Biology subjects

Seals, D. R.

Publications and source records attributed to Seals, D. R..

5 recordsLinked to original sources

bioRxiv2026

Integrated Multiomics Links Metabolic and Inflammatory Remodeling to Arterial Stiffness After the 4,486-km Trans Europe Footrace

RationaleRegular aerobic exercise protects against vascular aging and reshapes the circulating molecular milieu, but the relation between vascular function, circulating molecules, and exercise dose at extreme volumes remains poorly defined. The vascular and molecular consequences of chronic, multi-stage ultra-endurance running are particularly unclear. ObjectiveTo define circulating molecular signatures associated with vascular dysfunction following the 64-stage, 4,486-km Trans Europe Foot Race (TEFR). Methods and ResultsIntegrated multiomics analysis (proteomics, lipidomics, metabolomics) of plasma from 27 finishers revealed a coordinated systemic shift driving an oxidative phenotype. Specifically, we identified altered arginine metabolism and a universal upregulation of lipotoxic ceramides consistent with incomplete fatty acid oxidation. In conjunction, we identified upregulation of innate immune system pathways including the acute phase response and the complement system. Central pulse wave velocity (cPWV) increased significantly after the race, consistent with arterial stiffening. To test whether the post-race circulating milieu could directly influence vascular mechanics, naive murine aortic rings were incubated with participant plasma. Post-race plasma acutely increased aortic elastic modulus, and this effect was attenuated by the superoxide dismutase mimetic TEMPOL, supporting a ROS-dependent component. In human aortic endothelial cells (HAECs), post-race plasma increased reactive oxygen species generation without detectable changes in eNOS phosphorylation, total eNOS abundance, or stimulated nitric oxide production. Endothelial ROS responses were associated with components of the terminal complement pathway. ConclusionsExtreme multi-stage ultra-endurance exercise induces a distinct systemic milieu associated with arterial stiffening through ROS-sensitive mechanisms. This response is characterized by remodeling of arginine-related metabolism, ceramide accumulation, innate immune activation, and oxidative stress, without evidence of reduced measured eNOS abundance or stimulated NO production. These findings identify candidate molecular pathways linking prolonged metabolic stress to vascular dysfunction.

physiology↗

bioRxiv2025

Senolytic treatment with fisetin reverses age-related endothelial dysfunction partially mediated by SASP factor CXCL12

BackgroundAdvancing age is the strongest risk factor for cardiovascular diseases (CVDs), primarily due to progressive vascular endothelial dysfunction. Cellular senescence and the senescence-associated secretory phenotype (SASP) contribute to age-related endothelial dysfunction by promoting mitochondrial oxidative stress and inflammation, which reduce nitric oxide (NO) bioavailability. However, the molecular changes in senescent endothelial cells and their role in endothelial dysfunction with aging remain incompletely unclear. As such, in this study we sought to identify the endothelial cell senescence-related signalling pathways, endothelial-derived SASP factors, and their impact on endothelial function with aging. MethodsSingle-cell transcriptomics was performed on aortas from young (6 months) and old (27 months) mice with and without in vivo senolytic treatment with fisetin (100 mg/kg/day administered in an intermittent dosing paradigm) to characterize endothelial cell senescence and transcript expression changes. Circulating levels of SASP factors were measured to validate transcriptional changes. Plasma exposure and protein addition and inhibiton experiments were conducted in isolated mouse arteries and cultured human endothelial cells to determine the causal role of the circulating SASP milieu and specific SASP factors in mediating endothelial dysfunction and underlying mechanisms-of-action. ResultsSenescent endothelial cells exhibited elevated expression of SASP factors, particularly Cxcl12, which was reversed by fisetin supplementation, with responses also reflected in circulating CXCL12 concentrations. Plasma from old mice impaired endothelial function by inducing vascular cell senescence, reducing NO, increasing mitochondrial oxidative stress, and promoting endothelial-to-mesenchymal transition--effects partially driven by CXCL12 and prevented by fisetin. ConclusionsThese results identify the SASP and CXCL12 as drivers of age-related endothelial dysfunction and establish mechanisms of senolytic intervention with fisetin supplementation. NOVELTY AND SIGNFICANCEO_ST_ABSWhat is known?C_ST_ABSO_LIAdvancing age is the primary risk factor for cardiovascular disease, in part due to progressive endothelial dysfunction. C_LIO_LICellular senescence contributes to age-related endothelial impairment through the secretion of a pro-inflammatory milieu known as the senescence-associated secretory phenotype (SASP), which can affect neighboring cells and tissue function. C_LIO_LISenolytic compounds selectively eliminate senescent cells and improve vascular function in preclinical models of aging. C_LI What new information does this article contribute?O_LIEndothelial cells are highly susceptible to senescence with aging in vivo and are selectively cleared by senolytic treatment with the natural compound fisetin. C_LIO_LISingle-cell transcriptomic profiling identifies CXCL12 as the most highly upregulated SASP factor in senescent endothelial cells and in circulation with aging, both of which are reversed by senolytic treatment with fisetin. C_LIO_LIWe identify a specific circulating SASP factor, CXCL12, as a partial mediator of endothelial dysfunction by inducing mitochondrial oxidative stress, impairing nitric oxide bioavailability, and promoting endothelial-to-mesenchymal transition (Endo, which is restored by senolytic treatment with fisetin. C_LI SummaryThis study provides novel mechanistic insight into how senescent endothelial cells and their secretory products--particularily CXCL12--contribute to age-related endothelial dysfunction. It further demonstrates that senolytic treatment with fisetin reverses these effects, highlighting a promising translational strategy for targeting vascular aging and preserving endothelial health. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=68 SRC="FIGDIR/small/670216v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@b49a8org.highwire.dtl.DTLVardef@110da92org.highwire.dtl.DTLVardef@17dbd54org.highwire.dtl.DTLVardef@1906c6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2025

Cellular Senescence Mediates Doxorubicin Chemotherapy-Induced Aortic Stiffening: Role of Glycation Stress

BackgroundMechanisms underlying Doxorubicin (Doxo) chemotherapy-induced aortic stiffening are incompletely understood. ObjectivesDetermine the role of cellular senescence and the senescence-associated secretory phenotype (SASP) in mediating Doxo-induced aortic stiffening and the influence of senolytic therapy. MethodsAortic stiffness (aortic pulse-wave velocity [PWV]), and associated mechanisms were assessed in young adult p16-3MR mice, a model that allows for genetic-based clearance of senescent cells with ganciclovir [GCV]. Young (4-6 month) mice were injected with Doxo and subsequently treated with GCV or the senolytic ABT263. We evaluated the influence of SASP-associated circulating factors in plasma (the circulating SASP milieu) in mediating aortic stiffening ex vivo (aortic elastic modulus) and examined the contribution of glycation stress. ResultsDoxo increased aortic PWV (425D{+/-}D6 vs. control, 353D{+/-}D5Dcm/sec; P<0.05), an effect prevented by both GCV (348D{+/-}D4Dcm/sec) and ABT263 (342D{+/-}D7Dcm/sec; P<0.05 for both vs. Doxo). Plasma from Doxo-treated mice induced aortic stiffening ex vivo (P<0.05 vs. plasma from control mice), whereas plasma from Doxo-GCV and Doxo-ABT263 groups did not. Glycation stress was implicated in SASP-mediated aortic stiffening with Doxo, as inhibition of receptor mediated glycation stress signaling attenuated plasma-induced aortic stiffening. ConclusionCellular senescence and the circulating SASP milieu contribute to Doxo-induced aortic stiffening. Senolytics hold promise for preserving aortic stiffening following Doxo exposure. Translational perspectiveChemotherapy-induced cardiovascular toxicity is a concern for cancer survivors. This study identifies cellular senescence and the senescence-associated secretory phenotype (SASP) as underlying mechanisms of doxorubicin chemotherapy-induced aortic stiffening - an antecedent to overt cardiovascular disease (CVD). We also provide complementary lines of evidence that glycation stress mediates the mechanistic link between doxorubicin, cellular senescence, the SASP and aortic stiffening. Lastly, we demonstrate the efficacy of senolytic therapy for targeting cellular senescence, the SASP and glycation stress to prevent doxorubicin-induced aortic stiffening. These results offer a novel and clinically actionable approach to preserving vascular health in cancer survivors and mitigating CVD risk.

physiology↗

bioRxiv2025

Cellular Senescence Mediates Doxorubicin Chemotherapy-Induced Vascular Endothelial Dysfunction: Translational Evidence of Prevention with Senolytic Treatment

BackgroundMechanisms underlying Doxorubicin (Doxo) chemotherapy-induced vascular endothelial dysfunction are incompletely understood. ObjectivesDetermine the role of cellular senescence in mediating Doxo-induced vascular endothelial dysfunction and the influence of senolytic therapy as a therapeutic strategy to mitigate endothelial dysfunction with Doxo. MethodsEndothelial function (carotid artery endothelium-dependent dilation [EDD] to increasing concentrations of acetylcholine) and associated mechanisms were assessed in young adult p16-3MR mice (which allow for genetic-based clearance of senescent cells with ganciclovir [GCV]) injected with Doxo and subsequently treated with GCV or ABT263 (senolytic). We also assessed the influence of Doxo and ABT263 ex vivo on EDD to increased flow in human arterioles. ResultsLower peak EDD with Doxo (75{+/-}3% vs. control, 93{+/-}1%; P<0.05) was prevented with GCV (94{+/-}1%; P<0.05) and ABT263 (95{+/-}2%; P<0.05) treatment, which was mediated by preserved nitric oxide bioavailability and prevention of excess mitochondrial oxidative stress. In human arterioles, ex vivo Doxo exposure impaired peak EDD (Doxo, 32{+/-}10% vs. Control, 94{+/-}2%; P<0.05) which was prevented with concomitant incubation of Doxo with ABT263 (82{+/-}7%; P<0.05 vs. Doxo alone; P=0.63 vs. Control). ConclusionWe provide translational evidence that cellular senescence contributes to Doxo-induced vascular endothelial dysfunction and that senolytics hold promise for preserving vascular endothelial function following Doxo exposure.

physiology↗

bioRxiv2020

Healthy aging interventions reduce non-coding repetitive element transcripts

ABSTRACTTranscripts from non-coding repetitive elements (RE) in the genome may be involved in aging. However, they are often ignored in transcriptome studies on healthspan and lifespan, and their role in healthy aging interventions has not been characterized. Here, we analyze RE in RNA-seq datasets from mice subjected to robust healthspan- and lifespan-increasing interventions including calorie restriction, rapamycin, acarbose, 17-α-estradiol, and Protandim. We also examine RE transcripts in long-lived transgenic mice, and in mice subjected to high-fat diet, and we use RNA-seq to investigate the influence of aerobic exercise on RE transcripts with aging in humans. We find that: 1) healthy aging interventions/behaviors globally reduce RE transcripts, whereas aging and age-accelerating treatments increase RE expression; and 2) reduced RE expression with healthy aging interventions is associated with biological/physiological processes mechanistically linked with aging. Thus, RE transcript dysregulation and suppression are likely novel mechanisms underlying aging and healthy aging interventions, respectively.View Full Text

molecular biology↗