Prata, Larissa

ABSTRACT The senescent cell (SC) fate is linked to aging, multiple disorders and diseases, and physical dysfunction. Senolytics, agents that selectively eliminate 30%–70% of SCs, act by transiently disabling the senescent cell antiapoptotic pathways (SCAPs), which defend those SCs that are proapoptotic and pro‐inflammatory from their own senescence‐associated secretory phenotype (SASP). Consistent with this, a JAK/STAT inhibitor, Ruxolitinib, which attenuates the pro‐inflammatory SASP of senescent human preadipocytes, caused them to become “senolytic‐resistant”. Administering senolytics to obese mice selectively decreased the abundance of the subset of SCs that is pro‐inflammatory. In cell cultures, the 30%–70% of human senescent preadipocytes or human umbilical vein endothelial cells (HUVECs) that are senolytic‐resistant (to Dasatinib or Quercetin, respectively) had increased p16 INK4a , p21 CIP1 , senescence‐associated β‐galactosidase (SAβgal), γH2AX, and proliferative arrest similarly to the total SC population (comprising senolytic‐sensitive plus‐resistant SCs). However, the SASP of senolytic‐resistant SCs entailed less pro‐inflammatory/apoptotic factor production, induced less inflammation in non‐senescent cells, and was equivalent or richer in growth/fibrotic factors. Senolytic‐resistant SCs released less mitochondrial DNA (mtDNA) and more highly expressed the anti‐inflammatory immune evasion signal, glycoprotein non‐melanoma‐B (GPNMB). Transplanting senolytic‐resistant SCs intraperitoneally into younger mice caused less physical dysfunction than transplanting the total SC population. Because Ruxolitinib attenuates SC release of proapoptotic SASP factors, while pathogen‐associated molecular pattern factors (PAMPs) can amplify the release of these factors rapidly (acting as “senosensitizers”), senolytic‐resistant and senolytic‐sensitive SCs appear to be interconvertible.

Abstract Metabolic diseases, including obesity, Type 2 diabetes (T2D), and metabolic syndrome, are increasingly prevalent worldwide, driven by sedentary lifestyles, aging populations, and complex genetic and environmental factors. Traditionally understood as disorders of glucose and lipid metabolism, a growing body of evidence now implicates cellular senescence as a central, age‐related contributor to metabolic dysfunction. Senescent cells (SCs) accumulate in key metabolic tissues where they disrupt tissue function through the senescence‐associated secretory phenotype (SASP), a pro‐inflammatory and fibrogenic secretome. SASP factors exacerbate insulin resistance, chronic inflammation, and tissue remodeling, advancing the progression and complications of metabolic diseases. These insights have catalyzed the development of senotherapeutics, a class of interventions that includes senolytics (to eliminate SCs), senomorphics (to suppress SASP), and senosensitizers (to render resistant SCs more vulnerable to clearance). Although preclinical studies show promise, translation into clinical practice faces significant challenges, including identifying reliable biomarkers, understanding SC heterogeneity, and optimizing treatment timing and safety. As research advances, senotherapeutics may offer a transformative approach not only to managing metabolic diseases but also to mitigating associated comorbidities. The recognition that antidiabetic agents already in clinical use can modulate key features of senescence highlights a unique translational opportunity, suggesting that prevention of age‐related metabolic disorders may be achievable with therapies already available in routine clinical practice. Medicine is poised to enter a new era in which targeting cellular senescence could fundamentally reshape the prevention and treatment of age‐related metabolic disorders, offering the potential for improved healthspan and reduced disease burden across the lifespan.

AbstractBackgroundChronic wounds have been associated with an elevated burden of cellular senescence, a state of essentially irreversible cell cycle arrest, resistance to apoptosis, and a secretory phenotype. However, whether senescent cells contribute to wound chronicity in humans remains unclear. The objective of this article is to assess the role of clinicopathological characteristics and cellular senescence in the time‐to‐healing of chronic wounds.MethodsA cohort of 79 patients with chronic wounds was evaluated in a single‐center academic practice from February 1, 2005, to February 28, 2015, and followed for up to 36 months. Clinical characteristics and wound biopsies were obtained at baseline, and time‐to‐healing was assessed. Wound biopsies were analyzed histologically for pathological characteristics and molecularly for markers of cellular senescence. In addition, biopsy slides were stained for p16INK4a expression.ResultsNo clinical or pathological characteristics were found to have significant associations with time‐to‐healing. A Cox proportional hazard ratio model revealed increased CDKN1A (p21CIP1/WAF1) expression to predict longer time‐to‐healing, and a model adjusted for gender and epidermal hyperplasia revealed increased CDKN1A expression and decreased PAPPA expression to predict longer time‐to‐healing. Increased p16INK4a staining was observed in diabetic wounds compared to non‐diabetic wounds, and the same association was observed in the context of high dermal fibrosis.ConclusionsThe findings of this pilot study suggest that senescent cells contribute to wound chronicity in humans, especially in diabetic wounds.

Abstract The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS‐CoV‐2 infection. SARS‐CoV‐2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence‐associated secretory phenotype (SASP). The SASP can be amplified by infection‐related pathogen‐associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS‐CoV‐2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS‐CoV‐2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health‐funded, multicenter, placebo‐controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS‐CoV‐2 rtPCR‐positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long‐term care settings in the SARS‐CoV‐2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.

Senescent cells exacerbate COVID-19 Cellular senescence is a state elicited in response to stress signals and is associated with a damaging secretory phenotype. The number of senescent cells increases with advanced age and this in turn drives age-related diseases. Camell et al. show that senescent cells have an amplified inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (see the Perspective by Cox and Lord). This response is communicated to nonsenescent cells, suppressing viral defense mechanisms and increasing the expression of viral entry proteins. In old mice infected with a SARS-CoV-2–related virus, treatment with senolytics to reduce the senolytic cell burden reduced mortality and increased antiviral antibodies. Science , abe4832, this issue p. eabe4832 ; see also abi4474, p. 281

Abstract Aging is the biggest risk factor for the most serious chronic diseases and disabilities. Cellular senescence, a state in which cells stop dividing but release factors that damage other cells, may contribute to both age-related and chronic diseases. Removal of senescent cells from aged mice has been shown to delay aging and age–related disabilities. Our goal was to determine the ability of potential senolytic agents to remove senescent cells in a primate model. Several agents and combinations were tested including Fisetin, Navitoclax, combined Dasatinib and Quercetin, and combined Dasatinib and Fisetin. Here we describe the Dasatinib and Fisetin trial. Dasatinib is an FDA approved oral anticancer drug that has been used to treat chronic myelogenous leukemia in humans. Fisetin is a flavonoid that can be found in many plants, particularly strawberries, and acts as a coloring agent. After baseline measurements, six older (mean age=21 years) female rhesus monkeys (Macaca mulatta) were given a combined oral dose of Dasatinib (5 mg/kg) and Fisetin (100 mg/kg) on two consecutive days. Animals were additionally assessed at 1- and 7-weeks following dosing. At 7 weeks post dosing, there were fewer (p<0.05) p16+ cells in the epidermis compared to baseline. Similarly, there was a reduction (p<0.05) in p21+ cells in the epidermis at 1- and 7-weeks post dosing compared to baseline. There were no negative outcomes associated with treatment. This study provides preliminary evidence for the senolytic potential of combined Dasatinib and Fisetin treatment and indicates that pharmacological mitigation of age-related changes is possible.

Abstract Adipose tissue inflammation and dysfunction are associated with obesity‐related insulin resistance and diabetes, but mechanisms underlying this relationship are unclear. Although senescent cells accumulate in adipose tissue of obese humans and rodents, a direct pathogenic role for these cells in the development of diabetes remains to be demonstrated. Here, we show that reducing senescent cell burden in obese mice, either by activating drug‐inducible “suicide” genes driven by the p16 Ink4a promoter or by treatment with senolytic agents, alleviates metabolic and adipose tissue dysfunction. These senolytic interventions improved glucose tolerance, enhanced insulin sensitivity, lowered circulating inflammatory mediators, and promoted adipogenesis in obese mice. Elimination of senescent cells also prevented the migration of transplanted monocytes into intra‐abdominal adipose tissue and reduced the number of macrophages in this tissue. In addition, microalbuminuria, renal podocyte function, and cardiac diastolic function improved with senolytic therapy. Our results implicate cellular senescence as a causal factor in obesity‐related inflammation and metabolic derangements and show that emerging senolytic agents hold promise for treating obesity‐related metabolic dysfunction and its complications.