About

Anthony J. Donato, PhD, MS, is a faculty member in the Department of Internal Medicine at the Spencer Fox Eccles School of Medicine. His primary research focus is vascular aging, specifically the cellular, molecular, and tissue-specific events that lead to reductions in muscle blood flow during exercise, impair arterial endothelial function, and cause stiffening of large elastic arteries in older rodents and adults. These vascular phenotypes contribute to the age-related decline in functional capacity and the development of cardiovascular disease. His research aims to understand these processes and explore lifestyle interventions such as habitual exercise and caloric restriction that can ameliorate these vascular changes. Additionally, he investigates the cellular pathways conferring the vaso-protective effects of these lifestyle interventions and seeks to activate these pathways pharmacologically to replicate their benefits. Dr. Donato employs human, rodent, and cell models, utilizing a wide range of contemporary translational experimental techniques from microRNA gene expression to ultrasonography to address these questions. His work has contributed to understanding the mechanisms of vascular aging and potential therapeutic strategies to mitigate age-related vascular dysfunction.

Research topics

• Internal medicine
• Medicine
• Pharmacology
• Biology
• Biochemistry
• Gerontology
• Immunology
• Intensive care medicine
• Cell biology
• Bioinformatics
• Cancer research
• Endocrinology

Selected publications

• Compromised muscle energetics and intracellular O2 availability during dynamic contraction in the plantar flexor muscles of patients with systemic sclerosis

  Clinical Science · 2026-05-14

  articleOpen accessSenior author

  The fundamental intracellular mechanisms underlying exercise intolerance and muscle weakness in patients with systemic sclerosis (SSc) are poorly understood. Thus, in 6 SSc patients (55±11 yrs) and 6 age-matched healthy controls (50±13 yrs), we assessed both skeletal muscle metabolism and intracellular O2 availability in vivo during submaximal contractions. Specifically, during dynamic plantar flexion exercise at 40% of maximal aerobic power, we used a multi-modal approach combining phosphorus and proton MRS of deoxymyoglobin, to examine both skeletal muscle energy pathways and intracellular partial pressure of O2 (iPO2). Both myoglobin O₂ levels (SSc: 70±7% and controls: 79±4%; P=0.03;) and end-exercise iPO2 (SSc: 8±4 mmHg and controls: 17±8 mmHg; P=0.021; d=1.36) were lower in SSc than healthy controls. The rate of ATP synthesis from oxidative phosphorylation was also lower in SSc than controls (SSc:5.2±3.4 mM.min-1; Controls:11.8±3.6 mM. min-1; P=0.015) whereas PCr depletion was augmented (SSc:55±15 % from resting baseline; Controls:77±9 % from resting baseline; P=0.015). This shift toward a greater reliance on anaerobic metabolism led to an accumulation of inorganic phosphate diprotonated during exercise (P=0.037). Together, these findings indicate that critically low iPO2 severely limits oxidative phosphorylation rate even during moderate-intensity dynamic plantar flexion exercise in patients with SSc. The magnitude of the disease-induced shift in metabolism and iPO2 were so extensive that they were greater than the metabolic alterations found in patients suffering from advanced chronic cardiovascular diseases. In addition, the compensatory increase in anaerobic metabolism resulted in greater metabolites accumulation, which could amplify the susceptibility to muscle fatigue in SSc patients.

  PublisherDOI

• The right time, the right cell: the potential for precision senotherapy in pulmonary arterial hypertension

  American Journal of Physiology-Lung Cellular and Molecular Physiology · 2026-04-24

  articleOpen accessCorresponding

  Pulmonary arterial hypertension (PAH) is a fatal vasculopathy driven by proinflammatory signaling that leads to pulmonary vascular remodeling and ultimately, right ventricular failure. Existing therapies fail to eliminate dysfunctional cells or reverse pathologic remodeling. Cellular senescence, a state of persistent cell-cycle arrest coupled with proinflammatory signaling, has emerged as a compelling, yet complex, contributor to PAH pathophysiology. Human data indicate that senescent cells accumulate within remodeled pulmonary vascular lesions and may promote proliferation and apoptosis resistance in neighboring cells. However, preclinical studies testing senolytic therapies in PAH have yielded conflicting results, raising uncertainty about their translational potential. This review will synthesize the current literature regarding cellular senescence in PAH and propose that heterogeneity in 1) senescent cell type, 2) senolytic mechanisms and off-target susceptibility, and 3) the disease stage at the time of intervention can help explain divergent outcomes. By addressing these three key points, this review will identify practical considerations for advancing “precision senotherapy” in PAH, including dosing strategies favoring intermittent, short-course senolytic regimens, and combination treatment approaches. Together, these concepts provide a framework for designing safer, stage-aware, cell-informed senotherapeutic studies in PAH.

  PublisherDOI

• Aging and DNA damage are associated with the development of endothelial cell clonal expansion

  American Journal of Physiology-Heart and Circulatory Physiology · 2026-04-21 · 1 citations

  articleOpen accessSenior author

  Aging reshapes the vascular endothelium in unexpected ways. Using lineage tracing in mice, we show that endothelial cells undergo age-dependent clonal expansion, particularly in atheroprone regions exposed to disturbed blood flow. This process is amplified by DNA damage and reflects the selective expansion of preexisting clones rather than increased recruitment. Endothelial clonal expansion may represent an underrecognized mechanism driving vascular remodeling during aging and genotoxic stress.

  PublisherDOI

• Mechanisms of cellular senescence-induced vascular aging: evidence of senotherapeutic strategies

  The Journal of Cardiovascular Aging · 2025-03-20 · 11 citations

  articleOpen access

  Cardiovascular diseases (CVD) remain the leading cause of death worldwide, with advancing age being the primary, nonmodifiable risk factor. Vascular dysfunction, namely arterial stiffening and endothelial dysfunction, is the key antecedent to the development of clinical CVD with aging. Fundamental aging macro-mechanistic processes that drive vascular aging include excess oxidative stress, chronic inflammation, and declines in the vasodilatory molecule nitric oxide. An important hallmark of aging that contributes to the vascular aging processes is cellular senescence - a stress response characterized by cell cycle arrest and accompanied by the production and secretion of proinflammatory molecules (i.e., the senescence-associated secretory phenotype [SASP]). Excess senescent cells and the SASP have deleterious effects on vascular function and in states of CVD, making it a putative therapeutic target for improving vascular function and preventing or reversing CVD. This review will focus on the role of cellular senescence in age-related vascular dysfunction and CVD. We will examine established and emerging mechanisms underlying cellular senescence-induced vascular dysfunction. We will then discuss groups with impaired vascular function and high cellular senescence burden and examine strategies to reduce or remove excess senescent cells and the SASP in the groups who are likely to benefit most from these therapies. Finally, we will highlight the systemic effects of vascular senescent cell suppression on other tissues and organs, given the integrative role of the vasculature in physiology. Together, this review will underscore the imperative role of cellular senescence in vascular dysfunction and the need for a deeper understanding of the translational use of cellular senescence and SASP targeting therapies in groups with high senescent cell burden.

  PublisherOA PDFDOI

• Cardio-rheumatology: integrated care and the opportunities for personalized medicine

  Therapeutic Advances in Musculoskeletal Disease · 2025-07-01 · 5 citations

  reviewOpen access

  While severe vasculopathic manifestations of systemic sclerosis (SSc) are well-recognized, characterization of subclinical progressive vasculopathy contributing to cardiac involvement remains an unmet clinical need. This review highlights the evolving understanding of SSc heart involvement (SHI), including current standard clinical cardiac evaluation methods, prevalence of various cardiac manifestations of SHI, and advances at the forefront of precision medicine. Informed by this growing body of literature, we describe the development of a novel interdisciplinary cardio-rheumatology clinic at the Vanderbilt University Medical Center. Utilizing advances in imaging techniques and systemic retrieval and analysis of complex data sets, our dedicated cardio-rheumatology clinic offers opportunities for therapeutic advances and personalized medicine through mechanistic disease phenotyping in SSc. Nailfold capillaroscopy, thermography, and hand ultrasound with Doppler are acquired to characterize small vessel vasculopathy, while echocardiogram, ambulatory cardiac rhythm monitoring, cardiac magnetic resonance imaging, and cardiac positron emission tomography/computed tomography are utilized to characterize cardiac disease. By correlating vasculopathy imaging with cardiac manifestations, our cardio-rheumatology clinic aims to identify patients with SSc who would benefit from additional cardiac investigation even in the absence of cardiac symptomatology. This interdisciplinary collaboration may allow earlier detection of primary SHI, which is a common cause of death in SSc patients, resulting from both morpho-functional and electrical cardiac abnormalities. Our shared model of care and robust data acquisition facilitate clinical investigation by utilizing technological advances in data management. Using deep learning and pattern recognition, artificial intelligence (AI) offers opportunities to integrate data from imaging and monitoring techniques outlined in this report to provide quantifiable markers of disease progression and treatment efficacy. Given the potential for extensive AI data processing but the low prevalence of SSc, developing a multicenter cloud-based image sharing platform would accelerate clinical investigation in the field. Ultimately, we aim to tailor therapeutic decisions and risk mitigation strategies to improve SSc patient outcomes.

  PublisherDOI

• SUN-383 Thromboembolism In Patients With Atrial Fibrillation Due To Hyperthyroidism-a Systematic Review And Meta-analysis

  Journal of the Endocrine Society · 2025-10-01

  articleOpen access

  Abstract Disclosure: A. Khan: None. A. Aziz: None. H. Ahmed Elamin: None. J. Khan: None. M. Sadiq: None. F. Ata: None. S. Khalid: None. A.J. Qassim: None. M. Asif: None. A. Ahmed Elamin: None. H. Khalid: None. Z. Yousaf: None. M. Javaid: None. A. Fatima: None. J. Ikram: None. A. Brett-Morris: None. A. Donato: None. M.G. Husnain: None. Background: Hyperthyroidism (HTH) is a reversible etiology of atrial fibrillation (AFib). There is no definite evidence whether the risk of thromboembolism (TE) in AFib due to HTH is higher or lower compared to AFib without HTH. Objective: To assess the clinical outcomes and risk of TE in patients with AFib due to HTH. Methods: A systematic literature search of PUBMED, Scopus and Embase on articles reporting AFib due to HTH yielded 4938 results. 294 studies fulfilled inclusion criteria, of which 274 were included in individual patient data analysis and 20 in meta-analysis. Meta-analysis assessed the proportion of patients developing TE in patients with AFib due to HTH. The protocol was registered on PROSPERO (CRD42022352406). Results: Individual patient data analysis (274 articles) Data was available for 418 patients. The mean age was 54.8±14.8 years. The majority were females (58.1%). 58.4% had newly diagnosed HTH at the time of presentation. Graves’ disease was the most common etiology of HTH (55.7%). 22% of patients had thyroid storm. ICU admission rate was 21.3%. 15.6% had concomitant high-output cardiac failure. The mean CHA2DS2-VASc score was 1.3±1.2. 30.4% of patients were discharged on anticoagulation (80.5% on warfarin and 19.5% on direct oral anticoagulants). TE events were reported in 19.4% of patients. Patients with TE events were older (57±14 vs 52.3±14.7 years; p <0.001), predominantly females (34.4% vs. 18.8%; p = 0.008) and had a higher CHA₂DS₂-VASc score (1.6±0.2 vs. 1.2±0.1; p = 0.03) compared to those who did not have TE. There were no differences in number of comorbidities, type of thyroid disease, thyroid antibody status, and TSH level between the two groups. A statistically significant correlation was found between CHA₂DS₂-VASc score and TE events on spearman correlation analysis (p = 0.02). No correlation was found between free T4 levels at presentation and TE events development at the follow-up (p = 0.33). Meta-analysis (20 studies) A total of 20 observational cohort studies encompassing 30,729 patients with AFib due to HTH were included in the proportional meta-analysis. The pooled prevalence of thromboembolic events in this population was 11.64% (95% CI: 7.88% - 15.96%). However, substantial heterogeneity was observed among the included studies (I² = 89.3%, τ² = 0.0151, p < 0.0001), suggesting considerable variability in event rates across studies. Conclusion: Patients with AFib due to HTH with advanced age are at higher risk of developing TE events. CHA₂DS₂-VASc score can be used for risk stratification in these patients and as it correlates with the risk of TE in these patients. The pooled prevalence of TE events is 11.64%. However, there is significant heterogeneity in the literature, highlighting the possibility of publication bias that may have overstated event risks. A formal trial or registry would better answer the question of incidence of TE in HTH. Presentation: Sunday, July 13, 2025

  PublisherOA PDFDOI

• Glycocalyx-targeted therapy prevents age-related muscle loss and declines in maximal exercise capacity

  Aging · 2025-08-30 · 1 citations

  articleOpen accessSenior author

  -treated old mice. Collectively, these findings suggest that glycocalyx integrity is a critical determinant of physical function and that glycocalyx-targeted interventions may be a viable therapeutic strategy to treat age-related physical dysfunction.

  PublisherOA PDFDOI

• Sex differences in endothelial glycocalyx thickness and the response to glycocalyx‐targeted therapy among older adults

  Physiological Reports · 2025-06-01 · 2 citations

  articleOpen access

  Endothelial glycocalyx thickness declines with age, potentially increasing cardiovascular disease risk. However, sex differences in glycocalyx thickness and responses to glycocalyx-targeted therapies remain unclear. This post hoc analysis examined sex differences in glycocalyx thickness and the effects of Endocalyx Pro supplementation in older adults. We analyzed data from 22 participants in a prior clinical trial (NCT06071728) that assessed 12-week Endocalyx Pro (3712 mg/day) supplementation on vascular function. Glycocalyx thickness was estimated as the perfused boundary region (PBR) using the GlycoCheck, with higher PBR indicating smaller glycocalyx thickness. Postmenopausal females had higher PBR 4-25 than older males (2.11 ± 0.14 vs. 1.97 ± 0.13 μm; p = 0.02), particularly in microvessels 9-17 μm in diameter. Male sex (B [95% CI], -0.14 [-0.26, -0.02]; p = 0.02) and body mass index (BMI) (B [95% CI], -0.02 [-0.04, -0.01]; p = 0.01) were associated with lower PBR 4-25 in univariate analyses; however, when included in a multivariate model, the association with sex was attenuated (p = 0.15), while BMI remained significant (p = 0.04). After 12 weeks of Endocalyx Pro, PBR 4-25 increased in older males (+0.087 ± 0.148 μm) but decreased in postmenopausal females (-0.178 ± 0.148 μm; p = 0.009). In conclusion, we observed that postmenopausal females had smaller glycocalyx thickness, partially explained by BMI, and demonstrated a greater improvement with Endocalyx Pro, suggesting sex-specific therapy effects.

  PublisherOA PDFDOI

• Impact of T Cells on Metabolic Dysregulation in Aged Mice

  Physiology · 2025-05-01

  articleSenior author

  Decreased glucose tolerance ( GT ) and insulin sensitivity ( IS ), and impaired immune function contribute to metabolic diseases and are exhibited with advanced age. Our laboratory has previously demonstrated that GT is improved in old mice depleted of T cells. Here, we sought to elucidate the contributions of intrinsic changes to T cells and increased T cell recruitment to metabolic tissues regarding age-related metabolic dysfunction. We hypothesized that metabolic dysregulation will occur in young immuno-deficient mice in response to older T cells, and young T cells will improve metabolic function in aged mice, driven by lower T cell immune burden. T cells were isolated from young (4-6mo) or old (22-25mo) C57BL/6 (C57) mice spleens and transferred into young or old RAG1 -/- mice, which lack mature T and B cells. After 4 weeks, GT and insulin tolerance tests were performed to assess metabolic function. White adipose tissue (WAT) and liver, both sites of metabolic activity, were removed to assess T cell infiltration. Lifelong T cell absence resulted in higher fasting blood glucose ( FBG ) in young RAG1 -/- compared to C57 mice (p=.001). After T cell transfer to RAG1 -/- mice, there were main effects for mouse (p<.001) and T cell (p=.022) age, with old mice having a lower FBG than young regardless of T cell age received. Glucose intolerance (Area Under Curve, AUC ) observed in old vs young C57 mice (p=.0458) improved in old vs young RAG1 -/- mice lacking T cells (p=062). After adding T cells, speed of glucose recovery improved at some timepoints (group, p=.044), but not GT ( AUC ) in young RAG1 -/- mice (p=.300). There were no differences in GT among old RAG1 -/- mice without or with young or old T cells transferred (p=.219). IS ( AUC ) was similar between young and old RAG1 -/- mice (p=.474). After adding young, but not old T cells, IS was enhanced in young RAG1 -/- mice (p=.038). Young mice given young T cells were the most IS, while old mice given young T cells had the lowest IS (post hoc, p=.028). In WAT, there was a lower percentage of T cell infiltration in old mice that received young T cells, and a higher percentage in young mice that received young T cells (T cell Age, p=.7003; Mouse Age, p=.015; Interaction, p=.069). Among transfer groups, a greater proportion of CD8+ compared to CD4+ T cells infiltrated both WAT (p<.0001) and liver (p<.0001). Still, there were no mouse or T cell age related differences in CD4+ or CD8+ T cell infiltration into the WAT. Unlike in the WAT, neither total nor percentage T cell infiltration into the liver differed between young and old groups, although CD4+ T cells were higher in old mice regardless of T cell age (T cell Age, p=.054; Mouse Age, p<.0001). Overall, young mice demonstrated a higher proportion of CD8+ T cells infiltrating the liver compared to old mice (T cell age, p=.207; Mouse Age, p<.0001). Our findings show that mouse age has a more profound effect on FBG and GT than T cell age, with the absence of T cells improving GT in old, but not young mice. Supplementation of young or old T cells to old RAG1 -/- mice did not improve IS although young T cells improved IS of young mice. Young mice have superior glucose regulation compared to old mice. This may be because T cells are better able to infiltrate young WAT, which we have found in this study, resulting in greater control of immune function. The difference in T cell subpopulation in liver may partly explain isolated effects of T cell age on the IS of young, but not old mice. Overall, these results suggest that GT is more dependent on the age of the mouse and WAT T cell immune activity, with young mice faring better; whereas IS is more reliant on the interplay of T cell age-related properties and the subpopulation of T cells that home to the liver, with young T cells, particularly, improving IS. NIH-NIA, R01 AG060395. NIH-NHLBI T32 CRTP This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

  PublisherDOI

• Late‐Life Aerobic Exercise Attenuates <scp>DNA</scp> Damage and Telomere Dysfunction in Non‐Atheroprone but Not in Atheroprone Aortic Regions

  Aging Cell · 2025-08-27

  articleOpen accessSenior authorCorresponding

  Cellular senescence is a state of persistent cell cycle arrest and is a critical contributor to arterial aging. The primary drivers of cellular senescence are the DNA damage response (DDR) and telomere dysfunction, which is induced by increasing exposure to DNA-damaging stimuli such as atheroprone shear stress. While late-life aerobic exercise is an effective intervention to mitigate arterial aging, its specific impact on the DDR and telomere dysfunction is unknown and may not show uniform benefits across aortic regions subjected to atheroprone and non-atheroprone shear stress. This study investigates the influence of late-life aerobic exercise on DDR and telomere dysfunction in endothelial cells (EC) and vascular smooth muscle cells (VSMC) within the aortic regions exposed to distinct shear stress patterns. Old male C57BL6 mice were randomly assigned to a negative control (NC) group and habitual voluntary wheel running (VWR) groups for 16 weeks. The habitual VWR groups were further categorized into low (LR), moderate (MR), and high running (HR) groups based on their daily running distance throughout the intervention. EC and VSMC DDR and telomere dysfunction in NC, LR, and MR groups were comparable across the aortic regions. Interestingly, EC DDR and telomere dysfunction were mitigated in the non-atheroprone aortic regions in HR, but not in VSMC. These improvements were independent of telomere length. Collectively, these data provide evidence that late-life aerobic exercise selectively mitigates DDR and telomere dysfunction in ECs within non-atheroprone aortic regions, rather than atheroprone aortic regions, in an exercise volume-dependent manner, independent of telomere length.

  PublisherOA PDFDOI

Recent grants

• NIH Grant K01AG029337

  NIH · $613k · 2013

• Novel Methodology for Identification of Senolytics that Reduce Age-related Disease and Dysfunction

  NIH · $1.6M · 2016–2022

• NIH Grant R01AG040297

  NIH · $1.5M · 2016

• Impact of T cells on age-related vascular dysfunction: A translational approach

  NIH · $2.5M · 2019–2025

• NIH Grant K02AG045339

  NIH · $558k · 2019

Frequent coauthors

• Lisa A. Lesniewski

  University of Utah

  371 shared

• Russell S. Richardson

  University of Utah

  137 shared

• Ashley E. Walker

  University of Oregon

  127 shared

• Daniel R. Machin

  Florida State University

  110 shared

• Douglas R. Seals

  University of Colorado Boulder

  98 shared

• D. Walter Wray

  University of Utah

  76 shared

• Dean Y. Li

  65 shared

• Grant D. Henson

  University of Oregon

  65 shared

Labs

• Anthony J. Donato LabPI

Education

• Ph.D., Internal Medicine

  University of Utah

• M.S., Geriatrics

  University of Utah