D‐galactose‐induced cardiac ageing: A review of model establishment and potential interventions

Cardiovascular disease (CVD) is highly prevalent in an ageing society. The increased incidence and mortality rates of CVD are global issues endangering human health. There is an urgent requirement for understanding the aetiology and pathogenesis of CVD and developing possible interventions for preventing CVD in ageing hearts. It is necessary to select appropriate models and treatment methods. The D‐galactose‐induced cardiac ageing model possesses the advantages of low mortality, short time and low cost and has been increasingly used in the study of cardiovascular diseases in recent years. Therefore, understanding the latest progress in D‐galactose‐induced cardiac ageing is valuable. This review highlights the recent progress and potential therapeutic interventions used in D‐galactose‐induced cardiac ageing in recent years by providing a comprehensive summary of D‐galactose‐induced cardiac ageing in vivo and in vitro. This review may serve as reference literature for future research on age‐related heart diseases.     

NF-κB pathway activators as potential ageing biomarkers: targets for new therapeutic strategies

Chronic inflammation is a major biological mechanism underpinning biological ageing process and age-related diseases. Inflammation is also the key response of host defense against pathogens and tissue injury. Current opinion sustains that during evolution the host defense and ageing process have become linked together. Thus, the large array of defense factors and mechanisms linked to the NF-κB system seem to be involved in ageing process. This concept leads us in proposing inductors of NF-κB signaling pathway as potential ageing biomarkers. On the other hand, ageing biomarkers, represented by biological indicators and selected through apposite criteria, should help to characterize biological age and, since age is a major risk factor in many degenerative diseases, could be subsequently used to identify individuals at high risk of developing age-associated diseases or disabilities. In this report, some inflammatory biomarkers will be discussed for a better understanding of the concept of biological ageing, providing ideas on eventual working hypothesis about potential targets for the development of new therapeutic strategies and improving, as consequence, the quality of life of elderly population.     

Ageing and cancer as diseases of epigenesis

Cancer and ageing are often said to be diseases of development. During the past fifty years, the genetic components of cancer and ageing have been intensely investigated since development, itself, was seen to be an epiphenomenon of the genome. However, as we have learned more about the expression of the genome, we find that differences in expression can be as important as differences in alleles. It is easier to inactivate a gene by methylation than by mutation, and given that appropriate methylation is essential for normal development, one can immediately see that diseases would result as a consequence of inappropriate epigenetic methylation. While first proposed by Boris Vanyushin in 1973, recent studies have confirmed that inappropriate methylation not only causes diseases, and it also may be the critical factor in ageing and cancers.     

表观遗传调控健康衰老

衰老是自然界普遍存在的现象。衰老伴随着组织和器官功能的逐渐衰退,最终导致生物体死亡。衰老也是人们罹患老年性疾病如心血管疾病、神经退行性疾病、癌症、糖尿病等的主要风险因素。因此,延缓衰老对于预防和治疗衰老相关的疾病意义重大。衰老与遗传和表观遗传改变密切相关。最近,Nature杂志发表了中国科学院脑科学与智能技术卓越创新中心蔡时青研究组与中国科学院上海巴斯德研究所江陆斌研究组的合作成果。该研究发现了两个新的保守的表观调控因子妨碍健康衰老。     

Genetics of longevity. data from the studies on Sicilian centenarians

ABSTRACT: The demographic and social changes of the past decades have determined improvements in public health and longevity. So, the number of centenarians is increasing as a worldwide phenomenon. Scientists have focused their attention on centenarians as optimal model to address the biological mechanisms of "successful and unsuccessful ageing". They are equipped to reach the extreme limits of human life span and, most importantly, to show relatively good health, being able to perform their routine daily life and to escape fatal age-related diseases, such as cardiovascular diseases and cancer. Thus, particular attention has been centered on their genetic background and immune system. In this review, we report our data gathered for over 10 years in Sicilian centenarians. Based on results obtained, we suggest longevity as the result of an optimal performance of immune system and an over-expression of anti-inflammatory sequence variants of immune/inflammatory genes. However, as well known, genetic, epigenetic, stochastic and environmental factors seem to have a crucial role in ageing and longevity. Epigenetics is associated with ageing, as demonstrated in many studies. In particular, ageing is associated with a global loss of methylation state. Thus, the aim of future studies will be to analyze the weight of epigenetic changes in ageing and longevity.     

Immunosenescence and age-related viral diseases

Immunosenescence is described as a decline in the normal functioning of the immune system associated with physiologic ageing.Immunosenescence contributes to reduced efficacy to vaccination and increased susceptibility to infectious diseases in the elderly.Extensive studies of laboratory animal models of ageing or donor lymphocyte analysis have identified changes in immunity caused by the ageing process.Most of these studies have identified phenotypic and functional changes in innate and adaptive immunity.However,it is unclear which of these defects are critical for impaired immune defense against infection.This review describes the changes that occur in innate and adaptive immunity with ageing and some age-related viral diseases where defects in a key component of immunity contribute to the high mortality rate in mouse models of ageing.     

Ontogenetic model of ageing and disease formation and mechanisms of natural selection

It is known that increased mortality due to environmental hazards results, in the course of natural selection, in the shortening of maximum life span and acceleration of sexual maturation in a population subjected to an intensified pressure from external environment. As a consequence, the prereproductive period/maximum life span ratio appears to be approximately the same in each species. Mechanisms responsible for this are not clear yet. Since maximum life span is limited by both ageing and formation of certain diseases (in humans, the so-called main noninfectious diseases), the paper discusses four possible models of development of ageing and age-linked disease--ecological, genetic, degenerative (metabolic) and ontogenetic. It was found that it is the ontogenetic model only that can adequately account for the development of moderate shifts in the duration of both sexual maturation and maximum life span. It also provides the rationale for the pleotropic activity of genes during the development of the organism, its ageing and formation of age-connected diseases.     

Ageing and mesenchymal stem cells derived exosomes: Molecular insight and challenges

Ageing induces a great risk factor that participates in progressing various degenerative diseases morbidities. The main characteristic of ageing is the failure in maintaining homeostasis in the organs with a cellular senescence. Senescence is characterized by reduced cell growth, evade cellular death, and acquiring a senescence‐associated secretory phenotype (SASP). Mesenchymal stem cells (MSCs) are advantageous cells in regenerative medicine, exerting pleiotropic functions by producing soluble factors, such as exosomes. MSCs and their exosomes (MSCs‐Exo) kinetic are affected by ageing and other aged exosomes. Exosomes biogenesis from aged MSCs is accelerated and their exosomal cargoes, such as miRNAs, vary as compared to those of normal cells. Besides, exosomes from aged MSCs loss their regenerative potential and may negatively influence the function of recipient cells. MSCs‐Exo can improve ageing and age‐related diseases; however, the detailed mechanisms remain yet elusive. Although exosomes‐therapy may serve as a new approach to combat ageing, the translation of preclinical results to clinic needs more extensive investigation on exosomes both on their biology and related techniques. Overall, scrutiny on the effect of ageing on MSCs and vice versa is vital for designing novel therapy using MSCs with focus on the management of older individuals.     

Hemostasis and ageing

On March 19, 2008 a Symposium on Pathophysiology of Ageing and Age-Related Diseases was held in Palermo, Italy. The lecture of D. Mari on Hemostasis and ageing is summarized herein. Physiological ageing is associated with increased plasma levels of many proteins of blood coagulation together with fibrinolysis impairment. This may be of great concern in view of the known association between vascular and thromboembolic diseases and ageing. On the other hand, centenarians are characterized by a state of hypercoagulability and possession of several high-risk alleles and well-known atherothrombotic risk markers but this appears to be compatible with longevity and/or health. Parameters considered risk factors for atherosclerotic vascular diseases in young people may lose their biological significance in advanced age and assume a different role.     

Pathophysiology of ageing, longevity and age related diseases

On April 18, 2007 an international meeting on Pathophysiology of Ageing, Longevity and Age-Related Diseases was held in Palermo, Italy. Several interesting topics on Cancer, Immunosenescence, Age-related inflammatory diseases and longevity were discussed. In this report we summarize the most important issues. However, ageing must be considered an unavoidable end point of the life history of each individual, nevertheless the increasing knowledge on ageing mechanisms, allows envisaging many different strategies to cope with, and delay it. So, a better understanding of pathophysiology of ageing and age-related disease is essential for giving everybody a reasonable chance for living a long and enjoyable final part of the life.     

Mitochondrial DNA mutations and ageing

The mechanism by which we age has sparked a huge number of theories, and is an area of intense debate. As the elderly population rises, the importance of elucidating these mechanisms is becoming more apparent as age is the single biggest risk factor for a number of diseases such as cancer, diabetes and neurodegenerative disease. Mitochondrial DNA (MtDNA) mutations have been shown to accumulate in cells and tissues during the ageing process; however the question as to whether these mutations have a causal role in the ageing process remains an area of uncertainty. Here we review the current literature, and discuss the evidence for and against a causal role of mtDNA mutations in ageing and in the pathogenesis of age-related disease.     

Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells

The ageing of the global population brings about unprecedented challenges. Chronic age‐related diseases in an increasing number of people represent an enormous burden for health and social care. The immune system deteriorates during ageing and contributes to many of these age‐associated diseases due to its pivotal role in pathogen clearance, tissue homeostasis and maintenance. Moreover, in order to develop treatments for COVID‐19, we urgently need to acquire more knowledge about the aged immune system, as older adults are disproportionally and more severely affected. Changes with age lead to impaired responses to infections, malignancies and vaccination, and are accompanied by chronic, low‐degree inflammation, which together is termed immunosenescence. However, the molecular and cellular mechanisms that underlie immunosenescence, termed immune cell senescence, are mostly unknown. Cellular senescence, characterised by an irreversible cell cycle arrest, is thought to be the cause of tissue and organismal ageing. Thus, better understanding of cellular senescence in immune populations at single‐cell level may provide us with insight into how immune cell senescence develops over the life time of an individual. In this review, we will briefly introduce the phenotypic characterisation of aged innate and adaptive immune cells, which also contributes to overall immunosenescence, including subsets and function. Next, we will focus on the different hallmarks of cellular senescence and cellular ageing, and the detection techniques most suitable for immune cells. Applying these techniques will deepen our understanding of immune cell senescence and to discover potential druggable pathways, which can be modulated to reverse immune ageing.     

Autophagy: a cell repair mechanism that retards ageing and age-associated diseases and can be intensified pharmacologically

The process of ageing denotes a post-maturational deterioration of cells and organisms with the passage of time, an increased vulnerability to challenges and prevalence of age-associated diseases, and a decreased ability to survive. Causes may be found in an enhanced production of reactive oxygen species (ROS) and oxidative damage and not completed housekeeping, with an accumulation of altered ROS-hypergenerating organelles in older cells. It has been shown that autophagy is the only tier of defence against the accumulation of effete mitochondria and peroxisomes; that functioning of autophagy declines with increasing age and determinates cell and individual lifespan; that autophagy can be intensified by drugs; and that the pharmacological intensification of autophagy may be a big step towards retardation of ageing and prevention and therapy of age-associated diseases including neurodegeneration.     

Endothelial Cell Senescence and Age-Related Vascular Diseases

Advanced age is an independent risk factor for ageing-related complex diseases,such as coronary artery disease,stroke,and hypertension,which are common but life threatening and related to the ageing-associated vascular dysfunction.On the other hand,patients with progeria syndromes suffer from serious atherosclerosis,suggesting that the impaired vascular functions may be critical to organismal ageing,or vice versa.However,it remains largely unknown how vascular cells,particularly endothelial cell,become senescent and how the senescence impairs the vascular functions and contributes to the age-related vascular diseases over time.Here,we review the recent progress on the characteristics of vascular ageing and endothelial cell senescence in vitro and in vivo,evaluate how genetic and environmental factors as well as autophagy and stem cell influence endothelial cell senescence and how the senescence contributes to the agerelated vascular phenotypes.such as atherosclerosis and increased vascular stiffness,and explore the possibility whether we can delay the age-related vascular diseases through the control of vascular ageing.     

Zinc–gene interaction related to inflammatory/immune response in ageing

The pivotal role played by zinc-gene interaction in affecting some relevant cytokines (IL-6 and TNF-alpha) and heat shock proteins (HSP70-2) in ageing, successful ageing (nonagenarians) and the most common age-related diseases, such as atherosclerosis and infections, is now recognized. The polymorphisms of genes codifying proteins related to the inflammation are predictive on one hand in longevity, on the other hand they are associated with atherosclerosis or severe infections. Since the health life-span has a strong genetic component, which in turn also affected by nutritional factors like zinc, the association of these polymorphisms with innate immune response, zinc ion bioavailability and Metallothioneins (MT) homeostasis is an useful tool to unravel the role played by zinc-gene interactions in longevity, especially due to the inability of MT in zinc release in ageing and chronic inflammation. In ageing, this last fact leads to depressed innate immune response for host defence. In contrast, in very old age the inflammation is lower with subsequent more zinc ion bioavailability, less MT gene expression and satisfactory innate immunity. Therefore, the zinc-gene (IL-6, TNF-alpha, Hsp70-2) interactions, via MT homeostasis, are crucial to achieve successful ageing.     

Fingerprinting the diseased prostate: associations between BPH and prostate cancer

Two of the most common diseases which occur in ageing men relate to their prostate. BPH and prostate cancer are prevalent diseases which have an impact on most men as they age. The advent of gene expression analysis has provided an opportunity to examine these diseases in a novel fashion. These analyses, to date, have revealed associations between these two diseases which have not been previously identified. These commonalities include global genetic changes which occur throughout the prostates in individuals with these diseases. Understanding the fingerprints of these diseases is providing novel markers and treatment strategies for both BPH and prostate cancer.     

Advanced glycation end products and their receptor in age-related,non-communicable chronic inflammatory diseases; Overview of clinical evidence and potential contributions to disease

Age-related, non-communicable chronic inflammatory diseases represent the major 21st century health problem. Especially in Western countries, the prevalence of non-communicable diseases like chronic obstructive pulmonary disease, cardiovascular disease, type 2 diabetes and osteoporosis are exponentially rising as the population ages. These diseases are determined by common risk factors and share an age-related onset. The affected organs display evidence of accelerated ageing, and are hallmarked by chronic inflammation and oxidative stress. The receptor for advanced glycation end products (RAGE) has been implicated in a number of inflammatory diseases and plays a central role in amplifying inflammatory responses. Advanced glycation end product (AGE) formation and accumulation is accelerated under these conditions. Advanced glycation end products are not only linked to RAGE signaling and inflammation, but to various hallmarks of the ageing process. In addition to these biological functions, circulating levels of the soluble form of RAGE and of advanced glycation end products are candidate biomarkers for many age-related inflammatory diseases. The purpose of this review is to provide an overview of the mechanistic connections between RAGE and advanced glycation end products and the processes of inflammation and ageing. Furthermore, through the presented overview of AGE-RAGE alterations that have been described in clinical studies in chronic obstructive pulmonary disease, cardiovascular disease, type 2 diabetes and osteoporosis, and insight obtained from mechanistic in vitro and animal studies, it can be concluded that these AGE-RAGE disturbances are a common contributing factor to the inflammatory state and pathogenesis of these various conditions.