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"Erica Weiss"
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Plasma proteomic profile of age, health span, and all‐cause mortality in older adults
Aging is a complex trait characterized by a diverse spectrum of endophenotypes. By utilizing the SomaScan® proteomic platform in 1,025 participants of the LonGenity cohort (age range: 65–95, 55.7% females), we found that 754 of 4,265 proteins were associated with chronological age. Pleiotrophin (PTN; β[SE] = 0.0262 [0.0012]; p = 3.21 × 10−86), WNT1‐inducible‐signaling pathway protein 2 (WISP‐2; β[SE] = 0.0189 [0.0009]; p = 4.60 × 10−82), chordin‐like protein 1 (CRDL1; β[SE] = 0.0203[0.0010]; p = 1.45 × 10−77), transgelin (TAGL; β[SE] = 0.0215 [0.0011]; p = 9.70 × 10−71), and R‐spondin‐1(RSPO1; β[SE] = 0.0208 [0.0011]; p = 1.09 × 10−70), were the proteins most significantly associated with age. Weighted gene co‐expression network analysis identified two of nine modules (clusters of highly correlated proteins) to be significantly associated with chronological age and demonstrated that the biology of aging overlapped with complex age‐associated diseases and other age‐related traits. The correlation between proteomic age prediction based on elastic net regression and chronological age was 0.8 (p < 2.2E−16). Pathway analysis showed that inflammatory response, organismal injury and abnormalities, cell and organismal survival, and death pathways were associated with aging. The present study made novel associations between a number of proteins and aging, constructed a proteomic age model that predicted mortality, and suggested possible proteomic signatures possessed by a cohort enriched for familial exceptional longevity. Age‐associated proteomic changes studied using SomaScan assay showed a plethora of novel proteins and pathways to be associated with aging in older adults. Predicted age using elastic net regression captured mortality better than actual chronological age. Clusters of highly correlated proteins associated with chronological age were also associated with diverse phenotypes and traits giving clues for shared biology.
Journal Article
Organ aging signatures in the plasma proteome track health and disease
Animal studies show aging varies between individuals as well as between organs within an individual
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, but whether this is true in humans and its effect on age-related diseases is unknown. We utilized levels of human blood plasma proteins originating from specific organs to measure organ-specific aging differences in living individuals. Using machine learning models, we analysed aging in 11 major organs and estimated organ age reproducibly in five independent cohorts encompassing 5,676 adults across the human lifespan. We discovered nearly 20% of the population show strongly accelerated age in one organ and 1.7% are multi-organ agers. Accelerated organ aging confers 20–50% higher mortality risk, and organ-specific diseases relate to faster aging of those organs. We find individuals with accelerated heart aging have a 250% increased heart failure risk and accelerated brain and vascular aging predict Alzheimer’s disease (AD) progression independently from and as strongly as plasma pTau-181 (ref.
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), the current best blood-based biomarker for AD. Our models link vascular calcification, extracellular matrix alterations and synaptic protein shedding to early cognitive decline. We introduce a simple and interpretable method to study organ aging using plasma proteomics data, predicting diseases and aging effects.
Blood plasma protein data was combined with machine learning models for a simple method to determine differences in organ-specific aging; the study provides a basis for the prediction of diseases and aging effects using plasma proteomics.
Journal Article
Conscientious Objectors in Israel
InConscientious Objectors in Israel, Erica Weiss examines the lives of Israelis who have refused to perform military service for reasons of conscience. Based on long-term fieldwork, this ethnography chronicles the personal experiences of two generations of Jewish conscientious objectors as they grapple with the pressure of justifying their actions to the Israeli state and society-often suffering severe social and legal consequences, including imprisonment.While most scholarly work has considered the causes of animosity and violence in the Israeli-Palestinian conflict,Conscientious Objectors in Israelexamines how and under what circumstances one is able to refuse to commit acts of violence in the midst of that conflict. By exploring the social life of conscientious dissent, Weiss exposes the tension within liberal citizenship between the protection of individual rights and obligations of self-sacrifice. While conscience is a strong cultural claim, military refusal directly challenges Israeli state sovereignty. Weiss explores conscience as a political entity that sits precariously outside the jurisdictional bounds of state power. Through the lens of Israeli conscientious objection, Weiss looks at the nature of contemporary citizenship, examining how the expectations of sacrifice shape the politics of both consent and dissent. In doing so, she exposes the sacrificial logic of the modern nation-state and demonstrates how personal crises of conscience can play out on the geopolitical stage.
eBook
Genetic variants associated with age‐related episodic memory decline implicate distinct memory pathologies
BACKGROUND Approximately 40% of people aged ≥ 65 experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes. METHODS We investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All‐atom molecular dynamics simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline. RESULTS In addition to the common polygenic risk of Alzheimer's disease, we identified and replicated rare variant associations in ITSN1 and CRHR2. Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L‐serine synthesis. DISCUSSION Our study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogenous memory pathologies mediated by rare coding variants. Highlights We demonstrated the contribution of the common polygenic risk of Alzheimer's disease to episodic memory decline. We discovered and replicated two risk genes associated with episodic memory decline implicated by rare variants, were discovered and replicated. We demonstrated molecular mechanisms and potential novel memory pathologies underlying interfacial rare coding variants. Molecular dynamics simulations were performed to understand the downstream effects of risk rare coding variants.
Journal Article
A Frailty‐Based Plasma Proteomic Signature Capturing Overall Health and Well‐Being in Older Adults
Frailty is an age‐related syndrome characterized by an increased vulnerability to adverse health outcomes in the face of stressors. By deriving a blood‐based proteomic signature for frailty, the current study aimed to enhance the understanding of frailty biology and created a person‐specific predictor for the risk of frailty and other adverse age‐related health outcomes. A 25‐protein signature (proteomic frailty index [pFI]) predictive of the cumulative frailty index (FI) in the LonGenity cohort was derived using a penalized regression method. The pFI was significantly correlated with the FI at baseline (Pearson r = 0.58) and showed significant associations with age‐related chronic conditions, incident mortality, and clinical measures. In an independent cohort of 5195 participants in the Atherosclerosis Risk in Communities study, pFI was successfully validated with measured FI (r = 0.61, p < 0.001) and was associated with physical frailty at baseline (p < 0.001). The pFI was significantly associated with physical, clinical, and cognitive measures, as well as incident mortality (HR [95% CI] = 1.13 [1.12–1.14]) and dementia (HR [95% CI] = 1.07 [1.05–1.09]) after accounting for demographic factors. The pFI was further validated against FI (r = 0.45, p < 0.001) in a second independent study in 654 participants from the Baltimore Longitudinal Study of Aging. In conclusion, we identified and validated a 25‐protein signature as an index of frailty that also captures overall well‐being, health, and risk for key age‐related diseases. We derived a 25‐protein blood‐based frailty signature (proteomic frailty index, pFI) predictive of the cumulative frailty index. The pFI was validated across independent cohorts and was significantly associated with physical, clinical, and cognitive function, as well as incident mortality and dementia, highlighting its potential as a biomarker of overall health and aging.
Journal Article
Telehealth for the cognitively impaired older adult and their caregivers: lessons from a coordinated approach
The Covid-19 pandemic forced providers to alter their delivery of care to special populations, including older adults with cognitive impairment. The Montefiore–Einstein Center for the Aging Brain, a specialty multidisciplinary center for the evaluation and management of patients with neurodegenerative disorders, developed a coordinated approach (Coordinated Care At Risk/Remote Elderly program [CCARRE]) to reach our diverse population during the initial Covid-19 crisis in New York City, USA. In the tele-evaluation of the first 85 patients seen with CCARRE, we recognized unique factors that could improve patient care, lessen burden and optimize access to community resources. Lessons learned from the experience are shared.
Journal Article
Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults
While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.
Journal Article
Visual-somatosensory integration (VSI) as a novel marker of Alzheimer’s disease: A comprehensive overview of the VSI study
Identification of novel, non-invasive, non-cognitive based markers of Alzheimer’s disease (AD) and related dementias are a global priority. Growing evidence suggests that Alzheimer’s pathology manifests in sensory association areas well before appearing in neural regions involved in higher-order cognitive functions, such as memory. Previous investigations have not comprehensively examined the interplay of sensory, cognitive, and motor dysfunction with relation to AD progression. The ability to successfully integrate multisensory information across multiple sensory modalities is a vital aspect of everyday functioning and mobility. Our research suggests that multisensory integration, specifically visual-somatosensory integration (VSI), could be used as a novel marker for preclinical AD given previously reported associations with important motor (balance, gait, and falls) and cognitive (attention) outcomes in aging. While the adverse effect of dementia and cognitive impairment on the relationship between multisensory functioning and motor outcomes has been highlighted, the underlying functional and neuroanatomical networks are still unknown. In what follows we detail the protocol for our study, named The VSI Study, which is strategically designed to determine whether preclinical AD is associated with neural disruptions in subcortical and cortical areas that concurrently modulate multisensory, cognitive, and motor functions resulting in mobility decline. In this longitudinal observational study, a total of 208 community-dwelling older adults with and without preclinical AD will be recruited and monitored yearly. Our experimental design affords assessment of multisensory integration as a new behavioral marker for preclinical AD; identification of functional neural networks involved in the intersection of sensory, motor, and cognitive functioning; and determination of the impact of early AD on future mobility declines, including incident falls. Results of The VSI Study will guide future development of innovative multisensory-based interventions aimed at preventing disability and optimizing independence in pathological aging.
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