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ChREBP-mediated regulation of lipid metabolism in liver and brown adipose tissue of long-lived miceDe novo lipogenesis (DNL) is a metabolic process by which carbohydrates are converted into fatty acids and used for immediate energy or stored as triglycerides for later use. Increased DNL in brown adipose tissue (BAT) is believed to be a marker of metabolic health, but indicates poor metabolism if upregulated in hepatic tissue. ChREBP is a primary regulator of whole-body DNL and promotes production of key enzymes including fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA...
Workflow management systems (WMS) are essential for creating and automating multi-step data analyses and ensuring the reproducibility of biological insights. Although numerous WMS solutions exist, few provide deep integration of command-line software with the R and Bioconductor ecosystems, where a substantial portion of statistical modeling and downstream scientific analysis is performed by a large user base. systemPipeR addresses this gap by offering a unified environment that links R-based...
The New England Centenarian Study (NECS) provides a unique resource for the study of extreme human longevity (EL). To gain insight into biological pathways related to EL, chronological age and survival, we used an untargeted serum metabolomic approach (> 1400 metabolites) in 213 NECS participants, followed by integration of our findings with metabolomic data from four additional studies. Compared to their offspring and matched controls, EL individuals exhibited a distinct metabolic profile...
Geroscience research benefits from interdisciplinary approaches, team science, and collaborations, which collectively facilitate the discovery of aging mechanisms and their translation into tangible, clinical interventions. Since its inception in 2019, the Midwest Aging Consortium (MAC) has provided an engaging platform for aging researchers in the United States' Midwest to connect, collaborate, and exchange ideas. The Sixth Annual Research Symposium of the MAC held at the Mayo Clinic in...
Enrichment analysis is a cornerstone of "omics" data interpretation, enabling researchers to connect analysis results to biological processes and generate testable hypotheses. While well-established tools exist for transcriptomics and other omics layers, the development of robust enrichment resources for metabolomics remains comparatively limited. To address this gap, we developed hypeR-GEM, a methodology and associated R package that adapts gene set enrichment analysis to metabolomics....
Small-molecule sensing in plants is dominated by chemical-induced dimerization modules. In the abscisic acid (ABA) system, allosteric receptors recruit phosphatase effectors and achieve nM in vivo responses from µM receptor-ligand interactions. This sensitivity amplification could enable ABA receptors to serve as generic scaffolds for designing small-molecule sensors. To test this, we screened collections of mutant ABA-receptors against 2,726 drugs and other ligands and identified 553 sensors...
Tests that can predict whether a drug is likely to extend mouse lifespan could speed up the search for anti-aging drugs. We have applied a machine learning algorithm, XGBoost regression, to seek sets of plasma metabolites (n = 12,000) and peptides (n = 17,000) that can discriminate control mice from mice treated with one of five anti-aging interventions (n = 278 mice). When the model is trained on any four of these five interventions, it predicts significantly higher lifespan extension in mice...
A signature of 16 serum proteins that were previously profiled using the aptamer-based Somascan technology highlighted the roles of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE) and in inflammation. Here, the serum protein signature of APOE is validated and expanded using a combination of mass-spectrometry, ELISA, Luminex, blood transcriptomics, and antibody-based Olink serum proteomics. Some of the findings were replicated in the UK Biobank...
Aging impairs thermoregulatory capacity, yet the metabolic mechanisms remain unclear. We report an organ-resolved metabolome atlas of 2,875 structurally annotated metabolites of old (90-96 weeks) versus young mice (16 weeks) across 22 tissues and four biological matrices. For thermoregulation, aging induces widespread remodeling of mitochondrial cardiolipins, with severe depletion of nascent species in brown adipose tissue (BAT) and a compensatory shift in thermogenic workload from BAT to...
Extensive research has examined the direct effect of APOE alleles on cognitive decline. However, there is limited investigation into the effect of APOE that is explained or mediated through molecular pathways, such as lipids. In this study, we performed a causal mediation analysis to estimate both the direct effect of APOE2 and its indirect effect through 24 lipid species on cognitive function, measured from the digital Clock Drawing Test (CDT) in 1228 Long Life Family Study (LLFS) participants....
The New England Centenarian Study (NECS) provides a unique resource for the study of extreme human longevity (EL). To gain insight into biological pathways related to EL, chronological age and survival, we used an untargeted serum metabolomic approach (> 1,400 metabolites) in 213 NECS participants, followed by integration of our findings with metabolomic data from four additional studies. Compared to their offspring and matched controls, EL individuals exhibited a distinct metabolic profile...
Gaussian Graphical Models (GGMs) are a type of network modeling that uses partial correlation rather than correlation for representing complex relationships among multiple variables. The advantage of using partial correlation is to show the relation between two variables after "adjusting" for the effects of other variables and leads to more parsimonious and interpretable models. There are well established procedures to build GGMs from a sample of independent and identical distributed...
CONCLUSION: We find evidence for heterogeneity in the relationships between social and demographic variables and PAL test results in the large MindCrowd study database. This heterogeneity is likely due to individuals with and without concerns for their cognitive abilities participating in the study. We also find other types of evidence in the data set. Our results should motivate caution in the use of large epidemiological study or survey-oriented data sets to build predictive models of clinical...
Comparative genomics is a powerful approach to illuminate the genetic basis of phenotypic diversity across macro-evolutionary timescales. Recent advances in sequencing, genome assembly, annotation, and comparative methods promoted large-scale analyses that unveiled genomic determinants contributing to differences in cognition, metabolism, and body plans as well as phenotypes with biomedical relevance, such as cancer resistance, longevity, and viral tolerance. These studies highlight joint...
We constructed a polygenic protective score specific to Alzheimer's disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the USA, Europe, and Asia. This AD PPS did not include variants on apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial...
Metformin is the most commonly prescribed glucose-lowering agent worldwide for the treatment of type II diabetes. Due to evidence of improvements in healthspan and lifespan in model organisms, and mechanistic data relevant to the hallmarks of aging, it has been considered a promising candidate in the search for pharmacological interventions that may attenuate the ageing process in humans. Various epidemiological studies have been influential in generating support for this hypothesis. These...
We constructed a polygenic protective score specific to Alzheimer's disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the US, Europe, and Asia. This AD PPS did not include variants on Apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial...
We previously identified a signature of 16 serum proteins that highlighted a role of the e2 allele of APOE in lipid regulation via apolipoprotein B (APOB) and apolipoprotein E (APOE), and in inflammation. The serum proteins were profiled using the aptamer-based Somalogic technology. Here, we validate and expand the serum protein signature of APOE using a combination of mass-spectrometry, ELISA, Luminex, antibody-based Olink proteomics, and blood transcriptomics. We replicate the association...
Precision medicines, or those medicines that are tailored to individual genetic, molecular, physiologic, behavioral, and/or exposure profiles, are being developed at a rapid pace. However, just how precise these interventions are in terms of their mechanisms of action (MOAs), clinical effects, and utility in different individuals, are hard anticipate with current preclinical research and clinical trials strategies. To understand how various genes, processes, organs, clinical phenotypes, etc. may...
Apolipoprotein E (APOE) modifies human aging; specifically, the ε2 and ε4 alleles are among the strongest genetic predictors of longevity and Alzheimer's disease (AD) risk, respectively. However, detailed mechanisms for their influence on aging remain unclear. In the present study, we analyzed multi-omic association patterns across APOE genotypes, sex, and biological age (BA) axes in 2,229 community dwelling individuals. Our analysis, supported by validation in an independent cohort, identified...