer Review v1 https://doi.org/10.12688/f1000research.21599.1) Latest published: 30 Jan 2020, 9(F1000 Faculty Rev):68 ( https://doi.org/10.12688/f1000research.21599.1) Reviewer Status Abstract Invited Reviewers The brain undergoes two aging programs: chronological and 1 2 endocrinological. This is particularly evident in the female brain, which undergoes programs of aging associated with reproductive competency. version 1 Comprehensive understanding of the dynamic metabolic and 30 Jan 2020 neuroinflammatory aging process in the female brain can illuminate windows of opportunities to promote healthy brain aging. Bioenergetic crisis and chronic low-grade inflammation are hallmarks of brain aging and menopause and have been implicated as a unifying factor causally F1000 Faculty Reviews are written by members of connecting genetic risk factors for Alzheimer’s disease and other the prestigious F1000 Faculty. They are neurodegenerative diseases. In this review, we discuss metabolic commissioned and are peer reviewed before phenotypes of pre-menopausal, peri-menopausal, and post-menopausal publication to ensure that the final, published version aging and their consequent impact on the neuroinflammatory profile during each transition state. A critical aspect of the aging process is the dynamic is comprehensive and accessible. The reviewers metabolic neuro-inflammatory profiles that emerge during chronological who approved the final version are listed with their and endocrinological aging. These dynamic systems of biology are relevant names and affiliations. to multiple age-associated neurodegenerative diseases and provide a therapeutic framework for prevention and delay of neurodegenerative Pauline Maki, University of Illinois at Chicago, diseases of aging. While these findings are based on investigations of the 1 female brain, they have a broader fundamental systems of biology strategy Chicago, USA for investigating the aging male brain. Molecular characterization of 2 Walter A. Rocca, Mayo Clinic, Rochester, USA alterations in fuel utilization and neuroinflammatory mechanisms during these neuro-endocrine transition states can inform therapeutic strategies to Any comments on the article can be found at the mitigate the risk of Alzheimer’s disease in women. We further discuss a end of the article. precision hormone replacement therapy approach to target symptom profiles during endocrine and chronological aging to reduce risk for age-related neurodegenerative diseases. Keywords Menopause, metabolism, inflammation, aging, neurodegenerative disease, hormones Page 1 of 13 F1000Research 2020, 9(F1000 Faculty Rev):68 Last updated: 31 JAN 2020 Corresponding author: Roberta Diaz Brinton ([email protected]) Author roles: Wang Y: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing; Mishra A: Conceptualization, Writing – Original Draft Preparation, Writing – Review & Editing; Brinton RD: Conceptualization, Funding Acquisition, Project Administration, Supervision, Writing – Review & Editing Competing interests: No competing interests were disclosed. Grant information: This work was supported by National Institutes of Health grants AG053589 and P01-AG026572 to RDB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2020 Wang Y et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite this article: Wang Y, Mishra A and Brinton RD. Transitions in metabolic and immune systems from pre-menopause to post-menopause: implications for age-associated neurodegenerative diseases [version 1; peer review: 2 approved] F1000Research 2020, 9(F1000 Faculty Rev):68 (https://doi.org/10.12688/f1000research.21599.1) First published: 30 Jan 2020, 9(F1000 Faculty Rev):68 (https://doi.org/10.12688/f1000research.21599.1) Page 2 of 13 F1000Research 2020, 9(F1000 Faculty Rev):68 Last updated: 31 JAN 2020 Introduction respiratory capacity40. Beyond promoting mitochondrial bioener- The brain is the most energy-demanding organ in the body. getics in the brain, estrogen can further reduce ROS production60, In humans, the brain comprises 2% of total body mass yet promote calcium homeostasis, and protect cells from consumes 20% of total oxygen and 25% of glucose1,2, mak- apoptosis61, which collectively will promote mitochondrial ing the brain susceptible to even modest disruptions in energy function. homeostasis3–5. Indeed, the aging brain, even of healthy aging individuals, is marked by glucose hypometabolism and Decline in estrogen level during menopause is also associ- mitochondrial dysfunction6,7. These metabolic and bioenergetic ated with an increase in inflammation, marked by the increased phenotypes are exaggerated in multiple age-associated expression of pro-inflammatory cytokines—interleukin-8 (IL-8), neurodegenerative diseases (NDs), including Alzheimer’s disease tumor necrosis factor alpha (TNF-α), IL-6, and interferon gamma (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and (IFN-γ)—in response to T-cell activation47,62,63. Sexual dimor- amyotrophic lateral sclerosis (ALS)8–18. phism, especially with the decline of estrogen, is particularly evident in the immune system64,65. Post-menopausal women Both preclinical and clinical studies reveal that alteration in brain have increased CD4/CD8 ratios and T-cell proliferation and metabolic status during aging and in ND is accompanied by shifts activated T cell–mediated autoimmunity66,67. Multiple effects in energy sources, from glucose metabolism to fatty acid metab- in the periphery are a direct response to the loss of immunosup- olism and ketone bodies19–22. While this strategy serves as an pressive effects of estrogen. In the brain, estrogen is a master adaptation to sustain ATP production7, it also leads to increased regulator of glucose metabolism, neuronal and glial bioen- free radical production10,23,24, lipid peroxidation21,22,25,26, oxidative ergetics, and microglial inflammation68. The dysregula- stress27,28, and endoplasmic reticulum (ER) stress17,18. Increased tion of glucose metabolism in the brain is evident during the production of damage-associated molecular patterns (DAMPs), menopausal transition and can cause the accumulation of such as extracellular ATP29, mitochondrial DNA (mt-DNA), DAMPs, further causing the activation of innate and adaptive reactive oxygen species (ROS)30, ceramides31, oxidized low- immunity to induce chronic low-grade inflammation36. density lipoproteins32, and myelin debris21,33–35, further induces chronic systemic inflammation. Induction of chronic sys- Hormonal change associated with menopausal transition is a temic inflammation by metabolic stressors can serve as a missing gradual process spanning multiple years, thus allowing adap- mechanistic link from metabolic and bioenergetic dysfunction to tation in both metabolic and inflammatory function in the ND36. brain. Similarly, chronological aging before and after this endocrinological aging stage is coupled by systematic altera- In females, estrogen therapy initiated during the critical win- tions in metabolic and immune systems. Below, we review dows of peri-menopause to early menopause and surgi- these fluctuations in more detail during pre-menopausal, cal menopause has been shown to promote brain glucose peri-menopausal, and post-menopausal stages. metabolism37–46, reduce chronic inflammation47–50, and prevent cognitive decline51–57. Understanding the dismantling process of Chronological aging: prelude to endocrine aging estrogen-regulated metabolic and immune systems during both Aging is associated with a reduction in glucose metabolism chronological and endocrinological aging in the female brain can and consequent increase in chronic low-grade inflammation69 provide insights into ND prevention, diagnosis, and therapy. (Figure 1). Clinical studies revealed that regional cerebral blood In this review, we discuss metabolic changes during pre- flow in mesial frontal cortex is negatively correlated with age in menopausal aging, peri-menopausal aging, and post-menopausal young to mid-life adults70. Meta-analysis in adults between 20 aging; their impact on neuroinflammation during each of and 50 years of age suggested that the reduction in brain glu- the chronological and endocrinological transition stages; and cose uptake was most likely due to a reduction in brain aerobic the implications for NDs. glycolysis71. Similar findings were evident in a mouse model of the natural menopausal transition72. In comparison with young Menopause and estrogen regulation of brain female mice, mid-aged females had a significant reduction metabolism and inflammation in brain glucose uptake, which was accompanied by significant The menopausal transition is characterized by reproductive senes- down-regulation of neuronal glucose transporter 3 (GLUT3) and cence
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