SUN-648 Monogenic Syndromic Obesity of Alström Syndrome as a Model of Premature Aging

Abstract Disclosure: S. Ali: None. P. Thomas: None. N. Duggal: None. G. da Silva: None. T. Geberhiwot: None. In recent years, cellular senescence has emerged as a key contributor to the pathogenesis of metabolic syndrome (MetS) and its associated complications, including obesity and type 2 diabetes (T2D). We have previously shown that patients with Alström syndrome (AS), a monogenic form of obesity characterized by extreme insulin resistance (IR) and MetS, exhibit an increased biological phenotypic age. In this study, we propose AS as a model of accelerated aging.Patients with AS (n=10) were matched with healthy control volunteers (n=10) based on gender, BMI, and age, and underwent clinical assessments along with adipose tissue and skeletal muscle biopsies. We performed β-galactosidase staining and RNA sequencing (RNA-Seq) with SanMayo analysis on subcutaneous adipose tissue (AT). The IMM-AGE metric was used to assess immune age in peripheral blood mononuclear cells (PBMCs) via fluorescence-activated cell sorting (FACS). Reverse transcription polymerase chain reaction (RT-PCR) was performed on skeletal muscle (SM) to assess the expression of senescence- associated gene sets.Our results showed a significant increase in β-galactosidase staining (55.4 ± 11.3-fold) in adipocytes of AS patients compared to controls. Differential gene expression analysis of RNA-Seq data from AT revealed significant changes in the expression of 10 genes associated with increased senescence in adipocytes, including ANG, BMP6, FGF1, IL10, IL18, IQGAP2, PGF, PLAT, SELPLG, and SPX. In parallel, RT-PCR of SM exhibited similar gene expression changes in at least half of the senescence-associated gene sets identified in AT. Furthermore, the IMM-AGE score demonstrated a significant increase in immunological age relative to chronological age in AS patients compared to controls (P < 0.01).In conclusion, our findings demonstrate that cellular senescence is prevalent in both adipose tissue and skeletal muscle in AS. Although the mechanisms underlying senescence in AS remain unclear, our results suggest that senotherapy, combined with pharmacological and/or lifestyle interventions, could emerge as a potential treatment option for obesity and its associated complications Presentation: Sunday, July 13, 2025