The role of epigenetics in endothelial cell senescence is a cutting‐edge topic in ageing research. However, little is known of the relative contribution to pro‐senescence signal propagation provided by microRNAs shuttled by extracellular vesicles (EVs) released from senescent cells. Analysis of microRNA and DNA methylation profiles in non‐senescent (control) and senescent (SEN) human umbilical vein endothelial cells (HUVECs), and microRNA profiling of their cognate small EVs (sEVs) and large EVs demonstrated that SEN cells released a significantly greater sEV number than control cells. sEVs were enriched in miR‐21‐5p and miR‐217, which target DNMT1 and SIRT1. Treatment of control cells with SEN sEVs induced a miR‐21/miR‐217‐related impairment of DNMT1‐SIRT1 expression, the reduction of proliferation markers, the acquisition of a senescent phenotype and a partial demethylation of the locus encoding for miR‐21. MicroRNA profiling of sEVs from plasma of healthy subjects aged 40–100 years showed an inverse U‐shaped age‐related trend for miR‐21‐5p, consistent with senescence‐associated biomarker profiles. Our findings suggest that miR‐21‐5p/miR‐217 carried by SEN sEVs spread pro‐senescence signals, affecting DNA methylation and cell replication.

Despite the decline in their proliferative potential, senescent cells display a high metabolic activity. Senescent cells have been shown to acquire a more glycolytic state even in presence of high oxygen levels, in a way similar to cancer cells. The diversion of pyruvate, the final product of glycolysis, away from oxidative phosphorylation results in an altered bioenergetic state and may occur as a response to the enhanced oxidative stress caused by the accumulation of dysfunctional mitochondria. This metabolic shift leads to increased AMP/ATP and ADP/ATP ratios, to the subsequent AMPK activation, and ultimately to p53-mediated growth arrest. Mounting evidences suggest that metabolic reprogramming is critical to direct considerable amounts of energy toward specific activities related to the senescent state, including the senescence-associated secretory phenotype (SASP) and the modulation of immune responses within senescent cell tissue microenvironment. Interestingly, despite the relative abundance of oxygen in the vascular compartment, healthy endothelial cells (ECs) produce most of their ATP content from the anaerobic conversion of glucose to lactate. Their high glycolytic rate further increases during senescence. Alterations in EC metabolism have been identified in age-related diseases (ARDs) associated with a dysfunctional vasculature, including atherosclerosis, type 2 diabetes and cardiovascular diseases. In particular, higher production of reactive oxygen species deriving from a variety of enzymatic sources, including uncoupled endothelial nitric oxide synthase and the electron transport chain, causes DNA damage and activates the NAD⁺-consuming enzymes polyADP-ribose polymerase 1 (PARP1). These non-physiological mechanisms drive the impairment of the glycolytic flux and the diversion of glycolytic intermediates into many pathological pathways. Of note, accumulation of senescent ECs has been reported in the context of ARDs. Through their pro-oxidant, pro-inflammatory, vasoconstrictor, and prothrombotic activities, they negatively impact on vascular physiology, promoting both the onset and development of ARDs. Here, we review the current knowledge on the cellular senescence-related metabolic changes and their contribution to the mechanisms underlying the pathogenesis of ARDs, with a particular focus on ECs. Moreover, current and potential interventions aimed at modulating EC metabolism, in order to prevent or delay ARD onset, will be discussed.

The age-related changes of immune system functions are complex phenomena incompletely understood. The acquired immune system shows a functional decline in ability to respond to new pathogens during aging, whereas serum levels of inflammatory cytokines are increased with age. The source of this age-related systemic chronic inflammation, named inflammaging, was mainly attributed to the progressive activation of immune cells over time. However, recent studies have shown that the process of cellular senescence can be an important additional contributor to chronic inflammation, since senescent cells acquire a phenotype named “senescence-associated secretory phenotype” (SASP), characterized by the enhanced secretion of many inflammation modulators. Pathogen-associated molecular pattern receptors, in particular Toll-like receptors (TLRs), are key molecules in the response of innate immunity cells to pathological stimuli. An intriguing and innovative hypothesis is that the dysfunction of TLRs signaling and the acquisition of SASP can be two interconnected phenomena. The TLR family, including receptors and co-effector molecules, do not show a consistent age-dependent change across model systems. However, there is evidence for impaired downstream signaling events, including inhibition of positive and activation of negative modulators of TLR signaling. MicroRNAs (miRNAs) are a newly discovered class of gene regulators acting as post-transcriptional repressors of a number of genes. The miRNA property to finely-tune gene expression makes them right for immune system regulation, which requires precise control for proper activity. We reviewed evidences suggesting that miRNAs can modulate TLR signaling mainly by three different mechanisms: 1) miRNAs can directly target components of the TLR signaling system, 2) miRNA expression can be directly regulated by TLRs pathway activation and 3) miRNAs can directly activate the RNA-sensing TLRs, like TLR-8, in humans. We also reviewed how TLR signaling is modulated by miRNAs during aging, and how an impaired miRNAs/TLR signaling interaction in immune system cells and related cells, i.e. endothelial cells and adipocytes, can contribute to inflammaging observed in normal aging. Interestingly, this impairment appears accelerated in presence of the majors age-related diseases, such as cardiovascular diseases, diabetes, neurodegenerative diseases and cancers.

Ovarian cancer is one of the most dangerous gynecologic cancers worldwide and has a high fatality rate due to diagnosis at an advanced stage of the disease as well as a high recurrence rate due to the occurrence of chemotherapy resistance. In fact, chemoresistance weakens the therapeutic effects, worsening the outcome of this pathology. Solute Carrier Family 7 Member 11 (SLC7A11, also known as xCT) is the functional subunit of the $X_c^{-}$ system, an anionic L-cystine/L-glutamate antiporter expressed on the cell surface. SLC7A11 expression is significantly upregulated in several types of cancers in which it can inhibit ferroptosis and favor cancer cell proliferation, invasion and chemoresistance. SLC7A11 expression is also increased in ovarian cancer tissues, suggesting a possible role of this protein as a therapeutic target. In this review, we provide an overview of the current literature regarding the role of SLC7A11 in ovarian cancer to provide new insights on SLC7A11 modulation and evaluate the potential role of SLC7A11 as a therapeutic target.