Endocrine Abstracts

JOINT2894

Cellular senescence has been increasingly recognized as a key driver of metabolic syndrome (MetS) and its complications, including obesity and type 2 diabetes (T2D). Alström syndrome (AS), a monogenic form of obesity with extreme insulin resistance and T2D has previously been associated with increased biological aging. This study investigates AS as a model of accelerated aging through cellular senescence markers in metabolic tissues. Patients with AS (n=10) were matched with healthy control volunteers (n=10) based on gender, BMI, and age. Clinical assessments were conducted alongside adipose tissue (AT) and skeletal muscle (SM) biopsies. β-galactosidase staining and RNA sequencing (RNA-Seq) with SanMayo analysis were performed on subcutaneous adipose tissue (AT), while reverse transcription polymerase chain reaction (RT-PCR) assessed senescence associated gene expression in SM. The IMM-AGE metric, analysed via fluorescence-activated cell sorting (FACS) was used to evaluate immune aging in peripheral blood mononuclear cells (PBMCs). Patient with AS exhibited a 55.4±11.3-fold increase in β-galactosidase staining in adipocytes compared to controls. RNA-Seq analysis identified a gene expression signature associated with senescence in adipocytes. Quantitative RT-PCR of SM revealed overlapping gene expression changes in at least half of these senescence associated pathways in AT. Additionally, a significant increase in the IMM-AGE score indicated an increase in immunological age relative to chronological age in AS patients (P<0.01). These findings demonstrate a widespread senescence phenotype in adipose and skeletal muscle tissues in AS, supporting accelerated aging as part of the pathological presentation of AS. While the precise mechanisms remain unclear, our results suggest that senotherapies, combined with pharmacological and lifestyle interventions, could offer novel therapeutic strategies for obesity related metabolic dysfunction in AS.