A mouse model of Werner Syndrome: what can it tell us about aging and cancer?

The molecular mechanisms involved in mammalian aging and the consequent organ dysfunction/degeneration pathologies are not well understood. Studies of progeroid syndromes such as Werner Syndrome have advanced our understanding of how certain genetic pathways can influence the aging process on both cellular and molecular levels. In addition, improper maintenance of telomere length and the consequent cellular responses to dysfunctional telomeres have been proposed to promote replicative senescence that impact upon the onset of premature aging and cancer. Recent studies of the telomerase-Werner double null mouse link telomere dysfunction to accelerated aging and tumorigenesis in the setting of Werner deficiency. This mouse model thus provides a unique genetic platform to explore molecular mechanisms by which telomere dysfunction and loss of WRN gene function leads to the onset of premature aging and cancer.     

Aging of Brain: Role of Estrogen

The brain undergoes many structural and functional changes during aging. Some of these changes are regulated by estrogens which act mainly through their intracellular receptors, estrogen receptor ERα and ERβ. The expression of these receptors is regulated by several factors including their own ligand estrogen, and others such as growth hormone and thyroid hormone. The levels of these factors decrease during aging which in turn influence estrogen signaling leading to alterations in brain functions. In the present paper, we review the effects of aging on brain structure and function, and estrogen action and signaling during brain aging. The findings suggest key role of estrogen in the maintenance of brain functions during aging.     

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.     

The Yin and Yang of redox regulation

Abstract

Mammalian cells produce reactive oxygen and nitrogen species (ROS/RNOS) in response to an oxidative environment. Powerful antioxidant mechanisms have been developed in order to avoid oxidative stress by contributing to the maintenance of redox homeostasis. Traditionally, accumulation of ROS/RNOS is considered deleterious for cells as it can lead to loss of cellular function, aging, and cell death. Consequently, ROS/RNOS imbalance has been implicated in the etiology and/or progression of numerous pathologies such as cardiovascular diseases, inflammation, and cancer. An interesting concept that has emerged more recently is that not only have cells developed efficient systems to cope with ROS/RNOS accumulation but they have also learned to profit of them under certain circumstances. This notion is supported by data showing that ROS/RNOS can act as signaling molecules affecting the function and activity of a multiplicity of protein kinases and phosphatases controlling cellular homeostasis. This review does not provide an exhaustive overview of molecular mechanisms linked to ROS/RNOS generation and processing but includes relevant examples highlighting the dichotomic nature of these small molecules and the multitude of effects elicited by their accumulation. This aspect of ROS/RNOS ought to be taken into account particularly in novel therapeutic setups that aim to achieve high efficiency and minimal or no side effects.     

Differential maintenance and de novo methylating activity by three DNA methyltransferases in aging and immortalized fibroblasts.

Genomic methylation, which influences many cellular processes such as gene expression and chromatin organization, generally declines with cellular senescence although some genes undergo paradoxical hypermethylation during cellular aging and immortalization. To explore potential mechanisms for this process, we analyzed the methylating activity of three DNA methyltransferases (Dnmts) in aging and immortalized WI-38 fibroblasts. Overall maintenance methylating activity by the Dnmts greatly decreased during cellular senescence. In immortalized WI-38 cells, maintenance methylating activity was similar to that of normal young cells. Combined de novo methylation activity of the Dnmts initially decreased but later increased as WI-38 cells aged and was strikingly elevated in immortalized cells. To further elucidate the mechanisms for changes in DNA methylation in aging and immortalized cells, the individual Dnmts were separated and individually assessed for maintenance and de novo methylating activity. We resolved three Dnmt fractions, one of which was the major maintenance methyltransferase, Dnmt1, which declined steadily in activity with cellular senescence and immortalization. However, a more basic Dnmt, which has significant de novo methylating activity, increased markedly in activity in aging and immortalized cells. We have identified this methyltransferase as Dnmt3b which has an important role in neoplastic transformation but its role in cellular senescence and immortalization has not previously been reported. An acidic Dnmt we isolated also had increased de novo methylating activity in senescent and immortalized WI-38 cells. These studies indicate that reduced genome-wide methylation in aging cells may be attributed to attenuated Dnmt1 activity but that regional or gene-localized hypermethylation in aging and immortalized cells may be linked to increased de novo methylation by Dnmts other than the maintenance methyltransferase.     

Metabolic setpoint control mechanisms in different physiological systems at rest and during exercise

Using a number of different homeostatic control mechanisms in the brain and peripheral physiological systems, metabolic activity is continuously regulated at rest and during exercise to prevent catastrophic system failure. Essential for the function of these regulatory processes are baseline “setpoint” levels of metabolic function, which can be used to calculate the level of response required for the maintenance of system homeostasis after system perturbation, and to which the perturbed metabolic activity levels are returned to at the end of the regulatory process. How these setpoint levels of all the different metabolic variables in the different peripheral physiological systems are created and maintained, and why they are similar in different individuals, has not been well explained. In this article, putative system regulators of metabolic setpoint levels are described. These include that: (i) innate setpoint values are stored in a certain region of the central nervous system, such as the hypothalamus; (ii) setpoint values are created and maintained as a response to continuous external perturbations, such as gravity or “zeitgebers”, (iii) setpoint values are created and maintained by complex system dynamical activity in the different peripheral systems, where setpoint levels are regulated by the ongoing feedback control activity between different peripheral variables; (iv) human anatomical and biomechanical constraints contribute to the creation and maintenance of metabolic setpoints values; or (v) a combination of all these four different mechanisms occurs. Exercise training and disease processes can affect these metabolic setpoint values, but the setpoint values are returned to pre-training or pre-disease levels if the training stimulus is removed or if the disease process is cured. Further work is required to determine what the ultimate system regulator of metabolic setpoint values is, why some setpoint values are more stringently protected by homeostatic regulatory mechanisms than others, and the role of conscious decision making processes in determining the regulation of metabolic setpoint values.     

Glia as mediators of steroid hormone action on the nervous system: An overview.

This special issue on steroids and glia represents the intersection of two emerging themes in the neurosciences: (a) Glia actively modulate and participate in brain function throughout life, and (b) glia are sensitive to steroid hormones. This overview begins by reviewing some of the basic principles of steroid hormone action on the brain and introducing the various glia that inhabit the peripheral and central nervous system. A prominent theme among the articles that follow is that glia may be direct targets for steroid hormones since they possess steroid receptors and the promoter region of glial-specific genes such as glutamine synthetase contain hormone-responsive elements. The articles in this special issue discuss evidence that glia may mediate steroid action on the nervous system in the context of (a) steroid metabolism, which may control the hormonal microenvironment of neurons both in the normal and injured brain; (b) brain development including sexual differentiation; (c) synaptic plasticity which may underlie the cyclic release of luteinizing hormone releasing hormone in the female rodent brain; (d) neural repair and aging; and (e) brain immune function. Another theme among these articles is that glia influence neurons via specific secreted and cell-surface molecules, and that steroids affect this mode of communication by altering the level of glial production of these signaling molecules and/or the sensitivity of neurons to such signals.     

中枢神经损伤后影响轴突再生的因素

与周围神经不同 ,成年哺乳动物中枢神经损伤后轴突不能再生 ,往往造成不可逆的功能丧失。影响再生的原因相当复杂 ,胶质瘢痕形成、神经营养因子缺乏及存在诸多的抑制性因子等。本文就一些影响中枢神经再生的因子从其结构、分布、功能及可能的作用机制诸方面作一综述     

Functional genomics of brain aging and Alzheimer's disease: focus on selective neuronal vulnerability

Pivotal brain functions, such as neurotransmission, cognition, and memory, decline with advancing age and, especially, in neurodegenerative conditions associated with aging, such as Alzheimer's disease (AD). Yet, deterioration in structure and function of the nervous system during aging or in AD is not uniform throughout the brain. Selective neuronal vulnerability (SNV) is a general but sometimes overlooked characteristic of brain aging and AD. There is little known at the molecular level to account for the phenomenon of SNV. Functional genomic analyses, through unbiased whole genome expression studies, could lead to new insights into a complex process such as SNV. Genomic data generated using both human brain tissue and brains from animal models of aging and AD were analyzed in this review. Convergent trends that have emerged from these data sets were considered in identifying possible molecular and cellular pathways involved in SNV. It appears that during normal brain aging and in AD, neurons vulnerable to injury or cell death are characterized by significant decreases in the expression of genes related to mitochondrial metabolism and energy production. In AD, vulnerable neurons also exhibit down-regulation of genes related to synaptic neurotransmission and vesicular transport, cytoskeletal structure and function, and neurotrophic factor activity. A prominent category of genes that are up-regulated in AD are those related to inflammatory response and some components of calcium signaling. These genomic differences between sensitive and resistant neurons can now be used to explore the molecular underpinnings of previously suggested mechanisms of cell injury in aging and AD.     

The blood-brain barrier: Structure,function and therapeutic approaches to cross it

The blood-brain barrier (BBB) is constituted by a specialized vascular endothelium that interacts directly with astrocytes, neurons and pericytes. It protects the brain from the molecules of the systemic circulation but it has to be overcome for the proper treatment of brain cancer, psychiatric disorders or neurodegenerative diseases, which are dramatically increasing as the population ages. In the present work we have revised the current knowledge on the cellular structure of the BBB and the different procedures utilized currently and those proposed to cross it. Chemical modifications of the drugs, such as increasing their lipophilicity, turn them more prone to be internalized in the brain. Other mechanisms are the use of molecular tools to bind the drugs such as small immunoglobulins, liposomes or nanoparticles that will act as Trojan Horses favoring the drug delivery in brain. This fusion of the classical pharmacology with nanotechnology has opened a wide field to many different approaches with promising results to hypothesize that BBB will not be a major problem for the new generation of neuroactive drugs. The present review provides an overview of all state-of-the-art of the BBB structure and function, as well as of the classic strategies and these appeared in recent years to deliver drugs into the brain for the treatment of Central Nervous System (CNS) diseases.     

Increased Learning and Brain Long-Term Potentiation in Aged Mice Lacking DNA Polymerase μ

A definitive consequence of the aging process is the progressive deterioration of higher cognitive functions. Defects in DNA repair mechanisms mostly result in accelerated aging and reduced brain function. DNA polymerase µ is a novel accessory partner for the non-homologous end-joining DNA repair pathway for double-strand breaks, and its deficiency causes reduced DNA repair. Using associative learning and long-term potentiation experiments, we demonstrate that Polµ^−/− mice, however, maintain the ability to learn at ages when wild-type mice do not. Expression and biochemical analyses suggest that brain aging is delayed in Polµ^−/− mice, being associated with a reduced error-prone DNA oxidative repair activity and a more efficient mitochondrial function. This is the first example in which the genetic ablation of a DNA-repair function results in a substantially better maintenance of learning abilities, together with fewer signs of brain aging, in old mice.     

Molecular Mechanisms of Cellular Senescence in Neurodegenerative Diseases

Neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are characterized by several pathological features, including selective neuronal loss, aggregation of specific proteins, and chronic inflammation. Aging is the most critical risk factor of these disorders. However, the mechanism by which aging contributes to the pathogenesis of neurodegenerative diseases is not clearly understood. Cellular senescence is a cell state or fate in response to stimuli. It is typically associated with a series of changes in cellular phenotypes such as abnormal cellular metabolism and proteostasis, reactive oxygen species (ROS) production, and increased secretion of certain molecules via senescence-associated secretory phenotype (SASP). In this review, we discuss how cellular senescence contributes to brain aging and neurodegenerative diseases, and the relationship between protein aggregation and cellular senescence. Finally, we discuss the potential of senescence modifiers and senolytics in the treatment of neurodegenerative diseases.     

Blood–brain-barriers in aging and in Alzheimer’s disease

The aging process correlates with a progressive failure in the normal cellular and organ functioning; these alterations are aggravated in Alzheimer’s disease (AD). In both aging and AD there is a general decrease in the capacity of the body to eliminate toxic compounds and, simultaneously, to supply the brain with relevant growth and nutritional factors. The barriers of the brain are targets of this age related dysfunction; both the endothelial cells of the blood–brain barrier and the choroid plexus epithelial cells of the blood-cerebrospinal fluid barrier decrease their secretory capacity towards the brain and their ability to remove toxic compounds from the brain. Additionally, during normal aging and in AD, the permeability of the brain barriers increase. As such, a greater contact of the brain parenchyma with the blood content alters the highly controlled neural environment, which impacts on neural function. Of interest, the brain barriers are more than mere obstacles to the passage of molecules and cells, and therefore active players in brain homeostasis, which is still to be further recognized and investigated in the context of health and disease. Herein, we provide a review on how the brain barriers change during aging and in AD and how these processes impact on brain function.     

Collateral damage: cardiovascular consequences of chronic sympathetic activation with human aging

Adult aging in humans is associated with marked and sustained increases in sympathetic nervous system (SNS) activity to several peripheral tissues, including the heart, the gut-liver circulation, and skeletal muscle. This chronic activation of the peripheral SNS likely is, at least in part, a primary response of the central nervous system to stimulate thermogenesis to prevent further fat storage in the face of increasing adiposity with aging. However, as has been proposed in obesity hypertension, this tonic activation of the peripheral SNS has a number of adverse secondary cardiovascular consequences. These include chronic reductions in leg blood flow and vascular conductance, increased tonic support of arterial blood pressure, reduced limb and systemic alpha-adrenergic vasoconstrictor responsiveness, impaired baroreflex buffering, large conduit artery hypertrophy, and decreased vascular and cardiac responsiveness to beta-adrenergic stimulation. These effects of chronic age-associated SNS activation on the structure and function of the cardiovascular system, in turn, may have important implications for the maintenance of physiological function and homeostasis, as well as the risk of developing clinical cardiovascular and metabolic diseases in middle-aged and older adults.     

Neuronal--glial interactions during development and aging.

Integration of the central nervous system is an expression of cerebral homeostasis that is essential for the internal ability of the organism to adapt to its changing environment throughout life. It is generally accepted that neurons undergo no further division after differentiation, whereas glial cells continue to proliferate throughout life. The increase in glial cells with advanced age may reflect a compensatory process of the brain to overcome neuronal loss or neuronal functional changes that may occur with age. Therefore, these neuronal-glial interactions during development and aging may play a key role in the integrative capacity of the brain. One of the mechanisms contributing to brain stability is the blood-brain barrier, which regulates the neuronal-glial microenvironment in the mature organism. Neuronal intercommunication is mediated via neurotransmitter substances and a shift may occur from excitation to inhibition and vice versa in some CNS areas with aging. Studies of some aspects of cholinergic, monoaminergic and amino acid neurotransmission show that their maturational patterns are CNS-area specific and that some neurotransmitter processes decline with advanced age. Glial cells, besides participating in the regulation of extraneuronal environment, are also proposed to be involved in neurotransmission mechanisms in the adult and aging CNS and since they are the major CNS cellular compartment that changes with age they may thus contribute significantly to the maintenance of CNS integrative ability and adaptation with age.     

Age‐associated cholesterol reduction triggers brain insulin resistance by facilitating ligand‐independent receptor activation and pathway desensitization

In the brain, insulin plays an important role in cognitive processes. During aging, these faculties decline, as does insulin signaling. The mechanism behind this last phenomenon is unclear. In recent studies, we reported that the mild and gradual loss of cholesterol in the synaptic fraction of hippocampal neurons during aging leads to a decrease in synaptic plasticity evoked by glutamate receptor activation and also by receptor tyrosine kinase (RTK) signaling. As insulin and insulin growth factor activity are dependent on tyrosine kinase receptors, we investigated whether the constitutive loss of brain cholesterol is also involved in the decay of insulin function with age. Using long‐term depression (LTD) induced by application of insulin to hippocampal slices as a read‐out, we found that the decline in insulin function during aging could be monitored as a progressive impairment of insulin‐LTD. The application of a cholesterol inclusion complex, which donates cholesterol to the membrane and increases membrane cholesterol levels, rescued the insulin signaling deficit and insulin‐LTD. In contrast, extraction of cholesterol from hippocampal neurons of adult mice produced the opposite effect. Furthermore, in vivo inhibition of Cyp46A1, an enzyme involved in brain cholesterol loss with age, improved insulin signaling. Fluorescence resonance energy transfer (FRET) experiments pointed to a change in receptor conformation by reduced membrane cholesterol, favoring ligand‐independent autophosphorylation. Together, these results indicate that changes in membrane fluidity of brain cells during aging play a key role in the decay of synaptic plasticity and cognition that occurs at this late stage of life.     

Glia and glial polyamines. Role in brain function in health and disease

The roles of glia and polyamines (PA) in brain function and dysfunction are highlighted in this review. We emphasize that PA accumulation preferentially in glia, but not in neurons, is clearly evolutionarily determined; it is found throughout the brain, retina, peripheral nervous system, and in glial-neuronal co-cultures of multiple species, including man. This phenomenon raises key questions: (i) What are the mechanisms that underlie such uneven distribution, accumulation and release from glia? (ii) What are the consequences of PA fluxes within the brain on neuronal function? (iii) What are the roles of PAs in brain disorders and diseases? This review includes suggestions on the roles of PAs, such as putrescine (PT), spermidine (SPD), spermine (SPM) and their derivatives as novel glio-transmitters in brain since PA affect many neuronal and glial receptors, channels and transporters. Polyamines hitherto have been neglected, although it is evident that these molecules are key elements for normal brain function and their metabolic disorders, apparently, cause the development of many pathological syndromes and diseases. The study of endogenous PA allows one to put forward the basic principles of scientific research on glio-neuronal interactions and clinical therapies, which are based on the exclusivity of glial cells in terms of accumulation of PA and PA-dependent functions.