Biology subjects

Fuentealba, M.

Publications and source records attributed to Fuentealba, M..

12 recordsLinked to original sources

bioRxiv2026

Immuno-Proteomic Age of Cardiovascular Etiology (iPACE) Signature Predicts Cardiovascular Risk in Elderly Patients

Despite advances in clinical care, cardiovascular disease (CVD) remains the leading cause of disability and mortality worldwide. While age alone is a primary risk factor for CVD, accumulating evidence suggests the immune system influences the initiation and progression of CVD pathophysiology, particularly in heart failure with preserved ejection fraction (HFpEF) and atherosclerotic CVD (ASCVD). Here, using two independent cohorts of older adults, we develop a thirty-protein signature of age based on serum immune proteomics, which correlates with HFpEF and ASCVD risk and mortality (Immuno-Proteomic Age of Cardiovascular Etiology, iPACE). We find aging-related circulating immune proteins associated with ASCVD and HFpEF-specific resilience and susceptibility that may be used as potential prognostic, diagnostic, or therapeutic targets.

immunology↗

bioRxiv2026

Simulated microgravity induces aging phenotypes in human organoids

Simulated microgravity provides a controlled perturbation for testing how loss of mechanical load affects human tissues. After 24 hours in rotating-wall vessels, neural, cardiac and tonsil organoids developed tissue-specific transcriptional responses that overlapped published spaceflight datasets, accompanied by higher transcriptomic-age estimates in neural and cardiac models, altered cardiac-organoid contraction dynamics and modified tonsil-organoid antiviral gene-expression signatures. These findings establish a multi-organoid framework for studying acute responses to gravitational unloading.

molecular biology↗

bioRxiv2026

Inferring organ aging, hallmark of aging and senescence scores from blood and facial photographs

Aging progresses asynchronously across organs, motivating the development of organ-resolved aging clocks. Direct assessment of organ aging in living humans, however, is largely impractical. Here, we construct tissue-specific transcriptomic aging clocks and infer organ biological age from paired whole-blood (blood-organ age) and tissue RNA sequencing data in the GTEx project. We observe high variability both in the strength of aging signatures across organs and in the ability to predict organ age and organ scores from blood. Pathway analysis shows that organ aging clocks are dominated by biological processes that differ across tissues. Age-associated multi-organ modules identified in an aging multi-organ network correlation analysis and organ age features causally mediated through organ-blood-organ transcriptomic interactions support a role for systemic signaling in coupling organ aging processes. Given the established role of cellular senescence as a driver of tissue dysfunction and its tissue-specific accumulation during aging, we extend this framework to estimate burden of organ-level senescence and hallmarks of aging. Using senescence- and hallmark-associated gene sets, we derive tissue-specific senescence and hallmark scores (organ scores) and demonstrate that these burdens across multiple organs can be inferred from blood transcriptomes (blood-organ scores). Finally, in pursuit of extending these models to other blood omics and alternative non-invasive assessments, we evaluate whether blood methylation (methylation-blood-organ age and scores) and facial photographs (facial-blood-organ age and scores) can serve as proxies for blood-organ age and blood-organ scores in independent cohorts (Edifice Health and Health and Retirement Study). The methylation- and facial-blood-organ age and scores were associated with mortality in additional testing cohorts (Framingham Heart Study and IMDB-WIKI dataset). These results establish a cross-modal framework for inferring organ-specific aging and senescence from minimally invasive data.

bioinformatics↗

bioRxiv2026

Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related neurodegenerative disorders that display overlapping features. The hexanucleotide repeat expansion GGGGCC (G4C2) in the C9ORF72 gene is the most common cause of ALS and FTD, which results in the accumulation of dipeptide-repeat protein aggregates. Regulation of protein synthesis at the level of the initiation factor eIF2 has been suggested as a transversal event contributing to neurodegeneration in ALS and FTD. eIF2 phosphorylation blocks protein synthesis to alleviate protein misfolding overload, but conversely it can reduce the expression of synaptic proteins resulting in neuronal dysfunction. Dibenzoylmethane (DBM) is a small molecule that reverses the translational attenuation mediated by eIF2 phosphorylation which has been shown to alleviate neurodegeneration in prion-infected mice and Tau transgenic animals. Here we investigated the efficacy of the oral administration of DBM in protecting a mouse model of C9ORF72 pathogenesis. Treatment of mice with 0.5% of DBM mixture in powdered food ad libitum was sufficient to prevent cognitive impairment in C9ORF72 mice. Unexpectedly, DBM treatment did not modify the content of poly(GA) and poly(GR) protein inclusion in the hippocampus and brain cortex. Proteomic profiling of brain tissue indicated that DBM administration corrected nearly 70% of the changes in gene expression triggered by expanded G4C2, where the main pathways modified by DBM were related to cytoskeleton organization, ALS, and metabolic processes. Most proteins corrected by DBM in our C9ORF72 model were also altered in the brain of human FTD/ALS patients. Overall, our results reinforce the idea that targeting protein synthesis with small molecules in patients carrying C9ORF72 mutations may result in improved cognitive capacity.

molecular biology↗

bioRxiv2026

Quantification of domain-specific intrinsic capacity using mortality data

Functional health is centered on five domains of Intrinsic Capacity (IC): locomotion, cognition, vitality, psychological and sensory capacity. Therefore, measuring IC at the domain-specific level is the cornerstone for developing preventive interventions to help individuals preserve their independence. In this study, we used 63 clinical features from the UK Biobank to develop IC age, an 18-year mortality risk estimator that approximates an individuals biological age associated with the decline of each IC domain. By establishing proteomic surrogates of IC age, we find immune system activation across domains and provide a proteomic framework that may facilitate scalable monitoring of functional health decline.

systems biology↗

bioRxiv2026

Simulated Microgravity Recapitulates Aspects of Biological Aging in Humans

Spaceflight and microgravity profoundly affect human physiology and have been proposed to recapitulate key features of biological aging, yet the underlying mechanisms remain incompletely understood. Here, we performed whole-genome transcriptomic profiling to define immune cell alterations associated with both natural aging and simulated microgravity. Leveraging the longitudinal nature of the Stanford 1,000 immunomes Project, we compared peripheral blood mononuclear cells (PBMCs) exposed to rotating wall vessel bioreactor with matched samples collected up to 9 years later from the same individuals. We quantified changes across aging hallmarks, molecular pathways, gene modules, cellular energetics, disease risk and vaccine-response signatures. Microgravity-induced transcriptional closely tracked subject-level aging trajectories spanning across disease risk domains including those affecting the metabolic, musculoskeletal and circulatory systems, and multiple aging hallmarks involving nutrient sensing, intrinsic capacity, chronic inflammation, proteostasis, cellular senescence and metabolic regulation. Independent validation using Single-Cell Energetic Metabolism by Profiling Translation Inhibition (SCENITH) profiling confirmed these observed metabolic adaptations and revealed reduced mitochondrial dependence with minimal compensatory glucose dependence across immune cell subsets, features that strongly parallel aging biology. Consistent with previous findings, longitudinal changes indicated that close of 1/3 of participants do not follow population trajectories but these can be partly predicted with simulated microgravity exposure. Together, this within-donor framework establishes simulated microgravity as a scalable and experimentally tractable platform to model aspects of biological aging in humans and accelerating the prioritization of candidate countermeasures for spaceflight and aging on Earth.

immunology↗

bioRxiv2026

Proteogenomic Profiling Reveals a Distinct Endogenous p16INK4a-Associated Senescence Signature in the Human Ovary.

The tumor suppressor and cell cycle regulator, p16INK4a (p16), has been extensively linked to cellular senescence, and its accumulation can reflect endogenous senescence within ovarian tissue. However, gene and protein signatures associated with p16 have not been well defined in human tissue. We utilized immunohistochemical (IHC) staining for P16 to identify distinct positive (P16+) and negative (P16-) regions within the ovarian cortex and employed the GeoMx Digital Spatial Profiler for simultaneous proteomic and transcriptomic analyses on cortical tissue cores. Differential expression and translation between p16-positive and p16-negative cores identified genes and proteins that are cellular senescence related (e.g., CDKN1A, GADD45B, GADD45G, and MYC) or key regulators of the extracellular matrix (e.g., collagen I, ADAMTS4, and MMP11). Additionally, the transcriptomic signature identified here was significantly enriched for the spatially derived ovarian p16-associated signature, BuckSenOvary, but not for other senescence gene sets. Lastly, given the association between changes to the extracellular matrix in aged ovaries and ovarian cancer, we compared genes upregulated and downregulated in p16-positive regions relative to p16-negative regions against multiple ovarian cancer transcriptomic datasets. These findings provide new insight into the molecular landscape of naturally occurring ovarian senescence and its possible relationship to age-associated disease processes, including cancer development.

cell biology↗

bioRxiv2024

Blood Omics Models for System-Specific Mortality Risk Estimation

Traditional blood-based aging clocks provide an estimate of a persons overall biological age. However, physiological systems and organs age at different rates in an individual, and anti-aging interventions often target specific physiological systems. Therefore, there is a growing need for methods capable of assessing biological age at the level of specific physiological systems. Here, we used blood chemistry and cell count data from 456,180 individuals in the UK Biobank (UKB) to develop mortality-based predictors of biological age across 9 physiological systems matching WHOs International Classification of Disease (ICD-10) chapters (DiseaseAge). We applied DiseaseAge to the Health and Retirement Study (HRS) cohort and validated its ability to identify biologically older systems in individuals diagnosed or deceased from age-related diseases affecting those systems. For instance, individuals diagnosed with high blood pressure, heart attack, congestive heart failure, or angina exhibited a biologically older circulatory system than other systems. Similarly, individuals with accelerated aging in the circulatory, musculoskeletal, or respiratory systems displayed higher risk of mortality from conditions associated with these systems. Additionally, we showed that individuals within the top 5% biologically older metabolic, circulatory, respiratory and mental systems exhibited increased risk of developing diabetes, high blood pressure, lung disease and dementia, respectively. Finally, we used metabolomics and proteomics data in the UKB and epigenomics and transcriptomics in HRS to generate omics surrogates of DiseaseAge for all physiological systems and created an online resource for their calculation.

systems biology↗

bioRxiv2024

A Novel Blood-Based Epigenetic Clock for Intrinsic Capacity Predicts Mortality and is Associated with Clinical, Immunological and Lifestyle Factors

Age-related decline in intrinsic capacity (IC), defined as the sum of an individuals physical and mental capacities, is a cornerstone for promoting healthy aging and longevity, as it emphasizes maximizing function throughout the aging process instead of merely treating diseases. However, accurate assessments of IC are resource-intensive, and the molecular and cellular basis of its decline are poorly understood. Herein, we used the INSPIRE-T cohort, consisting of 1,014 individuals aged 20 to 102, to construct the IC clock, a DNA methylation (DNAm)-based predictor of IC trained on the clinical evaluation of cognition, locomotion, psychological well-being, sensory abilities, and vitality. In the Framingham Heart Study, age-adjusted DNAm IC correlates with first- and second-generation epigenetic clocks, predicts all-cause mortality, and is strongly associated with changes in molecular and cellular immune and inflammatory biomarkers, functional and clinical endpoints, health risk factors, and diet.

genomics↗

bioRxiv2023

Simultaneous neuronal expression of human amyloid-β and Tau genes drives global phenotypic and multi-omic changes in C. elegans

Alzheimers disease (AD) and Alzheimers related diseases (ADRD) are prevalent age-related neurodegenerative disorders characterized by the accumulation of amyloid-{beta} (A{beta}) plaques and Tau neurofibrillary tangles. The nematode Caenorhabditis elegans (C. elegans) serves as an invaluable model organism in diseases of old age-due to its rapid aging. Here we performed an unbiased systems analysis of a C. elegans strain expressing both A{beta} and Tau proteins within neurons. We set out to determine if there was a phenotypic interaction between A{beta} and Tau. In addition, we were interested in determining the temporal order of the phenotypic and multi-omic (geromic) outcomes. At an early stage of adulthood, we observed reproductive impairments and mitochondrial dysfunction consistent with disruptions in mRNA transcript abundance, protein solubility, and metabolite levels. Notably, the expression of these neurotoxic proteins exhibited a synergistic effect, leading to accelerated aging. Our findings shed light on the close relationship between normal aging and ADRD. Specifically, we demonstrate alterations to metabolic functions preceding age-related neurotoxicity, offering a resource for the development of new therapeutic strategies.

systems biology↗

bioRxiv2022

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer`s disease by improving synaptic function and proteostasis

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimers disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

animal behavior and cognition↗

bioRxiv2020

Transcriptomic profiling of long- and short-lived mutant mice implicates mitochondrial metabolism in ageing and shows signatures of normal ageing in progeroid mice

Genetically modified mouse models of ageing are the living proof that lifespan and healthspan can be lengthened or shortened, yet the molecular mechanisms behind these opposite phenotypes remain largely unknown. In this study, we analysed and compared gene expression data from 10 long-lived and 8 short-lived mouse models of ageing. Transcriptome-wide correlation analysis revealed that mutations with equivalent effects on lifespan induce more similar transcriptomic changes, especially if they target the same pathway. Using functional enrichment analysis, we identified 58 gene sets with consistent changes in long- and short-lived mice, 55 of which were up-regulated in long-lived mice and down-regulated in short-lived mice. Half of these sets represented genes involved in energy and lipid metabolism, among which Ppargc1a, Mif, Aldh5a1 and Idh1 were frequently observed. Based on the gene sets with consistent changes and also the whole transcriptome, we observed that the gene expression changes during normal ageing resembled the transcriptome of short-lived models, suggesting that accelerated ageing models reproduce partially the molecular changes of ageing. Finally, we identified new genetic interventions that may ameliorate ageing, by comparing the transcriptomes of 51 mouse mutants not previously associated with ageing to expression signatures of long- and short-lived mice and ageing-related changes. HighlightsO_LITranscriptomic changes are more similar within mutant mice that show either lengthened or shortened lifespan C_LIO_LIThe major transcriptomic differences between long- and short-lived mice are in genes controlling mitochondrial metabolism C_LIO_LIGene expression changes in short-lived, progeroid, mutant mice resemble those seen during normal ageing C_LI

genomics↗