In situ aging of auricular chondrocytes is not due to the exhaustion of their replicative potential

Summary Multiplication of chondrocytes during growth of rabbit auricular cartilage was estimated on the basis of total DNA determination and compared with the population doubling level reached by these chondrocytes in vitro. The results indicate that the in situ aging of auricular chondrocytes is caused by factors other than the intrinsic depletion of their growth potential.     

The role of insulin and IGF-1 signaling in longevity

There are many theories of aging and parameters that influence lifespan, including genetic instability, telomerase activity and oxidative stress. The role of caloric restriction, metabolism and insulin and insulin-like growth factor-1 signaling in the process of aging is especially well conserved throughout evolution. These latter factors interact with each other, the former factors and histone deacetylases of the SIR family in a complex interaction to influence lifespan.Received 8 July 2004; received after revision 25 August 2004; accepted 17 September 2004     

The role of dietary carbohydrates in organismal aging

Carbohydrates are essential nutrients that are used as a primary source of energy. Carbohydrate utilization should be properly controlled, as abnormal regulation of carbohydrate metabolism is associated with diseases, such as diabetes, cardiovascular diseases, and stroke. These metabolic syndromes have become a serious problem in developed countries, and there is an increased need for research examining the influence of carbohydrates on animal physiology. Diets enriched in glucose, a major carbohydrate, are also associated with accelerated aging in several model organisms, including yeast and Caenorhabditis elegans (C. elegans). Genetic factors that mediate the effects of high glucose diets on aging have been identified during the last decade, mostly through the use of C. elegans. In this review, we describe studies that determine the effects of carbohydrate-enriched diets on aging by focusing on the mechanisms through which evolutionarily conserved pathways mediate the lifespan-altering effects of glucose in C. elegans. These include the insulin/insulin-like growth factor-1, sterol-regulatory element-binding protein, and AMP-activated protein kinase signaling pathways. We also discuss the effects of various carbohydrates and carbohydrate-derived metabolites on aging in model organisms and cultured mammalian cells. Finally, we discuss how dietary carbohydrates influence health and aging in humans.     

When a theory of aging ages badly

According to the widely acknowledged mitochondrial free radical theory of aging (MFRTA), the macromolecular damage that results from the production of toxic reactive oxygen species (ROS) during cellular respiration is the cause of aging. However, although it is clear that oxidative damage increases during aging, the fundamental question regarding whether mitochondrial oxidative stress is in any way causal to the aging process remains unresolved. An increasing number of studies on long-lived vertebrate species, mutants and transgenic animals have seriously challenged the pervasive MFRTA. Here, we describe some of these new results, including those pertaining to the phenotype of the long-lived Mclk1 ^+/− mice, which appear irreconcilable with the MFRTA. Thus, we believe that it is reasonable to now consider the MFRTA as refuted and that it is time to use the insight gained by many years of testing this theory to develop new views as to the physiological causes of aging.     

多孔硅发光中的极化子效应

多孔硅体现了许多新光学性质，本文通过温度依赖的发光，傅立叶红外谱，时间分辨红外谱的观察。发现了些有规律的信息。众所周知，多孔硅在空气中陈化氧化，导致内部纳米尺寸减小。界面层由氢变为氧，我们发现同时伴随着电子态从本征态向极化子态的变化，前者随尺寸减小能量升高，表现为正常的量子限域效应。而后者却随尺寸减小能量降低。表现为量子限域极化子效应。温度依赖的发光谱型和强度变化也清楚地反映了尺寸依赖的极化子行为。因此，我们提出了个基本的物理模型来描述多孔硅中增强的极化子尺寸效应及其光学行为。     

Immune aging and autoimmunity

Age is an important risk for autoimmunity, and many autoimmune diseases preferentially occur in the second half of adulthood when immune competence has declined and thymic T cell generation has ceased. Many tolerance checkpoints have to fail for an autoimmune disease to develop, and several of those are susceptible to the immune aging process. Homeostatic T cell proliferation which is mainly responsible for T cell replenishment during adulthood can lead to the selection of T cells with increased affinity to self- or neoantigens and enhanced growth and survival properties. These cells can acquire a memory-like phenotype, in particular under lymphopenic conditions. Accumulation of end-differentiated effector T cells, either specific for self-antigen or for latent viruses, have a low activation threshold due to the expression of signaling and regulatory molecules and generate an inflammatory environment with their ability to be cytotoxic and to produce excessive amounts of cytokines and thereby inducing or amplifying autoimmune responses.     

Projection of population structure in China using least squares support vector machine in conjunction with a Leslie matrix model

China is a populous country that is facing serious aging problems due to the single‐child birth policy. Debate is ongoing whether the liberalization of the single‐child policy to a two‐child policy can mitigate China's aging problems without unacceptably increasing the population. The purpose of this paper is to apply machine learning theory to the demographic field and project China's population structure under different fertility policies. The population data employed derive from the fifth and sixth national census records obtained in 2000 and 2010 in addition to the annals published by the China National Bureau of Statistics. Firstly, the sex ratio at birth is estimated according to the total fertility rate based on least squares regression of time series data. Secondly, the age‐specific fertility rates and age‐specific male/female mortality rates are projected by a least squares support vector machine (LS‐SVM) model, which then serve as the input to a Leslie matrix model. Finally, the male/female age‐specific population data projected by the Leslie matrix in a given year serve as the input parameters of the Leslie matrix for the following year, and the process is iterated in this manner until reaching the target year. The experimental results reveal that the proposed LS‐SVM‐Leslie model improves the projection accuracy relative to the conventional Leslie matrix model in terms of the percentage error and mean algebraic percentage error. The results indicate that the total fertility ratio should be controlled to around 2.0 to balance concerns associated with a large population with concerns associated with an aging population. Therefore, the two‐child birth policy should be fully instituted in China. However, the fertility desire of women tends to be low due to the high cost of living and the pressure associated with employment, particularly in the metropolitan areas. Thus additional policies should be implemented to encourage fertility.     

Bacterial aging: from mechanistic basis to evolutionary perspective

Aging—defined as the progressive impairment of an organism’s functional capacity, resulting from deleterious changes in cells, organs, and biological systems—is one of the most fundamental features of Eukaryotes, from humans to the unicellular budding yeast Saccharomyces cerevisiae. It has recently been reported that this may also be the case for certain (if not all) types of bacteria. In this paper, the current view on the mechanistic background and evolutionary significance of bacterial kind of aging is presented, with particular emphasis on the role of asymmetric cell division, the characteristics of stationary growth phase, and the role of oxidative protein damage.     

Altered proteostasis in aging and heat shock response in C. elegans revealed by analysis of the global and de novo synthesized proteome

Protein misfolding and aggregation as a consequence of impaired protein homeostasis (proteostasis) not only characterizes numerous age-related diseases but also the aging process itself. Functionally related to the aging process are, among others, ribosomal proteins, suggesting an intimate link between proteostasis and aging. We determined by iTRAQ quantitative proteomic analysis in C. elegans how the proteome changes with age and in response to heat shock. Levels of ribosomal proteins and mitochondrial chaperones were decreased in aged animals, supporting the notion that proteostasis is altered during aging. Mitochondrial enzymes of the tricarboxylic acid cycle and the electron transport chain were also reduced, consistent with an age-associated energy impairment. Moreover, we observed an age-associated decline in the heat shock response. In order to determine how protein synthesis is altered in aging and in response to heat shock, we complemented our global analysis by determining the de novo proteome. For that, we established a novel method that enables both the visualization and identification of de novo synthesized proteins, by incorporating the non-canonical methionine analogue, azidohomoalanine (AHA), into the nascent polypeptides, followed by reacting the azide group of AHA by ‘click chemistry’ with an alkyne-labeled tag. Our analysis of AHA-tagged peptides demonstrated that the decreased abundance of, for example, ribosomal proteins in aged animals is not solely due to degradation but also reflects a relative decrease in their synthesis. Interestingly, although the net rate of protein synthesis is reduced in aged animals, our analyses indicate that the synthesis of certain proteins such as the vitellogenins increases with age.     

Mitochondrial bioenergetics decay in aging: beneficial effect of melatonin

Aging is a biological process characterized by progressive decline in physiological functions, increased oxidative stress, reduced capacity to respond to stresses, and increased risk of contracting age-associated disorders. Mitochondria are referred to as the powerhouse of the cell through their role in the oxidative phosphorylation to generate ATP. These organelles contribute to the aging process, mainly through impairment of electron transport chain activity, opening of the mitochondrial permeability transition pore and increased oxidative stress. These events lead to damage to proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid of the inner mitochondrial membrane, plays a pivotal role in several mitochondrial bioenergetic processes as well as in mitochondrial-dependent steps of apoptosis and in mitochondrial membrane stability and dynamics. Cardiolipin alterations are associated with mitochondrial bienergetics decline in multiple tissues in a variety of physiopathological conditions, as well as in the aging process. Melatonin, the major product of the pineal gland, is considered an effective protector of mitochondrial bioenergetic function. Melatonin preserves mitochondrial function by preventing cardiolipin oxidation and this may explain, at least in part, the protective role of this compound in mitochondrial physiopathology and aging. Here, mechanisms through which melatonin exerts its protective role against mitochondrial dysfunction associated with aging and age-associated disorders are discussed.     

Yeast aging research: recent advances and medical relevance

The molecular mechanisms of aging are most fully understood for the budding yeast Saccharomyces cerevisiae. Recent advances in our understanding of aging in this organism have enabled researchers to answer some fundamental questions about the aging process. Is aging due to a multitude of 'mechanisms' or can there be a key few? Can we design single-gene mutations that will prolong life? Can we prolong life whilst maintaining health and fecundity? The various contributing factors to yeast longevity, uncovered thus far, fall into three classes: DNA metabolism, heterochromatin, and metabolic activity. However, these separate classes may actually represent different aspects of the same aging mechanism based on genome stability. This review examines the recent advances in our understanding of yeast aging and discusses their relevance, if any, to the human condition.     

Endothelial dysfunction in the klotho mouse and downregulation of klotho gene expression in various animal models of vascular and metabolic diseases

The human aging process is associated with vascular endothelial dysfunction. However, humoral factors which might protect against endothelial dysfunction during aging have not yet been identified. We recently identified the klotho gene as a possible regulator of human aging. In the present study using the klotho-deficient heterozygous mouse, we examined whether the Klotho protein is a humoral factor protecting against endothelial dysfunction. We further cloned rat klotho cDNA and investigated whether klotho mRNA expression in rat kidney is altered under pathological conditions such as hypertension, hyperlipidemia, renal failure, and inflammatory stress. The Klotho protein itself, or its metabolites, promotes endothelial NO production in aorta as well as arterioles, and klotho mRNA in kidney is downregulated under sustained circulatory stress.     

Apoptosis and aging: increased resistance to apoptosis enhances the aging process

Apoptosis is a vital component in the evolutionarily conserved host defense system. Apoptosis is the guardian of tissue integrity by removing unfit and injured cells without evoking inflammation. However, apoptosis seems to be a double-edged sword since during low-level chronic stress, such as in aging, increased resistance to apoptosis can lead to the survival of functionally deficient, post-mitotic cells with damaged housekeeping functions. Senescent cells are remarkably resistant to apoptosis, and several studies indicate that host defense mechanisms can enhance anti-apoptotic signaling, which subsequently induces a senescent, pro-inflammatory phenotype during the aging process. At the molecular level, age-related resistance to apoptosis involves (1) functional deficiency in p53 network, (2) increased activity in the NF-κB-IAP/JNK axis, and (3) changes in molecular chaperones, microRNAs, and epigenetic regulation. We will discuss the molecular basis of age-related resistance to apoptosis and emphasize that increased resistance could enhance the aging process.     

The comparative biology of neuromelanin and lipofuscin in the human brain

Neuromelanin and lipofuscin are two pigments produced within the human brain that, until recently, were considered inert cellular waste products of little interest to neuroscience. Recent research has increased our understanding of the nature and interactions of these pigments with their cellular environment and suggests that these pigments may, indeed, influence cellular function. The physical appearance and distribution of the pigments within the human brain differ, but both accumulate in the aging brain and the pigments share some structural features. Lipofuscin accumulation has been implicated in postmitotic cell aging, while neuromelanin is suggested to function as an iron-regulatory molecule with possible protective functions within the cells which produce this pigment. This review presents comparative aspects of the biology of neuromelanin and lipofuscin, as well as a discussion of their hypothesized functions in brain and their possible roles in aging and neurodegenerative disease.     

Change in taste preference related to aging of taste cells in rat

Following the suppression of renewal of rat taste cells by vinblastine sulphate, the preference for sucrose decreased markedly while the aversion to quinine did not change. The results suggest that the sensitivity of taste cells to sucrose decreases with their aging, but the sensitivity to quinine increases.     

Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates

The insulin signaling pathway regulates whole-body glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan.     

Role of gut microbiota in aging-related health decline: insights from invertebrate models

Studies in mammals, including humans, have reported age-related changes in microbiota dynamics. A major challenge, however, is to dissect the cause and effect relationships involved. Invertebrate model organisms such as the fruit fly Drosophila and the nematode Caenorhabditis elegans have been invaluable in studies of the biological mechanisms of aging. Indeed, studies in flies and worms have resulted in the identification of a number of interventions that can slow aging and prolong life span. In this review, we discuss recent work using invertebrate models to provide insight into the interplay between microbiota dynamics, intestinal homeostasis during aging and life span determination. An emerging theme from these studies is that the microbiota contributes to cellular and physiological changes in the aging intestine and, in some cases, age-related shifts in microbiota dynamics can drive health decline in aged animals.     

Mechanism of age-dependent involution in embryonic chick notochords

To study the possible mechanism of the age-dependent involution of the notochord, isolated mesenchymefree notochords of chick embryos were cultured in vitro and compared with their counterparts in vivo. Two different aspects were evaluated: (1) DNA synthesis measured by [³H]thymidine incorporation and visualized by autoradiography and (2) cell death quantified by counting the number of pyknotic nuclei. The results demonstrate that [³H]thymidine uptake by notochords shows an age-dependent decrease in vitro as well as in vivo. The number of [³H]thymidine-labelled notochord cells, however, is higher in vitro than in vivo. At the same time, there is an age-dependent increase in pyknosis in the notochord in vivo and in vitro. So, during the aging process, the number of both pyknotic nuclei and of [³H]thymidine-labelled nuclei suggest a high turnover of notochord cells in vitro. From these results, we can conclude that the process of involution in aging notochord seems to be controlled by a programmed intrinsic process, which might be influenced partially by the microenvironment in vivo.