Ageing and free radicals.

Mammalian ageing is a universal phenomenon that is both obvious and inevitable, yet poorly understood, and under-researched at the molecular level. Numerous ageing theories have been proposed to explain the progressive and deleterious changes characteristic of ageing. One of the most popular of these is the 'free radical' theory of ageing, which proposes that ageing results from imperfect protection against tissue damage brought about by free radicals. Oxygen free radicals are constantly produced during aerobic metabolism, and certainly provide a universal mechanism for oxidative damage. However, a major obstacle to acceptance of the theory has been the poor record of antioxidants in prolonging the lifespan of small animals. Many other variables, such as genetic factors, temperature, activity and nutrition can affect lifespan, making it a highly complex multi-factorial process.     

Angiogenesis in inflammatory bowel disease

Both ulcerative colitis and Crohn's disease, the two major forms of inflammatory bowel diseases, are recognized, at the moment, as perplexing and challenging clinical entities, in which several molecules and cell types are implicated. Recent molecular evidence proposes the intestinal microvascular remodelling or angiogenesis, as a phenomenon implicated in the pathogenesis of these chronic inflammatory disorders, together with other proposed theories involved in the pathogenesis of inflammatory bowel diseases, such as genetic, microbacterial and immune factors. Intestinal damage is followed by a physiological angiogenesis, but the abnormal expression of pro- and anti-angiogenic molecules and the changes of vascular cell types could reflect a pathological vascular remodelling. Thus, the inflammation may be favoured and maintained by a pathological angiogenesis. A better understanding of the angiogenic process may facilitate the design of more effective therapies for chronic intestinal inflammation.     

Inflammation,the metabolic syndrome and cardiovascular risk

Over the past ten years it has become clear that cardiovascular disease (CVD) and atherosclerosis have a 'microinflammatory' component and are often associated with low levels of inflammatory markers that are in the upper part of the 'normal' range. In particular, diseases that predispose to CVD, such as the metabolic syndrome and type 2 diabetes, appear to have a very strong inflammatory component. While the inflammatory process is very complicated, single measures, such as C-reactive protein (CRP) or fibrinogen, have clear benefits as they summarise many different parts of the inflammatory process and are easy to apply. However, it is important to remember that the process of inflammation includes coagulation, fibrinolysis, complement activation, antioxidation, immune response and hormonal regulation through the hypothalamic-pituitary-adrenal axis. Furthermore, genetic variation, differences in exposure to environmental influences and the mass of inflammation-producing tissue (e.g. adipose tissue) can all influence responses. Thus, the relationship between atherosclerosis, the metabolic syndrome and inflammation is extraordinarily complex. Inflammatory markers such as CRP exhibit strong CVD-risk prediction that is consistent across sexes and a number of different populations. They reflect risk not only for 'vulnerable plaque' and myocardial infarction (MI) but also for other cardiovascular diseases. In fact, inflammation is associated with several, if not all, of the chronic diseases of old age, and it is now clear that there are important links between inflammation and general metabolism. For instance, visceral adiposity exerts a major influence on inflammation status. Medications that affect atherosclerosis appear to do so at least in part by influencing inflammation (for instance, the emerging pleiotropic effects of statins), and this has far-reaching ramifications for chronic diseases of old age and their treatment.     

Coagulation and inflammation. Molecular insights and diagnostic implications

Overwhelming evidence has linked inflammatory disorders to a hypercoagulable state. In fact, thromboembolic complications are among the leading causes of disability and death in many acute and chronic inflammatory diseases. Despite this clinical knowledge, coagulation and immunity were long regarded as separate entities. Recent studies have unveiled molecular underpinnings of the intimate interconnection between both systems. The studies have clearly shown that distinct pro-inflammatory stimuli also activate the clotting cascade and that coagulation in turn modulates inflammatory signaling pathways. In this review, we use evidence from sepsis and inflammatory bowel diseases as a paradigm for acute and chronic inflammatory states in general and rise hypotheses how a systematic molecular understanding of the "inflammation-coagulation" crosstalk may result in novel diagnostic and therapeutic strategies that target the inflammation-induced hypercoagulable state.     

Effect of Low Birth Weight on Women’s Health

PurposeThe theory of the developmental origins of health and disease hypothesizes that low birth weight (≤5.5 lb) indicative of poor fetal growth is associated with an increased risk of chronic, noncommunicable disease in later life, including hypertension, type 2 diabetes mellitus, and osteoporosis. Whether women are at greater risk than men is not clear. Experimental studies that mimic the cause of slow fetal growth are being used to examine the underlying mechanisms that link a poor fetal environment with later chronic disease and investigate how sex and age affect programmed risk. Thus, the aims of this review are to summarize the current literature related to the effect of low birth weight on women’s health and provide insight into potential mechanisms that program increased risk of chronic disease across the lifespan.MethodsA search of PubMed was performed with the keywords low birth weight, women’s health, female, and sex differences; additional terms included blood pressure, hypertension, renal, cardiovascular, obesity, glucose intolerance, type 2 diabetes, osteoporosis, bone health, reproductive senescence, menopause, and aging.FindingsThe major chronic diseases associated with low birth weight include high blood pressure and cardiovascular disease, impaired glucose homeostasis and type 2 diabetes, impaired bone mass and osteoporosis, and early reproductive aging.ImplicationsLow birth weight increases the risk of chronic disease in men and women. Low birth weight is also associated with increased risk of early menopause. Further studies are needed to fully address the effect of sex and age on the developmental programming of adult health and disease in women across their lifespan.     

The Achilles’ heel of cancer survivors: fundamentals of accelerated cellular senescence

Recent improvements in cancer treatment have increased the lifespan of pediatric and adult cancer survivors. However, cancer treatments accelerate aging in survivors, which manifests clinically as the premature onset of chronic diseases, such as endocrinopathies, osteoporosis, cardiac dysfunction, subsequent cancers, and geriatric syndromes of frailty, among others. Therefore, cancer treatment–induced early aging accounts for significant morbidity, mortality, and health expenditures among cancer survivors. One major mechanism driving this accelerated aging is cellular senescence; cancer treatments induce cellular senescence in tumor cells and in normal, nontumor tissue, thereby helping mediate the onset of several chronic diseases. Studies on clinical monitoring and therapeutic targeting of cellular senescence have made considerable progress in recent years. Large-scale clinical trials are currently evaluating senotherapeutic drugs, which inhibit or eliminate senescent cells to ameliorate cancer treatment–related aging. In this article, we survey the recent literature on phenotypes and mechanisms of aging in cancer survivors and provide an up-to-date review of the major preclinical and translational evidence on cellular senescence as a mechanism of accelerated aging in cancer survivors, as well as insight into the potential of senotherapeutic drugs. However, only with time will the clinical effect of senotherapies on cancer survivors be visible.

Cancer survival times have increased annually owing to advances in early detection and treatment that prolong patient survival. However, increasing survivorship has underscored the observation that cancer survivors develop age-related diseases prematurely, which cause significant morbidity, health expenditures, and mortality. Many cancer survivors have been exposed to chemotherapy, radiotherapy, or both; despite eradicating cancer cells, these therapies also damage normal cells to accelerate biologic aging, such that a discrepancy exists between their biologic and chronologic age (1). Considerable data exist regarding the phenotypes of accelerated aging. However, mechanical and molecular uncertainties have limited the study of these manifestations in a clinical context. Our Review discusses accelerated aging phenotypes in cancer survivors and the cellular mechanisms underpinning these phenomena. We then discuss the translational evidence on how accelerated aging phenotypes, mainly related to senescence, are being targeted while highlighting areas of uncertainty for future research to address.     

Cover Image,Volume 40, Issue 6

Senescence is a state of cell cycle arrest that plays an important role in embryogenesis, wound healing and protection against cancer. Senescent cells also accumulate during aging and contribute to the development of age-related disorders and chronic diseases, such as atherosclerosis, type 2 diabetes, osteoarthritis, idiopathic pulmonary fibrosis, and liver disease. Molecules that induce apoptosis of senescent cells, such as dasatinib, quercetin, and fisetin, produce health benefits and extend lifespan in animal models. We describe here the mechanism of action of senolytics and senomorphics, many of which are derived from plants and fungi. We also discuss the possibility of using such compounds to delay aging and treat chronic diseases in humans.     

Minerals

Essential minerals have many important roles, from physiology, dietary requirements and associated deficiencies to new disease preventive aspects related to dietary intake of minerals. Many important mechanisms of minerals, such as antioxidant scavenging actions, gene regulation and expression, and induction or suppression of apoptosis can be used to decrease the risk of many chronic non-transmissible maladies. Some minerals are also important for modulation of immune system activities that decrease the risk of infections, inflammatory disorders and cancer. It has been postulated that mitochondrial failure and oxidative stress are major events in cell aging and death. Thus, nutritional modulation of mitochon dria and antioxidant activities of minerals from foods help to reduce the risk of chronic diseases of aging.     

Rapamycin extends murine lifespan but has limited effects on aging

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin’s effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin’s longevity effects from effects on aging itself.     

Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine

Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.     

Molecular pathogenesis of inflammatory bowel disease: Genotypes,phenotypes and personalized medicine

Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.     

Inflamatory mechanisms in bronchial asthma and COPD

Both bronchial asthma and chronic obstructive pulmonary disease (COPD) are recognized as inflammatory diseases, although the inflammatory process for each disease is different. In this review, I describe some inflammatory molecules that seem to be involved in the inflammatory process in each disease.     

Moving towards a new generation of animal models for asthma and COPD with improved clinical relevance

Asthma and chronic obstructive pulmonary disease (COPD) are complex inflammatory airway diseases characterised by airflow obstruction that remain leading causes of hospitalization and death worldwide. Animal modelling systems that accurately reflect disease pathophysiology continue to be essential to the development of new therapies for both conditions. In this review, we describe preclinical in vivo models that recapitulate many of the features of asthma and COPD. Specifically, we discuss the pro's and con's of the standard models and highlight recently developed systems designed to more accurately reflect the complexity of both diseases. For instance, clinically relevant allergens (i.e. house dust mite) are now being used to mimic the inflammatory changes and airway remodelling that result after chronic allergen exposures. Additionally, systems are being developed to mimic steroid-resistant and viral exacerbations of allergic inflammation - aspects of asthma where there is an acute need for new therapies. Similarly, COPD models have evolved to align with the improved clinical understanding of the factors contributing to disease progression. This includes using cigarette smoke to model not only airway inflammation and remodelling, but some systemic changes (e.g. hypertension and skeletal muscle alterations) that are thought to influence disease. Further, mouse genetics are being exploited to gain insights into the genetics of COPD susceptibility. The new models of asthma and COPD described herein demonstrate that improved clinical understanding of the diseases and better preclinical models is an iterative process that will hopefully lead to therapies that can effectively manage severe asthma and COPD.     

Metabolic age modelling: the lesson from centenarians

Evolutionary theories of ageing, and data emerging from cellular and molecular biology of ageing, suggested that animals and humans capable of reaching an age close to the extreme limit of the life span should be equipped with a very efficient network of anti-ageing mechanisms. Indeed several evidences have demonstrated that starting from young to very old subjects, ageing is associated with a progressive remodelling. Thus, a new paradigm, the remodelling theory of age, was proposed. This theory, focusing on the human immune system, suggested that immunosenescence is the net result of the continuous adaptation of the body to the deteriorative changes occurring over time. According to this hypothesis, body resources are continuously optimized, and immunosenescence must be considered a very dynamic process including both loss and gain. Whether the metabolic pathways and the endocrine functions are also part of the age remodelling is not investigated. The aim of this review is to focus on the age-related changes in metabolic pathways and endocrine functions and to demonstrate that healthy centenarians (HC) represent the best living example of successful age-remodelling in whom the age remodelling has occurred without problems. In order to design the clinical picture of such successful ageing, anthropometric, endocrine and metabolic characteristics of healthy centenarians (HC), compared with aged subject, have been outlined.     

Biological aging processes underlying cognitive decline and neurodegenerative disease

Alzheimer’s disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview of changes in cognition, brain morphology, and neuropathological protein accumulation across the lifespan in humans, with complementary and mechanistic evidence from animal models. Next, we highlight selected aging processes that are differentially regulated in neurodegenerative disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular dysfunction, inflammation, and lipid dysregulation. We summarize research across clinical and translational studies to link biological aging processes to underlying ADRD pathogenesis. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. Collaboration across the fields of geroscience and neuroscience, coupled with the development of new translational animal models that more closely align with human disease processes, is necessary to advance novel therapeutic discovery in this realm.     

Healthy aging and disease: role for telomere biology?

Aging is a biological process that affects most cells, organisms and species. Human aging is associated with increased susceptibility to a variety of chronic diseases, including cardiovascular disease, Type 2 diabetes, neurological diseases and cancer. Despite the remarkable progress made during the last two decades, our understanding of the biology of aging remains incomplete. Telomere biology has recently emerged as an important player in the aging and disease process.     

Purinergic receptors: new targets for the treatment of gout and fibrosis

Adenosine triphosphate is involved in many metabolic reactions, but it has also a role as a cellular danger signal transmitted through purinergic receptors (PRs). Indeed, adenosine 5′‐triphosphate (ATP) can bind to PRs which are found in the membrane of many cell types, although the relative proportions of the receptor subtypes differ. PRs are classified according to genetic and pharmacological criteria and especially their affinities for agonists and their transduction mechanism (i.e. as metabotropic P2YRs or ionotropic P2XRs). Extracellular ATP release by activated or necrotic cells may activate various PRs and especially P2X7R, the best‐characterized PR, on immune cells. P2X7R is known to regulate the activation of the Nod‐like receptor (NLR)‐family protein, NLRP3 inflammasome, which permit the release of IL‐1β, a potent pro‐inflammatory cytokine. The P2X7R/NLRP3 pathway is involved in many inflammatory diseases, such as gout, and in fibrosis diseases associated with inflammatory process, liver or lung fibrosis. Some authors imaging also a real promising therapeutic potential of P2X7R blockage. Thus, several pharmaceutical companies have developed P2X7R antagonists as novel anti‐inflammatory drug candidates. Clinical trials of the efficacy of these antagonists are now underway. A better understanding of the P2X7R/NLRP3 signalling pathways permits the identification of targets and the development of a new class of drugs able to inhibit the fibrogenesis process and collagen deposition.     

Novel therapeutic strategies for lung disorders associated with airway remodelling and fibrosis

Inflammatory cell infiltration, cytokine release, epithelial damage, airway/lung remodelling and fibrosis are central features of inflammatory lung disorders, which include asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome and idiopathic pulmonary fibrosis. Although the lung has some ability to repair itself from acute injury, in the presence of ongoing pathological stimuli and/or insults that lead to chronic disease, it no longer retains the capacity to heal, resulting in fibrosis, the final common pathway that causes an irreversible loss of lung function. Despite inflammation, genetic predisposition/factors, epithelial–mesenchymal transition and mechanotransduction being able to independently contribute to airway remodelling and fibrosis, current therapies for inflammatory lung diseases are limited by their ability to only target the inflammatory component of the disease without having any marked effects on remodelling (epithelial damage and fibrosis) that can cause lung dysfunction independently of inflammation. Furthermore, as subsets of patients suffering from these diseases are resistant to currently available therapies (such as corticosteroids), novel therapeutic approaches are required to combat all aspects of disease pathology. This review discusses emerging therapeutic approaches, such as trefoil factors, relaxin, histone deacetylase inhibitors and stem cells, amongst others that have been able to target airway inflammation and airway remodelling while improving related lung dysfunction. A better understanding of the mode of action of these therapies and their possible combined effects may lead to the identification of their clinical potential in the setting of lung disease, either as adjunct or alternative therapies to currently available treatments.     

Molecular mechanisms of cardiomyocyte aging

Western societies are rapidly aging, and cardiovascular diseases are the leading cause of death. In fact, age and cardiovascular diseases are positively correlated, and disease syndromes affecting the heart reach epidemic proportions in the very old. Genetic variations and molecular adaptations are the primary contributors to the onset of cardiovascular disease; however, molecular links between age and heart syndromes are complex and involve much more than the passage of time. Changes in CM (cardiomyocyte) structure and function occur with age and precede anatomical and functional changes in the heart. Concomitant with or preceding some of these cellular changes are alterations in gene expression often linked to signalling cascades that may lead to a loss of CMs or reduced function. An understanding of the intrinsic molecular mechanisms underlying these cascading events has been instrumental in forming our current understanding of how CMs adapt with age. In the present review, we describe the molecular mechanisms underlying CM aging and how these changes may contribute to the development of cardiovascular diseases.