Chaib, Selim

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.

AbstractCellular senescence is an established cause of cell and tissue aging. Senescent cells have been shown to increase in multiple organs during aging, including the skin. Here we hypothesized that senescent cells residing in the skin can spread senescence to distant organs, thereby accelerating systemic aging processes. To explore this hypothesis, we initially observed an increase in several markers of senescence in the skin of aging mice. Subsequently, we conducted experiments wherein senescent fibroblasts were transplanted into the dermis of young mice and assessed various age‐associated parameters. Our findings reveal that the presence of senescent cells in the dermal layer of young mice leads to increased senescence in both proximal and distal host tissues, alongside increased frailty, and impaired musculoskeletal function. Additionally, there was a significant decline in cognitive function, concomitant with increased expression of senescence‐associated markers within the hippocampus brain area. These results support the concept that the accumulation of senescent cells in the skin can exert remote effects on other organs including the brain, potentially explaining links between skin and brain disorders and diseases and, contributing to physical and cognitive decline associated with aging.