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...

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.

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Background Rapid Autopsy Programs offer an opportunity to collect tissue from patients immediately after death, providing critical biological material necessary to develop more effective therapies and improve patient outcomes. Here, we present a step-by-step guide to build a cancer-focused Rapid Autopsy Program, based on our own experiences building “The Legacy Project” at the City of Hope Comprehensive Cancer Center. Methods The linear timeline of events is separated into four phases: 1) Building the Infrastructure, 2) Recruiting and Consenting, 3) Preparing for Death, and 4) Tissue Collection and Follow up. Important considerations and methods for adaptation are discussed throughout the protocol. Discussion Using these methods, we successfully collected a total of 533 specimens from 9 subjects. The average time from death to last specimen acquisition was 6.1 h (range: 4.03–7.66 h; median: 5.71 h). A diverse team with various areas of expertise is critical for successful program implementation. Our goal herein this protocol is to provide a comprehensive framework and foundation for other institutions to use as a model.

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Background: Rapid Autopsy Programs offer an opportunity to collect tissue from patients immediately after death, providing critical biological material necessary to develop more effective therapies and improve patient outcomes. Here, we present a step-by-step guide to build a cancer-focused Rapid Autopsy Program, based on our own experiences building “The Legacy Project” at the City of Hope Comprehensive Cancer Center. Methods: The linear timeline of events is separated into four phases: 1) Building the Infrastructure, 2) Recruiting and Consenting, 3) Preparing for Death, and 4) Tissue Collection and Follow up. Important considerations and methods for adaptation are discussed throughout the protocol. Discussion: Using these methods, we successfully collected a total of 533 specimens from 9 subjects. The average time from death to last specimen acquisition was 6.1 hours (range: 4.03 – 7.66 hours; median: 5.71 hours). A diverse team with various areas of expertise is critical for successful program implementation. Our goal herein this protocol is to provide a comprehensive framework and foundation for other institutions to use as a model.

Background: Colorectal adenoma (CRA) to cancer (CRC) progression involves epigenetic changes including DNA methylation. Here we performed whole genome Bisulfite Next-Generation Sequencing (WGBNGS) on a normal, a tubular adenoma and a tumor patients’ tissue DNA to elucidate epigenetic drivers in normal to cancer progression. Patients and Methods: Genomic DNA was isolated from fresh frozen tissues from a patient with normal colon, from a tubular adenoma lesion (20X depth was performed on these DNA samples., Alignment, mapping and CpG methylation analyses were done. Pyrosequencing and immunohistochemistry (IHC) were used to confirm selected methylation target genes. Results: We identified 94 unique CpG sites hypermethylated in 4 novel genes in adenoma compared to normal and 180 unique CpG sites in 7 genes in cancer. Ingenuity pathway analysis (IPA) showed that the methylated genes including a novel gene ATXN7L1 were involved in WNT pathway, ubiquitination process and cross-talk with B-catenin, in the adenoma. Three of the hypermethylated genes in cancer were, Loc100506436: a novel gene with 17 unique CpG sites (EGFR pathway, cRNA CpG site hypermethylated is part of MEK1/2), GPNMB with 7 unique CpG sites (membrane protein likely in complexes with integrins) and TNFAIP2 with 8 unique CpG sites (its role was noted in Head and neck cancer). IHC confirmed the lack of GPNMB expression in cancer tissues. Conclusion: This work provides insight into differential CpG island methylation profiles in CRA, CRC vs. normal colon tissue and provides a window into the more complex factors, including alteration of known and novel genes as multiple CpG methylation drivers in colorectal carcinogenesis. Investigations into the possible roles of the novel genes targets in the context of early and prognostic methylation biomarker are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 994. doi:1538-7445.AM2012-994