The biological basis of human aging remains one of the greatest unanswered scientific questions. Increasing evidence, however, points to a role for alterations in mitochondrial function as a potential central regulator of the aging process. Here, we focus primarily on three aspects of mitochondrial biology that link this ancient organelle to how and why we age. In particular, we discuss the role of mitochondria in regulating the innate immune system, the mechanisms linking mitochondrial quality control to age-dependent pathology, and the possibility that mitochondrial-to-nuclear signaling might regulate the rate of aging.
Jiyong Yang, Arnon Blum, Jie Liu, Toren Finkel
Non-resolving inflammation drives the development of clinically dangerous atherosclerotic lesions by promoting sustained plaque inflammation, large necrotic cores, thin fibrous caps, and thrombosis. Resolution of inflammation is not merely a passive return to homeostasis, but rather an active process mediated by specific molecules, including fatty acid–derived specialized pro-resolving mediators (SPMs). In advanced atherosclerosis, there is an imbalance between levels of SPMs and proinflammatory lipid mediators, which results in sustained leukocyte influx into lesions, inflammatory macrophage polarization, and impaired efferocytosis. In animal models of advanced atherosclerosis, restoration of SPMs limits plaque progression by suppressing inflammation, enhancing efferocytosis, and promoting an increase in collagen cap thickness. This Review discusses the roles of non-resolving inflammation in atherosclerosis and highlights the unique therapeutic potential of SPMs in blocking the progression of clinically dangerous plaques.
Canan Kasikara, Amanda C. Doran, Bishuang Cai, Ira Tabas
Aging is defined as the progressive deterioration of physiological function with age. Incidence of many pathologies increases with age, including neurological and cardiovascular diseases and cancer. Aging tissues become less adaptable and renewable, and cells undergo senescence, a process by which they “irreversibly” stop dividing. Senescence has been shown to serve as a tumor suppression mechanism with clear desirable effects. However, senescence also has deleterious consequences, especially for cardiovascular, metabolic, and immune systems. Sphingolipids are a major class of lipids that regulate cell biology, owing to their structural and bioactive properties and diversity. Their involvement in the regulation of aging and senescence has been demonstrated and studied in multiple organisms and cell types, especially that of ceramide and sphingosine-1-phosphate; ceramide induces cellular senescence and sphingosine-1–phosphate delays it. These discoveries could be very useful in the future to understand aging mechanisms and improve therapeutic interventions.
Magali Trayssac, Yusuf A. Hannun, Lina M. Obeid
Leukotrienes are powerful immune-regulating lipid mediators with established pathogenic roles in inflammatory allergic diseases of the respiratory tract — in particular, asthma and hay fever. More recent work indicates that these lipids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, and metabolic diseases as well as cancer. Biosynthesis of leukotrienes involves oxidative metabolism of arachidonic acid and proceeds via a set of soluble and membrane enzymes that are primarily expressed by cells of myeloid origin. In activated immune cells, these enzymes assemble at the endoplasmic and perinuclear membrane, constituting a biosynthetic complex. This Review describes recent advances in our understanding of the components of the leukotriene-synthesizing enzyme machinery, emerging opportunities for pharmacological intervention, and the development of new medicines exploiting both antiinflammatory and pro-resolving mechanisms.
Jesper Z. Haeggström
Chronic inflammation is an underlying feature of many diseases, including chronic obstructive pulmonary disease, rheumatoid arthritis, asthma, and multiple sclerosis. There is an increasing appreciation of the dysregulation of adaptive immunity in chronic inflammatory and allergic diseases. The discovery of specialized pro-resolving lipid mediators (SPMs) that actively promote the resolution of inflammation has opened new avenues for the treatment of chronic inflammatory diseases. Much work has been done focusing on the impact of SPMs on innate immune cells. However, much less is known about the influence of SPMs on the development of antigen-specific adaptive immune responses. This Review highlights the important breakthroughs concerning the effects of SPMs on the key cell types involved in the development of adaptive immunity, namely dendritic cells, T cells, and B cells.
Parker F. Duffney, Megan L. Falsetta, Ashley R. Rackow, Thomas H. Thatcher, Richard P. Phipps, Patricia J. Sime
Countless times each day, the acute inflammatory response protects us from invading microbes, injuries, and insults from within, as in surgery-induced tissue injury. These challenges go unnoticed because they are self-limited and naturally resolve without progressing to chronic inflammation. Peripheral blood markers of inflammation are present in many common diseases, including inflammatory bowel disease, cardiovascular disease, neurodegenerative disease, and cancer. While acute inflammation is protective, excessive swarming of neutrophils amplifies collateral tissue damage and inflammation. Hence, understanding the mechanisms that control the resolution of acute inflammation provides insight into preventing and treating inflammatory diseases in multiple organs. This Review focuses on the resolution phase of inflammation with identification of specialized pro-resolving mediators (SPMs) that involve three separate biosynthetic and potent mediator families, which are defined using the first quantitative resolution indices to score this vital process. These are the resolvins, protectins, and maresins: bioactive metabolomes that each stimulate self-limited innate responses, enhance innate microbial killing and clearance, and are organ-protective. We briefly address biosynthesis of SPMs and their activation of endogenous resolution programs as terrain for new therapeutic approaches that are not, by definition, immunosuppressive, but rather new immunoresolvent therapies.
Charles N. Serhan, Bruce D. Levy
Leukotrienes, a class of arachidonic acid–derived bioactive molecules, are known as mediators of allergic and inflammatory reactions and considered to be important drug targets. Although an inhibitor of leukotriene biosynthesis and antagonists of the cysteinyl leukotriene receptor are clinically used for bronchial asthma and allergic rhinitis, these medications were developed before the molecular identification of leukotriene receptors. Numerous studies using cloned leukotriene receptors and genetically engineered mice have unveiled new pathophysiological roles for leukotrienes. This Review covers the recent findings on leukotriene receptors to revisit them as new drug targets.
Takehiko Yokomizo, Motonao Nakamura, Takao Shimizu
Chronic inflammation is a risk factor for gastrointestinal cancer and other diseases. Most studies have focused on cytokines and chemokines as mediators connecting chronic inflammation to cancer, whereas the involvement of lipid mediators, including prostanoids, has not been extensively investigated. Prostanoids are among the earliest signaling molecules released in response to inflammation. Multiple lines of evidence suggest that prostanoids are involved in gastrointestinal cancer. In this Review, we discuss how prostanoids impact gastrointestinal cancer development. In particular, we highlight recent advances in our understanding of how prostaglandin E2 induces the immunosuppressive microenvironment in gastrointestinal cancers.
Dingzhi Wang, Raymond N. DuBois
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 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
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