Smith, Ulf

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.

Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant ( P association ≤5×10 −8 ) associations with PAD in 449 548 (N cases =12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit ) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1 ) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32–1.74], P diabetes =2.5×10 −9 , P interactionwithdiabetes =5.3×10 −7 ). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11–1.19], P smokers =9.3×10 −10 , P interactionwithsmoking =3.9×10 −5 ). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.