Phospholipids comprise a large body of lipids that define cells and organelles by forming membrane structures. Importantly, their complex metabolism represents a highly controlled cellular signaling network that is essential for mounting an effective innate immune response. Phospholipids in innate cells are subject to dynamic regulation by enzymes, whose activities are highly responsive to activation status. Along with their metabolic products, they regulate multiple aspects of innate immune cell biology, including shape change, aggregation, blood clotting, and degranulation. Phospholipid hydrolysis provides substrates for cell-cell communication, enables regulation of hemostasis, immunity, thrombosis, and vascular inflammation, and is centrally important in cardiovascular disease and associated comorbidities. Phospholipids themselves are also recognized by innate-like T cells, which are considered essential for recognition of infection or cancer, as well as self-antigens. This Review describes the major phospholipid metabolic pathways present in innate immune cells and summarizes the formation and metabolism of phospholipids as well as their emerging roles in cell biology and disease.
Valerie B. O’Donnell, Jamie Rossjohn, Michael J.O. Wakelam
Cellular senescence, a major tumor-suppressive cell fate, has emerged from humble beginnings as an in vitro phenomenon into recognition as a fundamental mechanism of aging. In the process, senescent cells have attracted attention as a therapeutic target for age-related diseases, including cardiovascular disease (CVD), the leading cause of morbidity and mortality in the elderly. Given the aging global population and the inadequacy of current medical management, attenuating the health care burden of CVD would be transformative to clinical practice. Here, we review the evidence that cellular senescence drives CVD in a bimodal fashion by both priming the aged cardiovascular system for disease and driving established disease forward. Hence, the growing field of senotherapy (neutralizing senescent cells for therapeutic benefit) is poised to contribute to both prevention and treatment of CVD.
Bennett G. Childs, Hu Li, Jan M. van Deursen
Senescent cells (SnCs) are associated with age-related pathologies. Osteoarthritis is a chronic disease characterized by pain, loss of cartilage, and joint inflammation, and its incidence increases with age. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells’ relevance to disease was unclear. In this Review, we summarize current knowledge of SnCs in the multiple tissues that constitute the articular joint. New evidence for the causative role of SnCs in the development of posttraumatic and age-related arthritis is reviewed along with the therapeutic benefit of SnC clearance. As part of their senescence-associated secretory phenotype, SnCs secrete cytokines that impact the immune system and its response to joint tissue trauma. We present concepts of the immune response to tissue trauma as well as the interactions with SnCs and the local tissue environment. Finally, we discuss therapeutic implications of targeting SnCs in treating osteoarthritis.
Ok Hee Jeon, Nathaniel David, Judith Campisi, Jennifer H. Elisseeff
Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation. In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non–cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored. In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.
Nicolás Herranz, Jesús Gil
Cellular senescence is a physiological phenomenon that has both beneficial and detrimental consequences. Senescence limits tumorigenesis and tissue damage throughout the lifetime. However, at the late stages of life, senescent cells increasingly accumulate in tissues and might also contribute to the development of various age-related pathologies. Recent studies have revealed the molecular pathways that preserve the viability of senescent cells and the ones regulating their immune surveillance. These studies provide essential initial insights for the development of novel therapeutic strategies for targeting senescent cells. At the same time they stress the need to understand the limitations of the existing strategies, their efficacy and safety, and the possible deleterious consequences of senescent cell elimination. Here we discuss the existing strategies for targeting senescent cells and upcoming challenges in translating these strategies into safe and efficient therapies. Successful translation of these strategies could have implications for treating a variety of diseases at old age and could potentially reshape our view of health management during aging.
Yossi Ovadya, Valery Krizhanovsky
Along with a general decline in overall health, most chronic degenerative human diseases are inherently associated with increasing age. Age-associated cognitive impairments and neurodegenerative diseases, such as Parkinson’s and Alzheimer’s diseases, are potentially debilitating conditions that lack viable options for treatment, resulting in a tremendous economic and societal cost. Most high-profile clinical trials for neurodegenerative diseases have led to inefficacious results, suggesting that novel approaches to treating these pathologies are needed. Numerous recent studies have demonstrated that senescent cells, which are characterized by sustained cell cycle arrest and production of a distinct senescence-associated secretory phenotype, accumulate with age and at sites of age-related diseases throughout the body, where they actively promote tissue deterioration. Cells with features of senescence have been detected in the context of brain aging and neurodegenerative disease, suggesting that they may also promote dysfunction. Here, we discuss the evidence implicating senescent cells in neurodegenerative diseases, the mechanistic contribution of these cells that may actively drive neurodegeneration, and how these cells or their effects may be targeted therapeutically.
Darren J. Baker, Ronald C. Petersen
Increased sugar consumption is increasingly considered to be a contributor to the worldwide epidemics of obesity and diabetes and their associated cardiometabolic risks. As a result of its unique metabolic properties, the fructose component of sugar may be particularly harmful. Diets high in fructose can rapidly produce all of the key features of the metabolic syndrome. Here we review the biology of fructose metabolism as well as potential mechanisms by which excessive fructose consumption may contribute to cardiometabolic disease.
Sarah A. Hannou, Danielle E. Haslam, Nicola M. McKeown, Mark A. Herman
The fundamental pathology in Alzheimer’s disease (AD) is neuronal dysfunction leading to cognitive impairment. The amyloid-β peptide (Aβ), derived from amyloid precursor protein, is one driver of AD, but how it leads to neuronal dysfunction is not established. In this Review, I discuss the complexity of AD and possible cause-and-effect relationships between Aβ and the vascular and hemostatic systems. AD can be considered a multifactorial syndrome with various contributing pathological mechanisms. Therefore, as is routinely done with cancer, it will be important to classify patients with respect to their disease signature so that specific pathologies, including vascular pathways, can be therapeutically targeted.
The clinical spectrum of congenital anomalies of the kidney and urinary tract (CAKUT) encompasses a common birth defect in humans that has significant impact on long-term patient survival. Overall, data indicate that approximately 20% of patients may have a genetic disorder that is usually not detected based on standard clinical evaluation, implicating many different mutational mechanisms and pathogenic pathways. In particular, 10% to 15% of CAKUT patients harbor an unsuspected genomic disorder that increases risk of neurocognitive impairment and whose early recognition can impact clinical care. The emergence of high-throughput genomic technologies is expected to provide insight into the common and rare genetic determinants of diseases and offer opportunities for early diagnosis with genetic testing.
Simone Sanna-Cherchi, Rik Westland, Gian Marco Ghiggeri, Ali G. Gharavi
Intratumoral fibrosis results from the deposition of a cross-linked collagen matrix by cancer-associated fibroblasts (CAFs). This type of fibrosis has been shown to exert mechanical forces and create a biochemical milieu that, together, shape intratumoral immunity and influence tumor cell metastatic behavior. In this Review, we present recent evidence that CAFs and tumor cells are regulated by provisional matrix molecules, that metastasis results from a change in the type of stromal collagen cross-link, and that fibrosis and inflammation perpetuate each other through proteolytic and chemotactic mediators released into the tumor stroma. We also discuss aspects of the emerging biology that have potential therapeutic value.
Mitsuo Yamauchi, Thomas H. Barker, Don L. Gibbons, Jonathan M. Kurie
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