SIRT6-mediated vascular smooth muscle cells senescence participates in the pathogenesis of abdominal aortic aneurysm. Atherosclerosis BACKGROUND AND AIMS:In this study, we carried out a clinical sample study, and in vivo and in vitro studies to evaluate the effect of SIRT6 and SIRT6-mediated vascular smooth muscle senescence on the development of abdominal aortic aneurysm (AAA). METHOD AND RESULTS:AAA specimen showed an increased P16, P21 level and a decreased SIRT6 level compared with control aorta. Time curve study of Ang II infusion AAA model showed similar P16, P21 and SIRT6 changes at the early phase of AAA induction. The in vivo overexpression of SIRT6 significantly prevented AAA formation in Ang II infusion model. The expression of P16 and P21 was significantly reduced after SIRT6 overexpression. SIRT6 overexpression also attenuated chronic inflammation and neo-angiogenesis in Ang II infusion model. The overexpression of SIRT6 could attenuate premature senescence, inflammatory response and neo-angiogenesis in human aortic smooth muscle cells (HASMC) under Ang II stimulation. CONCLUSIONS:SIRT6 overexpression could limit AAA formation via attenuation of vascular smooth muscle senescence, chronic inflammation and neovascularity. 10.1016/j.atherosclerosis.2024.117483

Mapping cellular senescence networks in human diabetic foot ulcers. GeroScience Cellular senescence, a cell fate defined by irreversible cell cycle arrest, has been observed to contribute to chronic age-related conditions including non-healing wounds, such as diabetic foot ulcers. However, the role of cellular senescence in the pathogenesis of diabetic foot ulcers remains unclear. To examine the contribution of senescent phenotypes to these chronic wounds, differential gene and network analyses were performed on publicly available bulk RNA sequencing of whole skin biopsies of wound edge diabetic foot ulcers and uninvolved diabetic foot skin. Wald tests with Benjamini-Hochberg correction were used to evaluate differential gene expression. Results showed that cellular senescence markers, CDKN1A, CXCL8, IGFBP2, IL1A, MMP10, SERPINE1, and TGFA, were upregulated, while TP53 was downregulated in diabetic foot ulcers compared to uninvolved diabetic foot skin. NetDecoder was then used to identify and compare context-specific protein-protein interaction networks using known cellular senescence markers as pathway sources. The diabetic foot ulcer protein-protein interaction network demonstrated significant perturbations with decreased inhibitory interactions and increased senescence markers compared to uninvolved diabetic foot skin. Indeed, TP53 (p53) and CDKN1A (p21) appeared to be key regulators in diabetic foot ulcer formation. These findings suggest that cellular senescence is an important mediator of diabetic foot ulcer pathogenesis. 10.1007/s11357-023-00854-x

New insights into molecular changes in skeletal muscle aging and disease: Differential alternative splicing and senescence. Solovyeva Elizaveta M,Ibebunjo Chikwendu,Utzinger Stephan,Eash John K,Dunbar Andrew,Naumann Ulrike,Zhang Yunyu,Serluca Fabrizio C,Demirci Sabrina,Oberhauser Berndt,Black Frederique,Rausch Martin,Hoersch Sebastian,Meyer Angelika S Mechanisms of ageing and development Progressive loss of muscle mass and function due to muscle fiber atrophy and loss in the elderly and chronically ill is now defined as sarcopenia. It is a major contributor to loss of independence, disability, need of long-term care as well as overall mortality. Sarcopenia is a heterogenous disease and underlying mechanisms are not completely understood. Here, we newly identified and used Tmem158, alongside Cdkn1a, as relevant senescence and denervation markers (SDMs), associated with muscle fiber atrophy. Subsequent application of laser capture microdissection (LCM) and RNA analyses revealed age- and disease-associated differences in gene expression and alternative splicing patterns in a rodent sarcopenia model. Of note, genes exhibiting such differential alternative splicing (DAS) are mainly involved in the contractile function of the muscle. Many of these splicing events are also found in a mouse model for myotonic dystrophy type 1 (DM1), underscoring the premature aging phenotype of this disease. We propose to add differential alternative splicing to the hallmarks of aging. 10.1016/j.mad.2021.111510

Unmasking Transcriptional Heterogeneity in Senescent Cells. Hernandez-Segura Alejandra,de Jong Tristan V,Melov Simon,Guryev Victor,Campisi Judith,Demaria Marco Current biology : CB Cellular senescence is a state of irreversibly arrested proliferation, often induced by genotoxic stress [1]. Senescent cells participate in a variety of physiological and pathological conditions, including tumor suppression [2], embryonic development [3, 4], tissue repair [5-8], and organismal aging [9]. The senescence program is variably characterized by several non-exclusive markers, including constitutive DNA damage response (DDR) signaling, senescence-associated β-galactosidase (SA-βgal) activity, increased expression of the cyclin-dependent kinase (CDK) inhibitors p16INK4A (CDKN2A) and p21CIP1 (CDKN1A), increased secretion of many bio-active factors (the senescence-associated secretory phenotype, or SASP), and reduced expression of the nuclear lamina protein LaminB1 (LMNB1) [1]. Many senescence-associated markers result from altered transcription, but the senescent phenotype is variable, and methods for clearly identifying senescent cells are lacking [10]. Here, we characterize the heterogeneity of the senescence program using numerous whole-transcriptome datasets generated by us or publicly available. We identify transcriptome signatures associated with specific senescence-inducing stresses or senescent cell types and identify and validate genes that are commonly differentially regulated. We also show that the senescent phenotype is dynamic, changing at varying intervals after senescence induction. Identifying novel transcriptome signatures to detect any type of senescent cell or to discriminate among diverse senescence programs is an attractive strategy for determining the diverse biological roles of senescent cells and developing specific drug targets. 10.1016/j.cub.2017.07.033

Senescence-Associated MicroRNAs. International review of cell and molecular biology Senescent cells arise as a consequence of cellular damage and can have either a detrimental or advantageous impact on tissues and organs depending on the specific cell type and metabolic state. As senescent cells accumulate in tissues with advancing age, they have been implicated in many age-related declines and diseases. The major facets of senescence include two pathways responsible for establishing and maintaining a senescence program, p53/CDKN1A(p21) and CDKN2A(p16)/RB, as well as the senescence-associated secretory phenotype. Numerous MicroRNAs influence senescence by modulating the abundance of key senescence regulatory proteins, generally by lowering the stability and/or translation of mRNAs that encode such factors. Accordingly, understanding the molecular mechanisms by which MicroRNAs influence senescence will enable diagnostic and therapeutic opportunities directed at senescent cells. Here, we review senescence-associated (SA)-MicroRNAs and discuss their implications in senescence-relevant pathologies. 10.1016/bs.ircmb.2017.03.008