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Autophagy Flux Is Remodeled Sex- and Cell Type-Specifically During Human Aging, and Is Linked to Reduced Physical Function in Older AdultsAutophagy is widely proposed to decline with age; however, direct evidence across human cell types remains limited. Moreover, it is unclear whether age-associated changes in autophagy-gene transcription are accompanied by corresponding changes in autophagic activity, and whether autophagic activity relates to physiological function during aging. We performed transcriptomic and functional autophagy analyses across subject-matched human cell types from a healthy aging cohort. Autophagy-related...
Objective: Despite most often used in research and medicine, it is unclear how well blood metabolite levels can reflect metabolic changes in tissues. Methods: We used untargeted metabolomic data from plasma, liver, gastrocnemius muscle, kidney, inguinal fat, and gonadal fat tissues from mice treated with lifespan-extending interventions: caloric restriction, rapamycin, canagliflozin, 17-α estradiol, and acarbose. Results: For each tissue, about 37% of the identified metabolites were also found...
MOTIVATION: Enrichment analysis is a cornerstone of "omics" data interpretation, enabling researchers to connect analysis results to biological processes and generate testable hypotheses. Enrichment analysis in metabolomics poses distinct challenges for interpretation and multi-omics integration due to the lack of well-defined and consistent connections to well-curated gene-centered biological knowledge repositories. To address these challenges, we developed hypeR-GEM, a methodology and...
We explored the epigenomic effects of vegan diet (VD) versus meat-rich diet (MR) and identified mechanisms that help to explain how VD affects epigenetic gene regulation. Genome-wide DNA methylation profiles in 48 healthy individuals were investigated after a 1-month randomized isocaloric dietary intervention comparing effects of a VD versus a MR. Genome-wide DNA methylation analysis revealed changes in differentially methylated positions following dietary intervention, with the VD group showing...
Human neurons develop more slowly than non-human primate (NHP) neurons, a phenomenon called neoteny, but research has primarily focused on neuron-intrinsic drivers. We hoped to further elucidate any species-specific divergence in function and the astrocytes' role in influencing species-specific neurodevelopment rate. In this study, we identified a delayed onset of gliogenesis in human versus NHP organoid models. Transcriptomic and ^(13)C metabolic flux analyses of iPSC-derived astrocytes...
The pace of aging can be delayed by mutations, dietary manipulations, and drugs, yet the metabolic mechanisms underlying longevity interventions remain poorly understood. Here we present a multi-tissue metabolomic analysis of male UM-HET3 mice treated from 4 to 12 months of age with five validated longevity interventions: rapamycin, acarbose, 17α-estradiol, canagliflozin, or caloric restriction. Using a feature-stabilized XGBoost pipeline applied to seven tissues, we show that metabolomic...
RSNet is an open-source R package that provides a resampling-based framework for robust and interpretable network inference, designed to address the limited-sample-size challenges common in high-dimensional (e.g., 'omics') data. It supports both the estimation of partial correlation networks modeled as Gaussian networks¹ and conditional Gaussian Bayesian networks for mixed data types that combine continuous and discrete variables². The framework incorporates multiple resampling strategies,...
De 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...
The HUPO Human Proteome Project (HPP) aims to complete the human protein parts list by detecting evidence of expression and of function for all proteins in the human proteome, and make proteomics an integral part of multiomics studies of health and disease. Here we describe the state of the 2025 HPP reference proteome of 19,435 proteins, based on GENCODE v48, UniProtKB 2025_03, Human Protein Atlas 24, MassIVE-KB 2023, and PeptideAtlas 2025-01. We evaluate the progress in the past year, with...
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...