Garovic, Vesna D.

Abstract Senescent cell accumulation and fibrosis play a fundamental role in kidney ageing. Our aim was to determine whether the angiotensin IV/insulin-regulated aminopeptidase (IRAP) axis of the renin-angiotensin system contributes to renal function decline, fibrosis, and senescent cell accumulation in aged mice. We studied the role of IRAP in kidney ageing using IRAP knockout (KO) mice, as well as in wild-type (WT) mice treated with an IRAP inhibitor. Complementary proximal tubule and collecting duct cell models were used to determine the mechanisms by which IRAP inhibition exerts protective effects. Glomerular filtration rate (GFR) declined by 25% in WT mice between 3 and 23 months of age, concomitant with marked increases in albumin excretion, glomerulosclerosis, tubulointerstitial fibrosis, and accumulation of senescent cells in the proximal tubules of the kidney. IRAP KO mice were protected against age-related decline in GFR, renal fibrosis, and senescence burden compared with age-matched WT mice. IRAP inhibition for 4 weeks (HFI-419, 500 ng/kg/min) in 28-month-old WT mice similarly prevented age-related decline in GFR and attenuated expression of cellular senescence markers. Using an in vitro model of cultured proximal tubule cells, IRAP inhibition mitigated the pro-senescent effects of oxidative stress. This was associated with shifts in the metabolic phenotype of proximal tubular cells, indicating the senoprotective effects of IRAP inhibition may be mediated in part via mitochondrial function. These studies provide evidence that IRAP deficiency is protective against chronic renal cellular senescence, fibrosis, and functional decline. Therefore, IRAP inhibition has therapeutic potential to attenuate pathological cardiorenal ageing through senoprotective mechanisms.

This study is the first to investigate cytokine profiles in women with advanced CKD and low sexual function. We found that lower levels of soluble CD40 ligand were independently linked to higher odds of having low sexual function. Principal component analysis demonstrated that a broader immune activation pattern was associated with higher odds of having low sexual function. Together, these findings suggest that immune signaling patterns may be relevant to sexual health in women with CKD.

Background: Hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), and preterm delivery are associated with higher long-term cardiovascular, metabolic, and kidney disease risk. Their implications for living kidney donation remain uncertain. Methods: We conducted a retrospective cohort study of 498 female living kidney donors (2000–2017) from the Mayo Clinic Living Donor Program with documented pregnancy histories, pre-donation CT angiography, implantation kidney biopsy, and measured GFR. Donors with prior HDP (n=45), GDM (n=18), or preterm delivery (n=65) were compared with donors without adverse pregnancy outcomes (APO; n=385). Kidney morphometry, histology, and function were analyzed with adjustment for age at donation and first pregnancy, parity, and hypertension. Post-donation kidney outcomes were assessed using surveys and medical record review. Results: Donors with prior HDP and GDM had higher BMI at donation (+7.9% and +8.9%; p=0.006 and 0.04), whereas donors with preterm delivery had lower BMI (−4.8%; p=0.03) compared with donors with no APO. After adjustment, donors with HDP showed no differences in kidney volumes, biopsy features, or kidney function at donation or during follow-up. Donors with GDM had larger total and cortical kidney volumes (9.5–10%), less arterial luminal stenosis, and higher 5-year post-donation eGFR (+15%; p=0.03). Donors with preterm delivery had a lower risk of eGFR <45 mL/min/1.73 m 2 (HR 0.28; p=0.03). Conclusions: Prior adverse pregnancy outcomes were not associated with adverse kidney structure at donation or accelerated kidney function decline post-donation. These findings support that APO history alone should not preclude living kidney donation when other eligibility criteria are met.

Abstract Introduction: There is growing focus on community-engaged research (CEnR) in the clinical and translational sciences, supportive policies, environments, and processes within academic medical centers. The purpose of this evaluation was to gather academic and community member perspectives on key actionable strategies for supporting CEnR in an academic medical center. Materials and Methods: We used a sequential mixed method design by first conducting qualitative in-depth interviews with academic leaders, investigators, and staff (total, n = 54) and focus group discussions with community members ( n = 33). Themes from these qualitative data informed the adaptation of an institutional survey that gathered perspectives from a broader group of academic and community members affiliated with the institution ( n = 85). Both qualitative and quantitative data were integrated to inform actionable strategies. Results: Survey findings revealed that the institution was perceived as committed to health equity and CEnR, but institutional respondents expressed more concerns than community members about instrumental support of the work. Interviews and focus groups highlighted the opportunity to better align research efforts with community needs through more robust CEnR infrastructure and through interface with the clinical practice to promote patient access. Academic and community members emphasized the need for authentic, sustained engagement beyond federal mandates, including financial investment, capacity-building, and fostering trust. Leaders acknowledged structural challenges, siloed efforts, and the necessity for stronger coordination to increase integration of community engagement into the institutional mission. Conclusion: Findings suggest that aligning academic leaders, researchers, staff perspectives, and community members is essential to support and promote CEnR at an institutional level.

Cellular senescence is an irreversible stress response, which leads to loss of cellular function and remodeling of the cellular secretory profile. In humans, pancreatic β cells undergo cellular senescence during the progression to type 2 diabetes (T2D). However, the mechanism linking β cell senescence to islet dysfunction remains unknown, and thus the therapeutic potential of targeting senescent cells in T2D is not established. Herein, we identified a subpopulation of senescent β cells expressing p21, which emerged early in the progression of T2D in humans and mice. Spatial transcriptomics and proteomics analyses confirmed senescence and loss of cellular identity in this subpopulation in humans. Functional analysis revealed lack of glucose responsiveness, high basal insulin secretion, and transcription of senescence-associated secretory phenotype (SASP) factors. SASP factors from p21 + β cells induced secondary senescence in neighboring cells, characterized by dysfunction and loss of identity. JAK inhibitors counteracted the induction of secondary senescence and restored β cell function in islets from humans with T2D and in mice fed a high-fat diet. These findings reveal the critical role of p21 + β cells in T2D pathogenesis and the therapeutic potential of targeting this pathophysiological process.

Importance Decentralized clinical trials (DCTs) aim to increase trial access for underrepresented populations (URP) and ensure study outcomes, conclusions, and policy-related decisions are applicable to diverse populations. Objective To assess trends in the percentage of accrued participants from more than 120 miles from the research site upon DCT program implementation. Design, Setting, and Participants This descriptive quality improvement study was conducted from January 2024 to March 2025 at Mayo Clinic, a US multiregional, academic medical center (AMC) comprising 3 sites and an affiliated, community-based health care system. All individuals who consented and/or accrued to an institutional review board–approved clinical trial were included. Exposure DCTs are defined as trials with at least 1 decentralized capability beyond remote consent. DCT program development began July 2022. By January 2024, remote consent, video telehealth visits, remote phlebotomy, and device services were implemented across all sites and departments. Remote monitoring and oral medication delivery were available on a limited basis. Prospective automated program and DCT participant data collection and quarterly reporting began in January 2024. Main Outcomes and Measures Percentage of all DCT accrued participants with a residential zip code more than 120 miles from 1 of 3 AMC sites. Results There were 7469 participants (median [IQR] age, 62 [51-70] years; 3594 [48.1%] female; 241 [3.2%] Asian, 391 [5.2%] Black or African American, and 6347 [85.0%] White individuals) accrued to 765 DCTs. During the study period, the percentage of DCT participants residing more than 120 miles from an AMC site ranged from 18.9% in the first quarter (Q1) of 2024 (383 of 2032 participants) to 29.6% in Q1 of 2025 (346 of 1170 participants). Of those accrued, 1147 (15.4%) were of a racial or ethnic URP, ranging from 12.5% in Q1 of 2024 (253 participants) to 17.4% in Q1 of 2025 (204 participants). There were 1554 (20.8%) participants from a rural location, ranging from 16.6% in Q1 of 2024 (338 participants) to 24.9% in Q1 of 2025 (291 participants). Additionally, by geospatial distance from an AMC site, the male-to-female ratio was nearly 50:50, and the age distribution appeared similar. Conclusions and Relevance In this quality improvement study of a DCT program implementation, DCT accruals trended favorably among those residing more than 120 miles from an AMC site and those of rural or URP populations. While these findings cannot be directly attributed to program implementation, they are reassuring that this strategy may address some barriers to clinical trial access. Future studies should assess the sustained effectiveness and scalability of DCT models in improving equitable trial access.

ABSTRACT Biological aging greatly impacts the body’s ability to handle glucose, and represents a major risk factor the development and progression of type 2 diabetes (T2D). Nonetheless, despite advances in cellular senescence research and the development of new senolytic therapies, the heterogeneity of cellular senescence in the human endocrine pancreas, as well as its roles in normal aging, remains to be elucidated at the single-cell level. Here, we performed single-cell–resolved spatial proteomics and transcriptomics on intact pancreas from 26 donors (ages 20–80) and multiplexed single-cell RNA sequencing and functional assays on dispersed islets from 14 donors (ages 34–69). We identify two discrete SnC subpopulations distinguished by relative expression of CDKN1A and CDKN2A. CDKN1A ⁺ senescent cells (SnCs) exhibit loss of β-cell identity, impaired insulin secretion, and a proinflammatory SASP associated with increased islet immune infiltration. In contrast, CDKN2A ⁺ SnCs retain transcriptional identity and functional competence, with lower inflammatory signaling. Together, these findings identify heterogeneous and functionally divergent senotypes in the human pancreas, distinguishing an adaptive ( CDKN2A ⁺) from a maladaptive ( CDKN1A ⁺) senescence program, thus providing a mechanism-guided framework for senescence-targeted therapies in T2D.

Circulating extracellular vesicles, proinflammatory/pro-oxidant metabolites, and history of preeclampsia may be used as biomarkers for diagnosis of early CAC in postmenopausal women.

Preeclampsia is a pregnancy-specific hypertensive disorder affecting up to 5% of pregnancies worldwide and is one of the leading causes of maternal and fetal morbidity and mortality globally. It is increasingly recognized that preeclampsia, from both clinical and pathophysiological standpoints, is a heterogeneous disease and that several mechanisms may lead to a clinical syndrome of hypertension, systemic disease, and proteinuria. Beyond its acute obstetric consequences, preeclampsia confers a significantly increased risk of future hypertension, cardiovascular disease, chronic kidney disease, and multimorbidity. Distinct underlying pathological mechanisms at the time of pregnancy may not only define clinical presentation and subtype of preeclampsia but may also make varying contributions to future cardiovascular and kidney disease. Emerging evidence implicates cellular senescence, a state of irreversible cell-cycle arrest accompanied by a proinflammatory senescence-associated secretory phenotype, as one of the mechanisms of preeclampsia that may serve as a mechanistic link between preeclampsia, accelerated cardiovascular aging, and future cardiovascular and kidney disease. This review synthesizes current evidence supporting the role of senescence in the pathophysiology of preeclampsia, demonstrated as accelerated epigenetic aging, increased senescence burden, and mesenchymal stem cell dysfunction, and discusses how persistence of senescence and propagation of senescent cells may contribute to vascular dysfunction decades after affected pregnancies. We further explore the translational implications of senolytic and senomorphic therapies as potential disease-modifying strategies in women with a history of preeclampsia.

ABSTRACT Importance Rural-urban disparities in chronic disease prevalence are well established; however, the extent to which individual-level socioeconomic status (SES) contributes to these disparities remains unclear. Objective To examine the associations of rurality and SES with the prevalence of five most burdensome chronic diseases among adults. Design We conducted a retrospective cross-sectional study of adults across 27 Upper Midwest counties using the Expanded Rochester Epidemiology Project (E-REP) medical record data linkage system to evaluate associations between rurality, SES and chronic disease prevalence. Prevalence of clinically diagnosed asthma, diabetes, hypertension, coronary heart disease, and mood disorders was identified from International Classification of Diseases ICD9/10 codes over a five-year period (2014-2019). Setting Population based Participants Adults over 18 years residing in the 27 E-REP counties, excluding those missing rural-urban residence status. Exposure HOUSES index, an individual-level measure of SES, served as the primary measure, while rurality based on Rural Urban Commuting Area (RUCA) codes 4-10 was the secondary measure. Main Outcome Prevalence of the five clinically diagnosed chronic diseases was identified using ICD9/10 codes from 2014–2019. Mixed effect logistic regression models were used and adjusted for demographics and general medical examination receipt, to assess rural-urban and SES differences for prevalence of each chronic disease. Results Among 455,802 adults with available HOUSES index, 42.8% lived in rural areas, 53.8% were female and 87.4% were non-Hispanic White. In the unadjusted analysis, rural and urban populations showed comparable asthma and CHD prevalence, while mood disorders, hypertension, and diabetes were more common in urban areas. After adjusting for demographic factors and healthcare utilization, rural-urban differences were no longer statistically significant, whereas SES remained strongly associated with all diseases in a dose response manner (e.g., adjusted Odds Ratio for hypertension (ref: HOUSES index Q4): 1.14, 1.27, and 1.42 for HOUSES index Q3, Q2, and Q1, respectively). Conclusions and Relevance Individual-level SES measured by the HOUSES index, was more strongly associated with chronic disease prevalence than rurality, supporting its integration into population health assessment and risk stratification.