Decline in brain glucose metabolism is a hallmark of late-onset Alzheimer's disease (LoAD). comprehensive understanding of the dynamic metabolic aging process in brain can provide insights into windows of opportunities to promote healthy brain aging. chronological and endocrinological aging are associated with brain glucose hypometabolism and mitochondrial adaptations in female brain. Using a rat model recapitulating fundamental features of the human menopausal transition, results of transcriptomic analysis revealed stage-specific shifts in bioenergetic systems of biology that were paralleled by bioenergetic dysregulation in midlife aging female brain. Transcriptomic profiles were predictive of outcomes from unbiased, discovery-based metabolomic and lipidomic analyses, which revealed a dynamic adaptation of the aging female brain from glucose centric to utilization of auxiliary fuel sources that included amino acids, fatty acids, lipids, and ketone bodies. coupling between brain and peripheral metabolic systems was dynamic and shifted from uncoupled to coupled under metabolic stress. Collectively, these data provide a detailed profile across transcriptomic and metabolomic systems underlying bioenergetic function in brain and its relationship to peripheral metabolic responses. Mechanistically, these data provide insights into the complex dynamics of chronological and endocrinological bioenergetic aging in female brain. Translationally, these findings are predictive of initiation of the prodromal / preclinical phase of LoAD for women in midlife and highlight therapeutic windows of opportunity to reduce the risk of late-onset Alzheimer's disease. Late onset Alzheimer's disease (LOAD) is a complex disease with approximately a 20-year prodromal period 1-3. The prodromal/preclinical phase of AD is associated with brain glucose hypometabolism, which can be detected in at-risk-groups before diagnosis of the disease, and is predictive of disease progression 4-13. Brain glucose hypometabolism, mitochondrial dysfunction, and reduced oxygen flow in the brain are considered primary risk factors for LOAD 14-18. On the cellular level, aging is associated with reduced glucose transporter expression, compromised hexokinase activity, phosphorylated (inactivated) PDH, and altered levels and activities of key enzymes involved in oxidative phosphorylation 19-36. On the molecular level, aging is associated with significant down regulation of nuclear encoded OXPHOS genes 19,37 and disrupted balance of NAD/NADH, AMP/ ATP, purine and pyrimidine pool 38,39. During midlife, females experience both chronological and endocrinological aging. The perimenopausal to menopausal transition is unique to females, and is linked to deficits in brain glucose metabolism and mitochondrial dysfunction 3,19,40 , which could contribute to the twofold greater lifetime risk of AD in females 41-43. Under normal conditions, brain utilizes glucose as its primary fuel source. Under stress conditions, the brain can adapt to utilize auxiliary fuel sources in respon...

Brain is the most energetically demanding organ of the body, and is thus vulnerable to even modest decline in ATP generation. Multiple neurodegenerative diseases are associated with decline in mitochondrial function, e.g., Alzheimer’s, Parkinson’s, multiple sclerosis and multiple neuropathies. Genetic variances in the mitochondrial genome can modify bioenergetic and respiratory phenotypes, at both the cellular and system biology levels. Mitochondrial haplotype can be a key driver of mitochondrial efficiency. Herein, we focus on the association between mitochondrial haplotype and risk of late onset Alzheimer’s disease (LOAD). Evidence for the association of mitochondrial genetic variances/haplotypes and the risk of developing LOAD are explored and discussed. Further, we provide a conceptual framework that suggests an interaction between mitochondrial haplotypes and two demonstrated risk factors for Alzheimer’s disease (AD), apolipoprotein E (APOE) genotype and chromosomal sex. We posit herein that mitochondrial haplotype, and hence respiratory capacity, plays a key role in determining risk of LOAD and other age-associated neurodegenerative diseases. Further, therapeutic design and targeting that involve mitochondrial haplotype would advance precision medicine for AD and other age related neurodegenerative diseases.

The brain undergoes two aging programs: chronological and endocrinological. This is particularly evident in the female brain, which undergoes programs of aging associated with reproductive competency. Comprehensive understanding of the dynamic metabolic and 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 connecting genetic risk factors for Alzheimer’s disease and other neurodegenerative diseases. In this review, we discuss metabolic phenotypes of pre-menopausal, peri-menopausal, and post-menopausal aging and their consequent impact on the neuroinflammatory profile during each transition state. A critical aspect of the aging process is the dynamic metabolic neuro-inflammatory profiles that emerge during chronological and endocrinological aging. These dynamic systems of biology are relevant to multiple age-associated neurodegenerative diseases and provide a therapeutic framework for prevention and delay of neurodegenerative diseases of aging. While these findings are based on investigations of the female brain, they have a broader fundamental systems of biology strategy for investigating the aging male brain. Molecular characterization of alterations in fuel utilization and neuroinflammatory mechanisms during these neuro-endocrine transition states can inform therapeutic strategies to mitigate the risk of Alzheimer’s disease in women. We further discuss a precision hormone replacement therapy approach to target symptom profiles during endocrine and chronological aging to reduce risk for age-related neurodegenerative diseases.

Perimenopause marks initiation of female reproductive senescence with age-of-onset 47% heritable suggesting that factors other than inheritance regulate this endocrine aging transition. To elucidate these factors, we characterized transcriptional and epigenomic changes across endocrine aging transitions using a rat model recapitulating characteristics of human perimenopause. RNAseq analysis revealed that hypothalamic aging precedes perimenopause. In the hypothalamus, global DNA methylation declined with both age and reproductive senescence. Treatment with the DNA-methyltransferase-1 inhibitor accelerated transition to reproductive senescence, menopause, whereas supplementation with the S-adenosyl-methionine precursor methionine delayed onset of perimenopause and endocrine aging. Genome-wide epigenetic analysis revealed DNA methylation of genes required for hormone signaling, glutamate signaling, and melatonin and circadian pathways. Specific epigenetic changes in these signaling pathways provide insight into origin of perimenopause-associated neurological symptoms such as insomnia. Collectively, these data provide evidence that female neuroendocrine aging precedes ovarian failure and that DNA methylation regulates the onset and duration of perimenopause.

Objective: PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. Methods: In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. Results: Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])−1.61, [−2.79, −0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (−1.38, −0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. Conclusion: Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.