Biology subjects

Arpawong, T. E.

Publications and source records attributed to Arpawong, T. E..

4 recordsLinked to original sources

bioRxiv2025

Form and function of actin impacts actin health and aging.

The actin cytoskeleton is a fundamental and highly conserved structure that functions in diverse cellular processes, yet its direct contribution to organismal aging remains unclear. Here, we systematically interrogated how genetic and pharmacologic perturbations of actin structure and function influence lifespan and various hallmarks of aging in Caenorhabditis elegans. Whole-animal and tissue-specific knockdown of actin and key actin-binding proteins (ABPs) - arx-2 (Arp2/3), unc-60 (cofilin), and lev-11 (tropomyosin) - led to premature disruption of filament organization, reduced lifespan, and tissue-specific physiological defects. Bulk and single-nucleus RNA-sequencing revealed that ABP knockdowns elicited a strongly "aged" transcriptome. Actin dysfunction broadly exacerbated many age-associated phenotypes, including mitochondrial dysfunction, lipid dysregulation, loss of proteostasis, impaired autophagy, and intestinal barrier failure. Pharmacological destabilization with Latrunculin A mirrored genetic knockdowns, while mild stabilization with Jasplakinolide modestly extended lifespan, emphasizing that optimal and finely-tuned actin function is critical for healthy aging. Finally, analysis of human genome-wide association data revealed that common ACTB polymorphisms correlate with differences in age-related decline in gait speed, suggesting evolutionary conservation of actins role in healthy aging. Taken together, our results provide a comprehensive and publicly accessible resource that maps, for the first time, how actin integrity intersects with diverse aging pathways across tissues and scales. This descriptive framework is intended to enable future mechanistic discovery by offering a deep, unbiased dataset that can be integrated with emerging studies to define how actin dynamics contribute to aging.

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↗

bioRxiv2022

Hepatic WDR23 proteostasis mediates insulin clearance by regulating insulin degrading enzyme activity

Clearance of circulating insulin is critical for metabolic homeostasis. In the liver, insulin is degraded by the activity of the insulin-degrading enzyme (IDE). Here we establish a hepatic regulatory axis for IDE through WDR23-proteostasis. Wdr23KO mice have increased IDE expression, reduced circulating insulin, and defective insulin responses. Genetically engineered human cell models lacking WDR23 also increase IDE expression and display dysregulated phosphorylation of insulin signaling cascade proteins, IRS-1, AKT2, MAPK, FoxO, and mTOR, similar to cells treated with insulin, which can be mitigated by chemical inhibition of IDE. Mechanistically, the cytoprotective transcription factor NRF2, a direct target of WDR23-Cul4 proteostasis, mediates the enhanced transcriptional expression of IDE when WDR23 is ablated. Moreover, an analysis of human genetic variation in WDR23 across a large naturally aging human cohort in the US Health and Retirement Study reveals a significant association of WDR23 with altered hemoglobin A1C (HbA1c) levels in older adults, supporting the use of WDR23 as new molecular determinant of metabolic health in humans.

cell biology↗

bioRxiv2021

Genetic variation in ALDH4A1 predicts muscle health over the lifespan and across species

Environmental stress can negatively impact organismal aging, however, the long-term impact of endogenously derived reactive oxygen species from normal cellular metabolism remains less clear. Here we define the evolutionarily conserved mitochondrial enzyme ALH-6/ALDH4A1 as a biomarker for age-related changes in muscle health by combining C. elegans genetics and a gene-wide association study (GeneWAS) from aged human participants of the US Health and Retirement Study (HRS)1-4. In a screen for mutations that activate SKN-1-dependent oxidative stress responses in the muscle of C. elegans5-7, we identified 96 independent genetic mutants harboring loss-of-function alleles of alh-6, exclusively. These genetic mutations map across the ALH-6 polypeptide, which lead to age-dependent loss of muscle health. Intriguingly, genetic variants in ALDH4A1 differentially impact age-related muscle function in humans. Taken together, our work uncovers mitochondrial alh-6/ALDH4A1 as a critical component of normal muscle aging across species and a predictive biomarker for muscle health over the lifespan.

genetics↗