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.
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.
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.
Metastatic disease is understudied largely because of inaccessibility to quality specimens for research use. The Legacy Project, a rapid or “warm”, autopsy program at City of Hope, seeks to overcome this challenge by collecting tissue from metastatic patients immediately (within 6 hours) after their death. This paradigm serves as a specimen resource to address many clinically relevant questions, such as disease heterogeneity and mechanisms driving disease progression. Using this model, we uncovered clinically relevant disease information that is normally unavailable while a subject is alive. In this study, 9 metastatic breast cancer patients and their families were approached and consented prior to death. The cohort includes a diversity of clinical presentations in terms of disease subtype, progression history, organ involvement, and final cause of death. A total of 533 specimens were collected across 9 subjects. The average time from death to specimen acquisition was 6.1 hours (range: 4.03 - 7.66 hours; median: 5.71 hours). Total number of specimens collected from each participant ranged from 38-75, with an average of 60 across all patients; the mean number of tumor-positive specimens collected was 29 (range 12-46); the mean number of non-cancer specimens collected was 31 (range 25-45). In patients with primary estrogen receptor (ER) positive disease, we observed variable heterogeneity in estrogen, progesterone, and ki67 status across metastatic lesions. Furthermore, we observed a profound shift in disease phenotype towards end of life, trending towards complete loss of hormone receptor expression and stark increase of Ki67 levels. At the time of procurement, one third of subjects exhibited clinically unidentified diseased sites in organs not commonly associated with breast cancer metastases a, including ovary, kidney, and pancreas. In two other instances, “resolved” bone specimens (as measured by absence of FTG uptake in PET/CT imaging) were later determined to be >30% tumor positive when assessed by H&E. While these preliminary findings generate more questions than answers regarding mechanisms of metastatic progression and resistance to therapy, they highlight the utility of rapid autopsy in a research setting. We suggest that many unanswered clinical questions can be addressed through interrogation of post-mortem tissues and we urge research institutions to thoughtfully consider adoption of the “rapid autopsy” model. Citation Format: Eliza R Bacon, Kena Ihle, Colt Egelston, Weihua Guo, Diana Simons, Peter P Lee, James Waisman. Utility of rapid autopsy in cancer research: Unexpected findings and lessons learned from warm autopsies of metastatic breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS19-16.
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