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The aging stress response 总被引:1,自引:0,他引:1
Aging is the outcome of a balance between damage and repair. The rate of aging and the appearance of age-related pathology are modulated by stress response and repair pathways that gradually decline, including the proteostasis and DNA damage repair networks and mitochondrial respiratory metabolism. Highly conserved insulin/IGF-1, TOR, and sirtuin signaling pathways in turn control these critical cellular responses. The coordinated action of these signaling pathways maintains cellular and organismal homeostasis in the face of external perturbations, such as changes in nutrient availability, temperature, and oxygen level, as well as internal perturbations, such as protein misfolding and DNA damage. Studies in model organisms suggest that changes in signaling can augment these critical stress response systems, increasing life span and reducing age-related pathology. The systems biology of stress response signaling thus provides a new approach to the understanding and potential treatment of age-related diseases. 相似文献
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The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage.
A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic
differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory,
most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage
and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of
cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response
pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly
or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and
apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly
adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological
modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative
disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right.
Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet,
exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over
the past decade has received considerable advances. The hormetic dose–response, challenging long-standing beliefs about the
nature of the dose–response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies
and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad
cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological
agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic
dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which
the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates
signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative
disorders. 相似文献
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Endoplasmic reticulum stress response and neurodegeneration 总被引:9,自引:0,他引:9
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Ekaterina V. Ilieva Alba Naudí Anton Kichev Isidre Ferrer Reinald Pamplona Manuel Portero-Otín 《Free radical biology & medicine》2010,48(10):1302-1310
Both oxidative and endoplasmic reticulum (ER) stress is associated with multiple neurodegenerative, age-related diseases. The rare disorder Pick disease (PiD) shares some pathological hallmarks of other neurodegenerative diseases that may be related to oxidative stress. Importantly, activation of an ER stress response, which is also involved in aging, has not yet been investigated in PiD. In this study, we assessed the implication of ER stress associated with oxidative stress in PiD as a potential mechanism involved in its pathogenesis. Samples from morphologically affected frontal cortex and apparently pathologically preserved occipital cortex showed region-dependent increases in different protein oxidative damage pathways. The oxidative modifications targeted antioxidant enzymes, proteases, heat shock proteins, and synaptic proteins. These effects were associated with compromised proteasomal function and ER stress in frontal cortex samples. In addition, we observed a depletion in ER chaperones (glucose-regulated proteins Grp78/BiP and glucose-regulated protein 94) and differences in tissue content and distribution of nuclear factor-erythroid 2 p45-related respiratory 2, required for cell survival during the unfolded protein response. These results demonstrate increased region-specific protein oxidative damage in PiD, with proteasomal alteration and dysfunctional ER stress response. We suggest this was caused by complete and specific depletion of Grp78/BiP, contributing to the pathophysiology of this neurodegenerative disease. 相似文献
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Chaperones and aging: role in neurodegeneration and in other civilizational diseases 总被引:6,自引:0,他引:6
Chaperones are highly conserved proteins responsible for the preservation and repair of the correct conformation of cellular macromolecules, such as proteins, RNAs, etc. Environmental stress leads to chaperone (heat-shock protein, stress protein) induction reflecting the protective role of chaperones as a key factor for cell survival and in repairing cellular damage after stress. The present review summarizes our current knowledge about the chaperone-deficiency in the aging process, as well as the possible involvement of chaperones in neurodegenerative diseases, such as in Alzheimer’s, Parkinson’s, Huntington- and prion-related diseases. We also summarize a recent theory implying chaperones as “buffers” of variations in the human genome, which role probably increased during the last 200 years of successful medical practice minimizing natural selection. Chaperone-buffered, silent mutations may be activated during the aging process, which leads to the phenotypic exposure of previously hidden features and might contribute to the onset of polygenic diseases, such as atherosclerosis, cancer, diabetes and several neurodegenerative diseases. 相似文献
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Oxidative stress as a result of either exogenous stimuli or cellular metabolism affects several cellular processes such as proliferation, apoptosis, cell death and senescence. Consequently, it is implicated in the pathogenesis of various human diseases like cancer, diabetes mellitus, atherosclerosis, neurodegenerative diseases and aging. Oxidative stress is implicated in carcinogenesis either by directly provoking DNA damage or through the regulation of intracellular signaling cascades. In both cases the cellular response to oxidative stress is determined by the cellular context. ARF, the alternative protein product of the CDKN2A locus has been recently recognized as a novel sensor of oxidative stress, in a β-catenin and Hsp70-mediated manner. Since, improved understanding of cellular responses to oxidative stress may facilitate the design of novel antineoplastic regimens, we herein review the mechanisms by which oxidative stress promotes carcinogenesis, focusing on the role of ARF as a sensor of oxidative stress. 相似文献
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Stress granules (SGs) are nonmembrane assemblies formed in cells in response to stress conditions. SGs mainly contain untranslated mRNA and a variety of proteins. RNAs and scaffold proteins with intrinsically disordered regions or RNA‐binding domains are essential for the assembly of SGs, and multivalent macromolecular interactions among these components are thought to be the driving forces for SG assembly. The SG assembly process includes regulation through post‐translational modification and involvement of the cytoskeletal system. During aging, many intracellular bioprocesses become disrupted by factors such as cellular environmental changes, mitochondrial dysfunction, and decline in the protein quality control system. Such changes could lead to the formation of aberrant SGs, as well as alterations in their maintenance, disassembly, and clearance. These aberrant SGs might in turn promote aging and aging‐associated diseases. In this paper, we first review the latest progress on the molecular mechanisms underlying SG assembly and SG functioning under stress conditions. Then, we provide a detailed discussion of the relevance of SGs to aging and aging‐associated diseases. 相似文献
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RNA damage and surveillance under oxidative stress 总被引:1,自引:0,他引:1
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The accumulation of damaged and aggregated proteins is a hallmark of aging and increased proteotoxic stress. To limit the toxicity of damaged and aggregated proteins and to ensure that the damage is not inherited by succeeding cell generations, a system of spatial quality control operates to sequester damaged/aggregated proteins into inclusions at specific protective sites. Such spatial sequestration and asymmetric segregation of damaged proteins have emerged as key processes required for cellular rejuvenation. In this review, we summarize findings on the nature of the different quality control sites identified in yeast, on genetic determinants required for spatial quality control, and on how aggregates are recognized depending on the stress generating them. We also briefly compare the yeast system to spatial quality control in other organisms. The data accumulated demonstrate that spatial quality control involves factors beyond the canonical quality control factors, such as chaperones and proteases, and opens up new venues in approaching how proteotoxicity might be mitigated, or delayed, upon aging. 相似文献
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Stadtman ER 《Free radical biology & medicine》2002,33(5):597-604
Tight linkage between aging and oxidative stress is indicated by the observations that reactive oxygen species generated under various conditions of oxidative stress are able to oxidize nucleic acids, proteins, and lipids and that aging is associated with the accumulation of oxidized forms of cellular constituents, and also by the fact that there is an inverse relationship between the maximum life span of organisms and the age-related accumulation of oxidative damage. Nevertheless, validity of the oxidative stress hypothesis of aging is questioned by (i) the failure to establish a causal relationship between aging and oxidative damage and (ii) lack of a consistent correlation between the accumulation of oxidative damage and aging. The present discussion is focused on the complexity of the aging process and suggests that discrepancies between various studies in this area are likely due to the fact that aging is not a single process and that the lack of consistent experimental results is partly explained by individual variations. Even so, there is overwhelming support for a dominant role of oxidative stress in the aging of some individuals. 相似文献
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Calabrese V Giuffrida Stella AM Calvani M Butterfield DA 《The Journal of nutritional biochemistry》2006,17(2):73-88
Aging is associated with a reduced ability to cope with physiological challenges. Although the mechanisms underlying age-related alterations in stress tolerance are not well defined, many studies support the validity of the oxidative stress hypothesis, which suggests that lowered functional capacity in aged organisms is the result of an increased generation of reactive oxygen and nitrogen species. Increased production of oxidants in vivo can cause damage to intracellular macromolecules, which can translate into oxidative injury, impaired function and cell death in vulnerable tissues such as the brain. To survive different types of injuries, brain cells have evolved networks of responses, which detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Among these, heat shock proteins form a highly conserved system responsible for the preservation and repair of the correct protein conformation. The heat shock response contributes to establishing a cytoprotective state in a wide variety of human diseases, including inflammation, cancer, aging and neurodegenerative disorders. Given the broad cytoprotective properties of the heat shock response, there is now a strong interest in discovering and developing pharmacological agents capable of inducing the heat shock response. Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders, and there is now evidence that it may play a critical role as modulator of cellular stress response in health and disease states. In the present review, we first discuss the role of nutrition in carnitine metabolism, followed by a discussion of carnitine and acetyl-l-carnitine in mitochondrial dysfunction, in aging, and in age-related disorders. We then review the evidence for the role of acetylcarnitine in modulating redox-dependent mechanisms leading to up-regulation of vitagenes in brain, and we also discuss new approaches for investigating the mechanisms of lifetime survival and longevity. 相似文献
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Reactive oxygen species, generated as normal by-products of aerobic metabolism or due to cellular stress, oxidize molecules and cause cell death by apoptosis. The accumulation of oxidized proteins is a hallmark of aging and a number of aging diseases. Oxidation can impair protein function as the proteins are unfolded leading to an increase of protein hydrophobicity and often resulting in the formation of toxic aggregates. The yeast Saccharomyces cerevisiae has been used as a eukaryotic model system to analyze the molecular mechanisms of oxidative stress protection. This paper reviews how the identification in yeast of specific damaged proteins has provided new insights into mechanisms of cytotoxicity and highlights the role of repair and degradative processes, including vacuolar/lysosomal and proteasomal proteolysis, in housekeeping after protein oxidative damage. 相似文献
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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. 相似文献
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Fatma N Singh P Chhunchha B Kubo E Shinohara T Bhargavan B Singh DP 《American journal of physiology. Cell physiology》2011,301(4):C954-C967
The multifunctional cytoprotective protein peroxiredoxin 6 (Prdx6) maintains cellular homeostasis and membrane integrity by regulating expression of intracellular reactive oxygen species (ROS) and phospholipid turnover. Using cells derived from targeted inactivation of Prdx6 gene or its depletion by RNA interference or aging, we showed that Prdx6 deficiency in cells evoked unfolded protein response (UPR), evidenced by increased expression or activation of proapoptotic factors, CHOP, ATF4, PERK, IRE-α and eIF2-α and by increased caspases 3 and 12 processing. Those cells displayed enhanced and sustained expression of endoplasmic reticulum (ER) stress-related chaperon proteins, Bip/glucose-regulated protein 78, calnexin, and calreticulin. Under cellular stress induced by hypoxia (1% O(2) or CoCl(2) treatment) or tunicamycin, Prdx6-deficient cells exhibited aberrant activation of ER stress-responsive genes/protein with higher expression of ROS, and died with apoptosis. Wild-type cells exposed to tunicamycin or hypoxia remained relatively insensitive with lower expression of ROS and ER-responsive genes than did Prdx6-deficient cells, but upregulation of ER stress responsive proteins or chaperones mimicked the UPR response of Prdx6-deficient or aging cells. Expression of Prdx6 blocked ER stress-induced deleterious signaling by optimizing physiologically aberrant expression of ER stress responsive genes/proteins in Prdx6-deficient cells or cells facing stressors, and rescued the cells from apoptosis. These findings demonstrate that impaired homeostasis and progression of pathogenesis in Prdx6-deficient lens epithelial cells or in aging cells should be blocked by a supply of Prdx6. The results provide a new molecular basis for understanding the etiology of several age-associated degenerative disorders, and potentially for developing antioxidant Prdx6-based therapeutics. 相似文献
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Regulation of proteasome-mediated protein degradation during oxidative stress and aging 总被引:2,自引:0,他引:2
Protein degradation is a physiological process required to maintain cellular functions. There are distinct proteolytic systems for different physiological tasks under changing environmental and pathophysiological conditions. The proteasome is responsible for the removal of oxidatively damaged proteins in the cytosol and nucleus. It has been demonstrated that proteasomal degradation increases due to mild oxidation, whereas at higher oxidant levels proteasomal degradation decreases. Moreover, the proteasome itself is affected by oxidative stress to varying degrees. The ATP-stimulated 26S proteasome is sensitive to oxidative stress, whereas the 20S form seems to be resistant. Non-degradable protein aggregates and cross-linked proteins are able to bind to the proteasome, which makes the degradation of other misfolded and damaged proteins less efficient. Consequently, inhibition of the proteasome has dramatic effects on cellular aging processes and cell viability. It seems likely that during oxidative stress cells are able to keep the nuclear protein pool free of damage, while cytosolic proteins may accumulate. This is because of the high proteasome content in the nucleus, which protects the nucleus from the formation and accumulation of non-degradable proteins. In this review we highlight the regulation of the proteasome during oxidative stress and aging. 相似文献
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Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death 总被引:12,自引:0,他引:12
A variety of debilitating diseases including diabetes, Alzheimer's, Huntington's, Parkinson's, and prion-based diseases are linked to stress within the endoplasmic reticulum (ER). Using S. cerevisiae, we sought to determine the relationship between protein misfolding, ER stress, and cell death. In the absence of ERV29, a stress-induced gene required for ER associated degradation (ERAD), misfolded proteins accumulate in the ER leading to persistent ER stress and subsequent cell death. Cells alleviate ER stress through the unfolded protein response (UPR); however, if stress is sustained the UPR contributes to cell death by causing the accumulation of reactive oxygen species (ROS). ROS are generated from two sources: the UPR-regulated oxidative folding machinery in the ER and mitochondria. Our results demonstrate a direct mechanism(s) by which misfolded proteins lead to cellular damage and death. 相似文献
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《Free radical research》2013,47(9):1070-1084
AbstractIn addition to serving as the power house of mammalian cells, mitochondria are crucial for the maintenance of cellular homeostasis in response to physiological or environmental changes. Several lines of evidence suggest that posttranslational modification (PTM) of proteins plays a pivotal role in the regulation of the bioenergetic function of mitochondria. Among them, reversible lysine acetylation of mitochondrial proteins has been established as one of the key mechanisms in cellular response to energy demand by modulating the flux of a number of key metabolic pathways. In this article, we focus on the role of Sirt3-mediated deacetylation in: (1) flexibility of energy metabolism, (2) activation of antioxidant defense, and (3) maintenance of cellular redox status in response to dietary challenge and oxidative stress. We suggest that oxidative stress-elicited down-regulation of Sirt3 plays a role in the pathophysiology of diabetes, cardiac hypotrophy, mitochondrial diseases, and age-related diseases. Besides, the physiological role of newly identified lysine acylation mediated by Sirt5 and its biochemical effects on oxidative metabolism are also discussed. Moreover, we have integrated the regulatory function of several protein kinases that are involved in the phosphorylation of mitochondrial enzymes during oxidative stress. Finally, the functional consequence of the synergistic regulation through diverse protein modifications is emphasized on the maintenance of the bioenergetic homeostasis and metabolic adaptation of the animal and human cells. Together, we have provided an updated review of PTM in mitochondrial biology and their implications in aging and human diseases through an intricate regulation of energy metabolism under oxidative stress. 相似文献