About

Lisa Lesniewski is an Associate Professor in the Department of Internal Medicine, Division of Geriatrics, and an Adjunct Associate Professor in the Department of Nutrition and Integrative Physiology. Her research focuses on understanding the mechanisms underlying vascular and metabolic dysfunction and disease with advancing age, as well as how these conditions are exacerbated by overweight and obesity. Her laboratory investigates the effects of aging and obesity on adipose tissue and its vasculature, recognizing adipose tissue as an endocrine organ that plays a central role in metabolic dysfunction in obesity. The lab explores how aging and obesity lead to dysfunction in adipose tissue and its associated vasculature, particularly examining the roles of telomere dysfunction, cellular senescence, and dysregulated signaling through the small GTPase ARF6.

Research topics

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

Selected publications

• 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 access

  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

• Beneficial effects of the senolytic cocktail, dasatinib and quercetin, on age-related vascular and metabolic dysfunction are lost in mice lacking T and B cells

  Physiology · 2025-05-01

  articleSenior author

  Aging is an independent risk factor of arterial and metabolic dysfunction, although the mechanisms remain incompletely understood. Cellular senescence, a persistent cell cycle arrest, accompanies age-related arterial and metabolic dysfunction. Reducing senescence burden after treatment with the senolytic cocktail, dasatinib and quercetin (D&Q), improves age-related arterial and metabolic dysfunction, although the tissues and/or cell types involved in these beneficial effects are unknown. At steady state, T cells play a critical role in eliminating senescent cells and suppressing inflammation. Likewise, evidence exist that aged T cells promote multiorgan aging and age-related systemic dysfunction. Previously, we have shown that T lymphocytes promote age-related arterial and metabolic dysfunction. Together, these raise a key question whether the beneficial effects of senolytic drugs are mediated through aged T cells. Here, we sought to test the hypothesis that T cells mediate the beneficial effects of senolysis in old mice. To test this hypothesis, 27-mo. Rag-/- mice (D&Q: n = 4, vehicle: n = 3), that lack functional T and B lymphocytes, were treated with D (5 mg/kg) & Q (50 mg/kg) for 3 consecutive days in every 15 days for 3 months. Arterial stiffness, assessed by aortic pulse wave velocity, was higher in D&Q (n = 4) compared to vehicle (n = 3) treated old RAG-/- mice. (P = 0.03). Likewise, endothelium-dependent dilation (EDD) to acetylcholine, assessed using pressure myography, was lower in isolated mesenteric arteries of the D&Q treated old RAG-/- mice compared to vehicle controls (P = 0.001). Differences in vasodilation between the treatment groups were abolished after L-NAME incubation, indicating that the impairment in EDD resulted from lower nitric oxide bioavailability in the D&Q treated RAG-/- mice (P = 0.73). Glucose (2 g/kg body mass, IP, GTT) and insulin (1 U/kg body mass, IP, ITT) tolerance tests were performed in fasted (4-6 hr) mice to assess systemic metabolic function. There were no differences in glucose or insulin tolerance between the D&Q (n = 4) and vehicle (n = 3) treated old RAG-/- mice(P = 0.65 & 0.33). These results suggest that the beneficial effects of senolytic treatment in old mice may require T and/or B cells. Future studies could employ the adoptive transfer of T cells from control mice to Rag-/- mice as well as antibody mediated T cell depletion in combination with senolytic treatment to explore the necessity of T cells in the beneficial effects of senolysis. NIA. Grant Numbers: R01 AG048366, R01 AG050238, R01 AG060395U.S. Department of Veterans Affairs. Grant Numbers: I01 BX002151, I01 BX004492 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

• MitoQ reduces senescence burden in doxorubicin-treated endothelial cells by reducing mitochondrial ROS and DNA damage

  American Journal of Physiology-Heart and Circulatory Physiology · 2025-09-30 · 6 citations

  articleOpen access

  Doxorubicin (DOXO) is a widely used chemotherapy drug that can damage blood vessels and promote cardiovascular disease. This study shows that MitoQ, a mitochondria-targeted antioxidant, protects endothelial cells from DOXO-induced oxidative stress, DNA damage, and senescence. By preserving mitochondrial health, MitoQ may prevent vascular toxicity in cancer patients receiving DOXO, offering a potential strategy to improve cardiovascular outcomes in survivorship.

  PublisherDOI

• Senolytic therapy increases replicative capacity by eliminating senescent endothelial cells

  Experimental Gerontology · 2025-09-08 · 2 citations

  articleOpen access

  Aging is the greatest risk factor for cardiovascular diseases (CVD) and is characterized by inflammation, oxidative stress, and cellular senescence. Cellular senescence is a state of persistent cell cycle arrest triggered by stressors such as DNA damage and telomere attrition. Senescent endothelial cells (ECs) can impair vascular function and promote inflammation, thereby contributing to CVD progression. Senolytics, a class of drugs that selectively eliminate senescent cells, have been shown to remove senescent ECs, but their effects on the replicative capacity and genomic integrity of aged, endothelial cultures remain unclear. In this study, we treated replicative senescent human umbilical vein endothelial cells (HUVECs), used as a model of aged ECs, with Talabostat (10 μM), a novel senolytic, and Navitoclax, 1.0 μM). We hypothesized that senescent cell clearance would be associated with increased proliferative activity and reduced markers of senescence, DNA damage, and telomere dysfunction. Both compounds effectively reduced senescent cell burden, which was accompanied by an increase in cumulative population doublings. Talabostat treatment led to reductions in mean telomere length, DNA damage markers (53BP1), and telomere dysfunction-induced foci (TIFs), suggesting a possible link between increased proliferation and replication-associated telomere attrition. In contrast, Navitoclax treatment increased mitochondrial reactive oxygen species (mtROS) and maintained levels of DNA damage and telomere dysfunction comparable to the vehicle group. Overall, these findings indicate that both Navitoclax and Talabostat can reduce senescent EC burden and promote proliferation in aged EC cultures. Talabostat appears more effective, as it is associated with lower oxidative stress and improved genomic integrity. These results provide insight into how distinct senolytics differentially influence aging-related phenotypes in endothelial cells.

  PublisherDOI

• Impact of T Cells on Metabolic Dysregulation in Aged Mice

  Physiology · 2025-05-01

  article

  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

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

  Aging · 2025-08-30 · 1 citations

  articleOpen access

  -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

• Clearing Senescent Endothelial Cells with Senolytics Restores Replicative Capacity

  Physiology · 2025-05-01

  article

  Aging is a major risk factor for cardiovascular diseases (CVD) and is marked by inflammation, oxidative stress, and cellular senescence. Cellular senescence, a persistent cell cycle arrest, is characterized by the secretion of inflammatory cytokines known as the Senescence Associated Secretory Phenotype (SASP). Accumulation of senescent endothelial cells (ECs) is associated with CVDs such as heart failure, coronary artery disease, and atherosclerosis. However, the potential of senescent cell removal to improve EC proliferation is still unknown. Here, we hypothesize that the senolytics rescue the EC replication capacity and prevent premature senescence in aged ECs. To test this, we utilized senolytics, drugs that selectively induce cell death in senescent cells and improve physiological function and lifespan in old mice. Human umbilical vein endothelial cells (HUVECs) were cultured until replicative senescence. Cells were then treated with DMSO (vehicle), REC-4249 (a novel senolytic from Recursion Pharmaceuticals) at 10uM, or ABT-263 (a BCL-2 inhibitor and established senolytic) at 1.0uM to remove senescent cells. Young HUVECs (passage 4) were used as a non-senescent control. To confirm senescence induction and clearance by senoltyics, we evaluated the senescence markers senescence-associated beta-galactosidase (SA-β-gal), mRNA expression of the tumor suppressors p16, p21, and p53, as well as proliferation rates using population doubling (PD) curve analysis and Bromodeoxyuridine (BrdU) incorporation. Compared to vehicle-treated ECs, senolytics reduced EC senescence as demonstrated by SA-β-gal positive cells 48 hours post-treatment (fig.2, A and B, p<0.001) and mRNA expression of p16, p21, and p53 five days post-treatment. (fig 2 C, p<0.001). To determine if senolysis increased EC proliferation capacity, we calculated the net number of doublings by analyzing the PD difference between 5 days before treatment (DBT) and 5 days after treatment (DAT), and between 5 DAT and 29 DAT. The net number of doublings increased by approximately 3 and 3.8 times in ABT-246 and REC-4249, respectively (fig 3 A, p<0.001). Likewise, BrdU incorporation was elevated, indicative of higher proliferation capacity at 5 DAT (fig 3 B, ABT-263, (p=0.044, and REC-4249, p=0.015). Interestingly, restored proliferation was sustained by 29 DAT (fig 3 C, ABT-263, p=0.040, and REC-4249, p=0.005). Overall, these data suggest that the removal of the senescent ECs with senolytics is sufficient to restore their replicative capacity. Highlighting a promising therapeutic avenue for enhancing endothelial function and mitigating aging-related CVD. Future studies will aim to elucidate whether this restoration is mediated through SASP factors or juxtacrine signaling to determine the mechanism underlies the beneficial effects of senolytics observed in vivo. NIH, R01 AG060395, R01 AG048366, T32 HL139451, F31 AG076312, R01 AG077751, R01 AG076748, Nora Eccles Treadwell Foundation (NETF) 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 access

  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

• Early-life thymectomy results in visceral adipose tissue inflammation and glucose intolerance

  Immunity & Ageing · 2025-10-01 · 1 citations

  articleOpen access

  We have previously demonstrated that proinflammatory T cells in adipose tissue and the liver play a mechanistic role in glucose intolerance in old mice. Further, we and others have demonstrated that early life thymectomy results in a T cell phenotype that shares many features of classical T cell aging in an otherwise young healthy mouse. In this investigation, we sought to test the hypothesis that inducing premature T cell aging via early life thymectomy results in T cell mediated inflammation of the liver and visceral adipose tissue, as well as glucose intolerance in otherwise young mice. Mice were thymectomized at three weeks of age. At 9 months of age, thymectomized mice exhibited glucose intolerance that was independent of body mass along with greater frailty. Thymectomized mice exhibited blunted proportions of naïve and greater proportions of memory cells in the spleen, liver and perigonadal adipose tissue (pgWAT). Bulk RNAseq of the pgWAT revealed that thymectomized mice exhibited an upregulation of genes responsible for immune activation, chemokine signaling, and inflammation along with a downregulation of genes responsible for metabolic function. We also found that T cells in the pgWAT of thymectomized mice exhibited greater chemokine receptor expression as well as increased markers of histopathological inflammation that were independent of greater adipose tissue expansion. These results suggest that early life thymectomy results in T cell mediated pgWAT inflammation, systemic glucose intolerance and frailty in adult mice.

  PublisherOA PDFDOI

• Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice

  Arteriosclerosis Thrombosis and Vascular Biology · 2024-03-28 · 11 citations

  articleOpen accessSenior author

  BACKGROUND: Much of what we know about insulin resistance is based on studies from metabolically active tissues such as the liver, adipose tissue, and skeletal muscle. Emerging evidence suggests that the vascular endothelium plays a crucial role in systemic insulin resistance; however, the underlying mechanisms remain incompletely understood. Arf6 (ADP ribosylation factor 6) is a small GTPase that plays a critical role in endothelial cell function. Here, we tested the hypothesis that the deletion of endothelial Arf6 will result in systemic insulin resistance. METHODS: Cdh5CreER+). Endothelium-dependent vasodilation was assessed using pressure myography. Metabolic function was assessed using a battery of metabolic assessments including glucose and insulin tolerance tests and hyperinsulinemic-euglycemic clamps. We used a fluorescence microsphere-based technique to measure tissue blood flow. Skeletal muscle capillary density was assessed using intravital microscopy. RESULTS: Endothelial Arf6 deletion impaired insulin-stimulated vasodilation in white adipose tissue and skeletal muscle feed arteries. The impairment in vasodilation was primarily due to attenuated insulin-stimulated nitric oxide bioavailability but independent of altered acetylcholine-mediated or sodium nitroprusside-mediated vasodilation. Endothelial cell-specific deletion of Arf6 also resulted in systematic insulin resistance in normal chow-fed mice and glucose intolerance in high-fat diet-fed obese mice. The underlying mechanisms of glucose intolerance were reductions in insulin-stimulated blood flow and glucose uptake in the skeletal muscle and were independent of changes in capillary density or vascular permeability. CONCLUSIONS: Results from this study support the conclusion that endothelial Arf6 signaling is essential for maintaining insulin sensitivity. Reduced expression of endothelial Arf6 impairs insulin-mediated vasodilation and results in systemic insulin resistance. These results have therapeutic implications for diseases that are associated with endothelial cell dysfunction and insulin resistance such as diabetes.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R21AG033755

  NIH · $332k · 2013

• NIH Grant R01AG048366

  NIH · $1.7M · 2022

• NIH Grant F32DK072815

  NIH · $44k · 2006

• Role of ARF6 in atherosclerotic burden and severity

  NIH · 2019–2023

• NIH Grant K01AG033196

  NIH · $375k · 2013

Frequent coauthors

• Anthony J. Donato

  Geriatric Research Education and Clinical Center

  371 shared

• Ashley E. Walker

  University of Oregon

  109 shared

• Dean Y. Li

  85 shared

• Weiquan Zhu

  University of Utah

  65 shared

• Grant D. Henson

  University of Oregon

  61 shared

• Kirk R. Thomas

  Oklahoma Medical Research Foundation

  56 shared

• Ling Jing

  Guangdong Provincial People's Hospital

  55 shared

• Christopher C. Gibson

  Recursion (United States)

  52 shared

Labs

• TVP LabPI

Education

• Ph.D.

  University of Utah

• M.A.

  University of Utah