Biology subjects

Chen, K. L.

Publications and source records attributed to Chen, K. L..

7 recordsLinked to original sources

bioRxiv2026

Organelle Aging Predicts Human Disease

Aging affects cellular organelles differently, but whether subcellular aging predicts human disease remains unknown. Here, we integrated organelle-enriched proteins in plasma and cerebrospinal fluid proteomes from 61,931 individuals to model aging of 10 organelles across the human lifespan. Organelle aging was heterogeneous with lysosomes, plasma membranes, and Golgi compartments accelerating rapidly after age 60. Individuals with four or more prematurely aged compartments exhibited up to 22-fold higher kidney disease risk and up to 8-fold higher mortality risk. Major diseases are characterized by distinct organelle aging signatures and disease risk increased with the number of accelerated organelles. APOE-{varepsilon}4 dosage was associated with lysosomal and mitochondrial aging and reduced PDP1 levels, implicating altered energy metabolism. Decomposition of organelle signature coefficients into biological programs further showed that diseases are associated with distinct subcellular patterns. These findings establish organelle-resolved aging as a measurable dimension of human biology, revealing subcellular mechanisms underlying disease susceptibility and resilience.

systems biology↗

bioRxiv2026

Sexual reproduction impacts vertebrate organ aging

Sexual reproduction is a central component of life. Yet, an unanswered question remains: how does sexual reproduction shape physiology and health across an individual's lifetime? Unlike other external factors such as diet and exercise, the impact of sexual reproduction on organ health during aging is far less studied, particularly in vertebrates. Here, we develop the short-lived killifish as a vertebrate model to study how lifelong mating affects organ aging. We discover that mating regulates liver aging in a cell-type and sex-specific manner. In old female livers, mating dampened hepatocyte inflammation and reduced myeloid cell levels, and machine-learning models predicted that mating led to a 'younger' transcriptomic age in several liver cell types. Functionally, mating reduced hepatic accumulation of several lipid classes and was associated with enhanced female resilience against the liver toxin acetaminophen. More broadly, mating induced anti-inflammatory and metabolic rewiring transcriptomic signatures in the brain and gut, indicating that mating may affect vertebrate organ aging more globally. Using publicly available human datasets and plasma proteomics aging clocks, we observed an association between sexual experience and a 'younger' plasma proteomic age of several cell types, including hepatocytes. Our work provides evidence that lifelong mating reshapes the physiological context during aging in a vertebrate, highlighting an understudied connection between vertebrate sexual history, health, and aging.

genomics↗

bioRxiv2026

Cellular Aging Signatures in the Plasma Proteome Record Human Health and Disease

Aging is asynchronous across cells and organs, but whether plasma proteins can capture cell type-specific aging and predict disease and mortality remains unknown. We developed machine learning models to estimate the biological age of more than 40 distinct cell types--spanning neuronal, immune, glial, endocrine, epithelial, and musculoskeletal origins--using over 7,000 plasma proteins measured in 60,000 individuals across three cohorts, comprising the largest human plasma proteomics aging study to date. Individuals showed heterogeneous aging profiles, with 20-25% exhibiting accelerated aging in a single cell type and 1-3% across ten or more cell types. APOE genotype showed antagonistic aging effects in different cell types: APOE4 carriers exhibited older astrocytes but younger macrophages, while APOE2 carriers showed the inverse. Cellular aging signatures were uniquely associated with disease status and predicted incident disease and mortality over 15 years of follow-up. Amyotrophic lateral sclerosis (ALS) showed the strongest association with skeletal myocyte aging (hazard ratio = 12.7 for extreme accelerated versus youthful aging). In Alzheimers disease (AD), prevalent cases showed accelerated aging across multiple neural and peripheral cell types, with extreme astrocyte aging conferring AD risk comparable to APOE4 carrier status. Moreover, extreme astrocyte aging increased AD risk in APOE4/4 carriers threefold, while youthful astrocytes strikingly reduced risk. Beyond neurodegeneration, respiratory cell aging identified smokers at 58% higher lung cancer risk, and myeloid aging identified normoglycemic individuals at higher diabetes risk. Both specific cellular vulnerabilities and cumulative aging burden influenced survival, wherein youthful immune or neuronal profiles were protective. A polycellular aging risk score provided robust mortality risk stratification across platforms and cohorts. These findings establish a framework for quantifying biological aging at the cellular resolution using plasma proteomics, revealing heterogeneity in aging trajectories and their impact on disease susceptibility and resilience.

neuroscience↗

bioRxiv2022

Multi-omics Analysis Identifies IgG2b Class-Switching with ALCAM-CD6 Co-Stimulation in Lymph Nodes During Advanced Inflammatory-Erosive Arthritis

Defective lymphatic drainage and B-cell translocation into joint-draining lymph node sinuses are pathogenic phenomena in patients with severe rheumatoid arthritis (RA). However, the molecular mechanisms underlying this lymphatic dysfunction remain poorly understood. Here, by utilizing spatial and single-cell transcriptomics in tumor necrosis factor transgenic (TNF-Tg) mice, we characterized functional genomic changes in popliteal lymph nodes (PLNs) of "Early" and "Advanced" RA to determine the mechanisms orchestrating B-cell differentiation. We first show that Ighg2b expression localized to Marco+ sinuses and negatively correlated with bone volumes in ipsilateral joints. We further reveal that Advanced PLNs exhibited a concomitant accumulation of iron-laden macrophages and T-cells. Mechanistically, crosstalk between ALCAM+ macrophages and CD6+ T-cells was identified as a co-stimulatory pathway promoting IgG2b class-switching. These findings were validated by immunohistochemistry, flow cytometry, ELISPOT, and clinical correlates. Collectively, we propose that ALCAM-CD6 co-stimulation activates T cells, initiating IgG2b class-switching and plasma cell differentiation in RA flare.

immunology↗

bioRxiv2020

The Endothelial Protein C Receptor plays an essential role in the maintenance of Pregnancy

Placenta-mediated pregnancy complications are a major challenge in the management of maternal-fetal health. Maternal thrombophilia is a suspected risk factor but the role of thrombotic processes in these complications and the potential for antithrombotic treatment have remained unclear. Endothelial Protein C Receptor (EPCR) is an anticoagulant protein highly expressed in the placenta. EPCR autoantibodies and specific gene variants of EPCR are associated with poor pregnancy outcomes. In mice, fetal EPCR deficiency results in placental failure and in utero death. Adult EPCR-deficient mice generated by maintaining placental expression exhibit plasma markers of thrombophilia without overt thrombosis. We demonstrate that inactivation of clotting factor VIII or Protease Activated Receptor 4 (Par4), Par3 or integrin IIb in the mother allows placental development and intrauterine survival of murine embryos lacking EPCR. Rescued EPCR-deficient embryos exhibit thrombosis in placental venous sinuses at late gestation and a high rate of neonatal lethality. In contrast to fetal EPCR deficiency, maternal deficiency of EPCR results in frequent stillbirths and maternal death accompanied by pathological findings that resemble placental abruption and consumptive coagulopathy. Inactivation of Par4, but not clotting factor VIII, prevents maternal death and restores normal pregnancy outcomes. These observations establish a cause-effect relationship between maternal thrombophilia and placental abruption. They demonstrate that sites of uteroplacental thrombosis and the potential response to antithrombotic intervention may differ with gestational age and maternal versus fetal origin of thrombophilia. Our findings highlight the potential for therapeutic inhibition of thrombin-mediated platelet activation in a subset of pregnancy complications. KEY POINTSO_LIMurine model establishes a cause-effect relationship between maternal thrombophilia, retroplacental hemorrhage and severe pregnancy complications. C_LIO_LIThrombin-mediated activation of maternal platelets is a key event in thrombophilia-associated pregnancy complications and a potential target of therapeutic intervention. C_LIO_LIMaternal venous channels in uteroplacental circulation are additional sites of thrombotic pathology associated with adverse neonatal outcomes. C_LI

physiology↗

bioRxiv2020

Loss of vacuolar acidity results in iron sulfur cluster defects and divergent homeostatic responses during aging in Saccharomyces cerevisiae

The loss of vacuolar/lysosomal acidity is an early event during aging that has been linked to mitochondrial dysfunction. However, it is unclear how loss of vacuolar acidity results in age-related dysfunction. Through unbiased genetic screens, we determined that increased iron uptake can suppress the mitochondrial respiratory deficiency phenotype of yeast vma mutants, which have lost vacuolar acidity due to genetic disruption of the vacuolar ATPase proton pump. Yeast vma mutants exhibited nuclear localization of Aft1, which turns on the iron regulon in response to iron sulfur cluster (ISC) deficiency. This led us to find that loss of vacuolar acidity with age in wildtype yeast causes ISC defects and a DNA damage response. Using microfluidics to investigate aging at the single cell level, we observe grossly divergent trajectories of iron homeostasis within an isogenic and environmentally homogeneous population. One subpopulation of cells fails to mount the expected compensatory iron regulon gene expression program, and suffers progressively severe ISC deficiency with little to no activation of the iron regulon. In contrast, other cells show robust iron regulon activity with limited ISC deficiency, which allows extended passage and survival through a period of genomic instability during aging. These divergent trajectories suggest that iron regulation and ISC homeostasis represent a possible target for aging interventions.

molecular biology↗

bioRxiv2018

Dynamics of age-related catastrophic mitotic failures and recovery in yeast

Genome instability is a hallmark of aging and contributes to age-related disorders such as progeria, cancer, and Alzheimers disease. In particular, nuclear quality control mechanisms and cell cycle checkpoints have generally been studied in young cells and animals where they function optimally, and where genomic instability is low. Here, we use single cell imaging to study the consequences of increased genomic instability during aging, and identify striking age-associated genome missegregation events. During these events the majority of mother cell chromatin, and often both spindle poles, are mistakenly sent to the daughter cell. This breakdown in mitotic fidelity is accompanied by a transient cell cycle arrest that can persist for many hours, as cells engage a retrograde transport mechanism to return chromosomes to the mother cell. The repetitive ribosomal DNA (rDNA) has been previously identified as being highly vulnerable to age-related replication stress and genomic instability, and we present several lines of evidence supporting a model whereby expansion of rDNA during aging results in nucleolar breakdown and competition for limited nucleosomes, thereby increasing risk of catastrophic genome missegregation.

molecular biology↗