Neuroendocrinology and ovarian aging

The ovarian aging, a dynamic process that precedes the clinical manifestations of menopause, can be assessed using ovarian reserve biomarkers. It is well-known that reproduction during the later years of reproductive life has known limitations that challenge the success of assisted reproduction. Therefore, a review of the neuroendocrine modifications during this critical period of reproductive life may help to elucidate the ovarian aging process and its impact on reproduction. In this review, we aim to further the discussion of neuroendocrine changes taking place during the ovarian aging process that may impact reproductive function.     

Involvement of microtubules in modifications associated with cellular aging.

Microtubules are ubiquitous cellular components involved in the control of cell structure and functions, such as cell division, regulation of shape and polarity, intracellular transport, etc. Consequently, any alteration affecting them in structure or function has a good chance of affecting the cell and generally leads to cell dysfunctions. This has been shown for instance, after treatment with microtubule-interacting drugs. Cellular aging is also characterized by the appearance of various cell dysfunctions, but the possible involvement of the microtubules in the aging process, although a rather tempting hypothesis, has not yet been extensively investigated. In this paper, I will first rapidly review the different components that build, organize and control the microtubules in normal cells, independently of the aging process. I will then consider the possible involvement of the microtubules in the aging process, more particularly in models of cells aging in vitro and in aging neuronal cells, which have been the most extensively investigated. There is some evidence for alterations in the microtubule organization both in cells aging in vitro and in the aging brain. But the interpretation of these data awaits further experiments, taking into account the latest progress in tubulin genetics and in microtubule biochemistry. Microtubules could also represent one of the cellular targets affected after signal transduction and could thus be involved in the resulting cellular responses. This hypothesis will be discussed, as it offers new insights into the regulation of microtubule organization, dynamics and functions in normal cells, which will be worthwhile to investigate during the aging process.     

Proteasome activation delays aging in vitro and in vivo

Aging is a natural biological process that is characterized by a progressive accumulation of macromolecular damage. In the proteome, aging is accompanied by decreased protein homeostasis and function of the major cellular proteolytic systems, leading to the accumulation of unfolded, misfolded, or aggregated proteins. In particular, the proteasome is responsible for the removal of normal as well as damaged or misfolded proteins. Extensive work during the past several years has clearly demonstrated that proteasome activation by either genetic means or use of compounds significantly retards aging. Importantly, this represents a common feature across evolution, thereby suggesting proteasome activation to be an evolutionarily conserved mechanism of aging and longevity regulation. This review article reports on the means of function of these proteasome activators and how they regulate aging in various species.     

Revisiting an age-old question regarding oxidative stress

Significant advances in maintaining health throughout life can be made through a clear understanding of the fundamental mechanisms that regulate aging. The Oxidative Stress Theory of Aging (OSTA) is probably the most well studied mechanistic theory of aging and suggests that the rate of aging is controlled by accumulation of oxidative damage. To directly test the OSTA, aging has been measured in several lines of mice with genetic alterations in the expression of enzymatic antioxidants. Under its strictest interpretation, these studies do not support the OSTA, as modulation of antioxidant expression does not generally affect mouse life span. However, the incidence of many age-related diseases and pathologies is altered in these models, suggesting that oxidative stress does significantly influence some aspects of the aging process. Further, oxidative stress may affect aging in disparate patterns among tissues or under various environmental conditions. In this review, we summarize the current literature regarding aging in antioxidant mutant mice and offer several interpretations of their support of the OSTA.     

Epigenetic changes associated with oocyte aging

It is well established that the decline in female reproductive outcomes is related to postovulatory aging of oocytes and advanced maternal age. Poor oocyte quality is correlated with compromised genetic integrity and epigenetic changes during the oocyte aging process. Here, we review the epigenetic alterations, mainly focused on DNA methylation, histone acetylation and methylation associated with postovulatory oocyte aging as well as advanced maternal age. Furthermore, we address the underlying epigenetic mechanisms that contribute to the decline in oocyte quality during oocyte aging.     

Brain cholesterol in normal and pathological aging

Correct lipid homeostasis at the plasma membrane is essential for cell survival and performance. These are critically challenged in the aging brain. Changes in the levels of cholesterol, a major membrane component especially enriched in neurons, accompany the brain aging process. They also occur in neurodegenerative diseases. Understanding the causes and consequences of these changes is a crucial step when trying to delay the cognitive decline, which comes with age, or to design strategies to fight neurodegenerative disorders such as Alzheimer's disease. We here review work that has contributed to this understanding.     

Melatonin and mitochondria in aging

The worldwide prolongation of mean life expectancy has resulted in a rapid increase of the size of the elderly population, both in numbers and as a proportion of the whole. In addition, the incidence of age-related diseases is obviously increasing as the population ages. Finding means to preserve optimal health in old age has become a primary goal of biomedical research. Aging is a multifactorial process that includes progressive cellular loss, endocrine and metabolic deficits, reduced defense mechanisms and functional losses that increase the risk of death. Mitochondria fulfill a number of essential cellular functions and play a key role in the aging process. Melatonin, which is synthesized in the pineal gland and other organs, plays a role in the biologic regulation of aging. Noctural melatonin serum levels are high during childhood and diminish substantially as people age. Melatonin preserves mitochondrial homeostasis, reduces free radical generation, e.g., by enhancing mitochondrial glutathione levels; it also safeguards proton potential and ATP synthesis by stimulating complex I and IV activities. In this article, we review the role of melatonin and mitochondria in aging.     

Defective DNA-damage repair induced by nuclear lamina dysfunction is a key mediator of smooth muscle cell aging

Accumulation of DNA damage is a major driving force of normal cellular aging and has recently been demonstrated to hasten the development of vascular diseases such as atherosclerosis. VSMCs (vascular smooth muscle cells) are essential for vessel wall integrity and repair, and maintenance of their proliferative capacity is essential for vascular health. The signalling pathways that determine VSMC aging remain poorly defined; however, recent evidence implicates persistent DNA damage and the A-type nuclear lamins as key regulators of this process. In the present review, we discuss the importance of the nuclear lamina in the spatial organization of nuclear signalling events, including the DNA-damage response. In particular, we focus on the evidence suggesting that prelamin A accumulation interferes with nuclear spatial compartmentalization by disrupting chromatin organization and DNA-damage repair pathways to promote VSMC aging and senescence.     

Aging: is oxidative stress a marker or is it causal?

Rapid developments in free radical biology and molecular technology have permitted exploration of the free radical theory of aging. Oxidative stress has also been implicated in the pathogenesis of a number of diseases. Studies have found evidence of oxidative damage to macromolecules (DNA, lipids, protein), and data in transgenic Drosophila melanogaster support the hypothesis that oxidative injury might directly cause the aging process. Additional links between oxidative stress and aging focus on mitochondria, leading to development of the mitochondrial theory of aging. However, despite the number of studies describing the association of markers of oxidative damage with advancing age, few, if any definitively link oxidative injury to altered energy production or cellular function. Although a causal role for oxidative stress in the aging process has not been clearly established, this does not preclude attempts to reduce oxidative injury as a means to reduce morbidity and perhaps increase the healthy, useful life span of an individual. This review highlights studies demonstrating enhanced oxidative stress with advancing age and stresses the importance of the balance between oxidants as mediators of disease and important components of signal transduction pathways.     

Cancer and aging: symposium of the 27th annual meeting of the Japanese society for biomedical gerontology, Tokyo

Although many hypotheses have been proposed to explain the strong link between aging and cancer, the exact mechanisms responsible for the increased frequency of occurrence of cancer with advancing age have not been fully defined. Recent evidence indicates that malregulation of the apoptotic process may be involved in some aging process as well as in the development of cancer. Although it is still under debate how apoptosis is expressed during aging in vivo, this phenomenon is an important factor in unwinding the complicated mechanisms that link cancer and aging. In this review, we report on the discussion at the symposium of the 27th annual meeting of the Japanese society for biomedical gerontology, regarding recent findings from aging and carcinogenesis studies using animal models, the characteristics of cancer in patients with Werners syndrome, the epigenetic changes in human cancers and aging, and the characteristics of human cancers in the elderly. It was concluded that apoptosis plays a role in the aging process and carcinogenesis in vivo, likely as an inherent protective mechanism against various kinds of damages to genes/chromosomes.     

Apoptosis in the aging process

Although many hypotheses have been proposed to explain the aging process, the exact mechanisms are not well defined. Recent accumulating evidence indicates that dysregulation of the apoptotic process may be involved in some aging processes; however, it is still debatable how exactly apoptosis is expressed during aging in vivo. In this review, we discuss recent findings related to apoptosis of individual organs during aging and their significance. We demonstrate that aging enhances apoptosis and susceptibility to apoptosis in several types of intact cells. In contrast, in certain genetically damaged, initiated, and preneoplastic cells, aging suppresses these age-associated apoptotic changes. In various cells, apoptosis enhances the elimination of damaged and dysfunctional cells presumably caused by oxidative stress, glycation, and DNA damage. In these cases, the incidence of apoptosis correlates with the level of accumulated injury. It is concluded that apoptosis plays an important role in the aging process and tumorigenesis in vivo probably as an inherent protective mechanism against age-associated tumorigenesis.     

Changes of the brain synapses during aging. New aspects

The process of brain aging is an interaction of age-related losses and compensatory mechanisms. This review is focused on the changes of the synaptic number and structure, their functional implications, regarding neurotransmission, as well as the electrical activity of neuronal circuits. Moreover, the importance of calcium homeostasis is strongly emphasized. It is also suggested that many neuronal properties are preserved, as a result of adaptive mechanisms, and that a series of interdependent factors regulate brain aging. The "new frontier" in research is the challenge of understanding the effects of aging, both to prevent degenerative diseases and reduce their consequences. New aspects are considered a) the role of nitric oxide, b) free radicals and apoptosis, c) impaired cerebral microcirculation, d) metabolic features of aging brain, e) the possible neuroprotective role of insulin-like growth factor-1 (IGF-1) and ovarian steroids and e) stress and aging. These numerous multifactorial approaches are essential to understand the process of aging. The more we learn about it, the more we realize how to achieve "successful" aging.     

Epigenetic changes during aging and their reprogramming potential

The aging process results in significant epigenetic changes at all levels of chromatin and DNA organization. These include reduced global heterochromatin, nucleosome remodeling and loss, changes in histone marks, global DNA hypomethylation with CpG island hypermethylation, and the relocalization of chromatin modifying factors. Exactly how and why these changes occur is not fully understood, but evidence that these epigenetic changes affect longevity and may cause aging, is growing. Excitingly, new studies show that age-related epigenetic changes can be reversed with interventions such as cyclic expression of the Yamanaka reprogramming factors. This review presents a summary of epigenetic changes that occur in aging, highlights studies indicating that epigenetic changes may contribute to the aging process and outlines the current state of research into interventions to reprogram age-related epigenetic changes.     

The pyruvate dehydrogenase complex as a therapeutic target for age-related diseases

Considerable research has been conducted on mitochondrial biology as it pertains to aging. However, relatively little attention has been accorded the pyruvate dehydrogenase complex (PDC) relative to how we grow old and acquire age-related diseases. The purpose of this review is threefold: first, to describe the physiological chemistry of the PDC and define its place in normal cellular bioenergetics; second, to compare and contrast the pathogenesis and clinical features of congenital PDC deficiency with discrete examples of age-associated dysfunction of the complex; and third, to summarize recent findings in Caenorhabditis elegans that shed additional new light on the significance of the PDC to the aging process.     

Current understanding of ovarian aging

The reproductive system of human female exhibits a much faster rate of aging than other body systems. Ovarian aging is thought to be dominated by a gradual decreasing numbers of follicles, coinciding with diminished quality of oocytes. Menopause is the final step in the process of ovarian aging. This review focuses on the mechanisms underlying the ovarian aging involving a poor complement of follicles at birth and a high rate of attrition each month, as well as the alternated endocrine factors. We also discuss the possible causative factors that contribute to ovarian aging, e.g., genetic factors, accumulation of irreparable damage of microenvironment, pathological effect and other factors. The appropriate and reliable methods to assess ovarian aging, such as quantification of follicles, endocrine measurement and genetic testing have also been discussed. Increased knowledge of the ovarian aging mechanisms may improve the prevention of premature ovarian failure.     

褪黑素延缓哺乳动物衰老的作用及其机制的研究进展

褪黑素(melatonin)在哺乳动物中是主要由松果体分泌的一种多功能吲哚激素,具有抗氧化、调节睡眠、调节昼夜节律、增强免疫力、抑制肿瘤等作用,在哺乳动物的复杂衰老进程中发挥重要作用。本文从氧化应激和能量代谢两个方面综述了褪黑素在哺乳动物中延缓衰老的作用机制。褪黑素通过清除自由基、激发抗氧化作用以及保护线粒体功能从而减缓氧化应激;通过调节代谢感知、重建昼夜节律以及促进能量消耗调节能量代谢。最后对该领域今后可能的发展方向进行了展望。     

The importance of being subtle: small changes in calcium homeostasis control cognitive decline in normal aging

Aging is a complex, multifactorial process. One of the features of normal aging of the brain is a decline in cognitive functions and much experimental attention has been devoted to understanding this process. Evidence accumulated in the last decade indicates that such functional changes are not due to gross morphological alterations, but to subtle functional modification of synaptic connectivity and intracellular signalling and metabolism. Such synaptic modifications are compatible with a normal level of activity and allow the maintenance of a certain degree of functional reserve. This is in contrast to the changes in various neurodegenerative diseases, characterized by significant neuronal loss and dramatic and irreversible functional deficit. This whole special issue has been initiated with the intention of focusing on the processes of normal brain aging. In this review, we present data that shows how subtle changes in Ca(2+) homeostasis or in the state of various Ca(2+)-dependent processes or molecules, which occur in aging can have significant functional consequences.