The role of senescence,telomere dysfunction and shelterin in vascular aging

In the United States and other westernized nations, CVDs are the leading cause of death in adults over 65 years of age. Large artery stiffness and endothelial dysfunction are increased with age and age‐associated arterial dysfunction is an important antecedent of CVDs. One age‐associated change that may contribute to vascular dysfunction and CVD risk is an increase in the number of resident senescent cells in the vasculature. Senescent cells display a pro‐oxidant, pro‐inflammatory phenotype known as the SASP. However, the mechanisms that drive the SASP and the vascular aging phenotype remain elusive. A putative mechanism is the involvement of oxidative stress and inflammation in telomere function. Telomeres are the end caps of chromosomes which are maintained by a six‐protein complex known as shelterin. Disruption of shelterin can uncap telomeres and induce cellular senescence. Accordingly, in this review, we propose that oxidative stress and inflammation disrupt shelterin in vascular cells, driving telomere dysfunction and that this mechanism may be responsible for the induction of SASP. The proposed mechanisms may represent some of the initial changes that lead to vascular dysfunction in advanced age.     

Metabolic changes in the auditory cortex in presbycusis demonstrated by MR spectroscopy

In humans, aging is accompanied by the deterioration of the hearing function — presbycusis. The major etiology for presbycusis is the loss of hair cells in the inner ear; less well known are changes in the central auditory system. Therefore, we used 1 H magnetic resonance spectroscopy at 3 T tomograph to examine metabolite levels in the auditory cortex of three groups of subjects: young healthy subjects less than 30 years old and subjects older than 65 years either with mild presbycusis corresponding to their age or with expressed presbycusis. Hearing function in all subjects was examined by pure tone audiometry (125–16000 Hz). Significant differences were found in the concentrations of glutamate and N-acetylaspartate, with lower levels in aged subjects. Lactate was particularly increased in subjects with expressed presbycusis. Significant differences were not found in other metabolites, including GABA, between young and elderly subjects. The results demonstrate that the age-related changes of the inner ear are accompanied by a decrease in the excitatory neurotransmitter glutamate as well as a lactate increase in the auditory cortex that is more expressed in elderly subjects with large hearing threshold shifts.     

Characterization of skeletal alterations in a model of prematurely aging mice

An age-related bone loss occurs, apparently associated with the concomitant increase in an oxidative stress situation. However, the underlying mechanisms of age-related osteopenia are ill defined since these studies are time consuming and require the use of many animals (mainly rodents). Here, we aimed to characterize for the first time the bone status of prematurely aging mice (PAM), which exhibit an increased oxidative stress. Tibiae from adult (6 months) PAM show an increase in bone mineral density (BMD) and bone mineral content (assessed by bone densitometry) versus those in their normal counterparts (non-prematurely aging mice, NPAM) and similarly decreased in both kinds of mouse with age. However, at this bone site, trabecular BMD (determined by μ-computerized tomography) was similar in both adult PAM and old (18 months) NPAM. Femurs from these groups of mice present an increase in oxidative stress, inflammation, osteoclastogenic, and adipogenic markers, but a decrease in the gene expression of osteoblastic differentiation markers and of the Wnt/β-catenin pathway. Our findings show that adult PAM recapitulate various age-related bone features, and thus are a suitable model for premature bone senescence studies.     

氧化损伤标志物与中枢神经系统疾病

中枢神经系统疾病中自由基的增加引发氧化应激,从而导致中枢神经系统损伤,故氧化损伤标志物的检测对疾病的早期诊断、病情评价及预后均具有重要意义。本文主要介绍氧化损伤中脂质、蛋白质、DNA的氧化生物标志物以及相关酶和非酶抗氧化剂的间接标志物。过去10年,虽然报道了中枢神经系统疾病的一些氧化应激标志物,但仍需寻找同时具备敏感度高和专一性强的氧化损伤标志物。     

Pathogenesis of presbycusis in animal models: a review

Presbycusis is the most common cause of hearing loss in aged subjects, reducing individual's communicative skills. Age related hearing loss can be defined as a progressive, bilateral, symmetrical hearing loss due to age related degeneration and it can be considered a multifactorial complex disorder, with both environmental and genetic factors contributing to the aetiology of the disease.The decline in hearing sensitivity caused by ageing is related to the damage at different levels of the auditory system (central and peripheral). Histologically, the aged cochlea shows degeneration of the stria vascularis, the sensorineural epithelium, and neurons of the central auditory pathways. The mechanisms responsible for age-associated hearing loss are still incompletely characterized.This work aims to give a broad overview of the scientific findings related to presbycusis, focusing mainly on experimental studies in animal models.     

Aging increases mitochondrial DNA damage and oxidative stress in liver of rhesus monkeys

While the mechanisms of cellular aging remain controversial, a leading hypothesis is that mitochondrial oxidative stress and mitochondrial dysfunction play a critical role in this process. Here, we provide data in aging rhesus macaques supporting the hypothesis that increased oxidative stress is a major characteristic of aging and may be responsible for the age-associated increase in mitochondrial dysfunction. We measured mitochondrial DNA (mtDNA) damage by quantitative PCR in liver and peripheral blood mononuclear cells of young, middle age, and old monkeys and show that older monkeys have increases in the number of mtDNA lesions. There was a direct correlation between the amount of mtDNA lesions and age, supporting the role of mtDNA damage in the process of aging. Liver from older monkeys showed significant increases in lipid peroxidation, protein carbonylations and reduced antioxidant enzyme activity. Similarly, peripheral blood mononuclear cells from the middle age group showed increased levels in carbonylated proteins, indicative of high levels of oxidative stress. Together, these results suggest that the aging process is associated with defective mitochondria, where increased production of reactive oxygen species results in extensive damage at the mtDNA and protein levels. This study provides valuable data based on the rhesus macaque model further validating age-related mitochondrial functional decline with increasing age and suggesting that mtDNA damage might be a good biomarker of aging.     

Oxidative damage during aging targets mitochondrial aconitase

The mechanisms that cause aging are not well understood. The oxidative stress hypothesis proposes that the changes associated with aging are a consequence of random oxidative damage to biomolecules. We hypothesized that oxidation of specific proteins is critical in controlling the rate of the aging process. Utilizing an immunochemical probe for oxidatively modified proteins, we show that mitochondrial aconitase, an enzyme in the citric acid cycle, is a specific target during aging of the housefly. The oxidative damage detected immunochemically was paralleled by a loss of catalytic activity of aconitase, an enzyme activity that is critical in energy metabolism. Experimental manipulations which decrease aconitase activity should therefore cause a decrease in life-span. This expected decrease was observed when flies were exposed to hyperoxia, which oxidizes aconitase, and when they were given fluoroacetate, an inhibitor of aconitase. The identification of a specific target of oxidative damage during aging allows for the assessment of the physiological age of a specific individual and provides a method for the evaluation of treatments designed to affect the aging process.     

Mitochondria and cardiovascular aging

Old age is a major risk factor for cardiovascular diseases. Several lines of evidence in experimental animal models have indicated the central role of mitochondria both in lifespan determination and in cardiovascular aging. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and biogenesis as well as the crosstalk between mitochondria and cellular signaling in cardiac and vascular aging. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging include endothelial dysfunction, reduced vascular elasticity, and chronic vascular inflammation. Both cardiac and vascular aging involve neurohormonal signaling (eg, renin-angiotensin, adrenergic, insulin-IGF1 signaling) and cell-autonomous mechanisms. The potential therapeutic strategies to improve mitochondrial function in aging and cardiovascular diseases are also discussed, with a focus on mitochondrial-targeted antioxidants, calorie restriction, calorie restriction mimetics, and exercise training.     

Evolving insight into the role of mitochondrial DNA mutations in aging

Mitochondria have occupied a central place in theories on the underlying cellular mechanisms of eukaryotic aging for several decades and much debate has ensued regarding the role of oxidative stress and mitochondrial genomic damage in these processes. Mouse models with greatly enhanced mitochondrial mutagenesis have produced dramatic aging-like phenotypes but recent results have led some to reassess whether such models are relevant to naturally occurring aging mechanisms. Here, we discuss the evolving insight that may be gained from these models regarding the contribution of mitochondrial DNA mutations to aging.     

Oxidative DNA damage as a marker of aging in WI-38 human fibroblasts

Cause-effect relationships between oxidative stress, DNA damage and aging were investigated in WI-38 human diploid fibroblasts at 21, 41 or 58 population doublings (PDs), corresponding to young, middle age or old fibroblasts, respectively. Oxidative DNA damage was evaluated by immunohistochemical detection of 8-hydroxy-2'deoxyguanosine (8-OHdG) adducts or by single cell microgel electrophoresis (COMET assay). Aging was evaluated by growth rate, senescence-associated-beta-galactosidase (SA-beta galactosidase) activity, cell cycle distribution, and expression of p21. Our results demonstrate that (i) oxidative DNA damage is proportional to the age of cells (ii) DNA damage in old/58 PDs cells reflects both an increased susceptibility to oxidative stress, induced by acute exposure to sub-lethal concentrations of hydrogen peroxide (H(2)O(2)), and a reduced efficiency of repair mechanisms. We also show that mild chronic oxidative stress, induced by prolonged exposure to 5 microM H(2)O(2), accelerates aging in fibroblasts. In fact, this treatment increased 8-OHdG levels, SA-beta-galactosidase activity, and G0/G1 cell cycle arrest in middle age/41 PDs, making them similar to H(2)O(2)-untreated old/58 PDs cells. Although other mechanisms may concur in mediating the effects of H(2)O(2), these results lend support to the concept that oxidative stress may be a key determinant of aging. Measurements of oxidative DNA damage might therefore be exploited as reliable marker of cellular aging.     

Sirt1 regulates aging and resistance to oxidative stress in the heart

Silent information regulator (Sir)2, a class III histone deacetylase, mediates lifespan extension in model organisms and prevents apoptosis in mammalian cells. However, beneficial functions of Sir2 remain to be shown in mammals in vivo at the organ level, such as in the heart. We addressed this issue by using transgenic mice with heart-specific overexpression of Sirt1, a mammalian homolog of Sir2. Sirt1 was significantly upregulated (4- to 8-fold) in response to pressure overload and oxidative stress in nontransgenic adult mouse hearts. Low (2.5-fold) to moderate (7.5-fold) overexpression of Sirt1 in transgenic mouse hearts attenuated age-dependent increases in cardiac hypertrophy, apoptosis/fibrosis, cardiac dysfunction, and expression of senescence markers. In contrast, a high level (12.5-fold) of Sirt1 increased apoptosis and hypertrophy and decreased cardiac function, thereby stimulating the development of cardiomyopathy. Moderate overexpression of Sirt1 protected the heart from oxidative stress induced by paraquat, with increased expression of antioxidants, such as catalase, through forkhead box O (FoxO)-dependent mechanisms, whereas high levels of Sirt1 increased oxidative stress in the heart at baseline. Thus, mild to moderate expression of Sirt1 retards aging of the heart, whereas a high dose of Sirt1 induces cardiomyopathy. Furthermore, although high levels of Sirt1 increase oxidative stress, moderate expression of Sirt1 induces resistance to oxidative stress and apoptosis. These results suggest that Sirt1 could retard aging and confer stress resistance to the heart in vivo, but these beneficial effects can be observed only at low to moderate doses (up to 7.5-fold) of Sirt1.     

Recent progress in testing the longevity determinant and dysdifferentiation hypotheses of aging

An overview of the longevity determinant and dysdifferentiation hypotheses is presented, highlighting some of the major postulates and predictions. Results of recent experiments testing these hypotheses are discussed, including the search for specific longevity determinant genes and evidence that cancer and aging may have common causative mechanisms of action and control. Regulation of oxidative stress is considered a potential longevity determinant mechanism and methods and results testing this prediction are reviewed. Possibility of enhancing protective mechanisms against oxidative stress is discussed by way of intervention of central regulatory mechanisms of antioxidants using the cyclase-arachidonic acidcyclooxygenase (GAC model).     

Mitochondrial protein oxidation and degradation in response to oxidative stress and aging

Mitochondria are a major source of intracellular reactive oxygen species (ROS), the production of which increases with age. These organelles are also targets of oxidative damage. The deleterious effects of ROS may be responsible for impairment of mitochondrial function observed during various pathophysiological states associated with oxidative stress and aging. An important factor for protein maintenance in the presence of oxidative stress is enzymatic reversal of oxidative modifications and/or protein degradation. Failure of these protein maintenance systems is likely a critical component of the aging process. Mitochondrial matrix proteins are sensitive to oxidative inactivation and oxidized proteins are known to accumulate during aging. The ATP-stimulated mitochondrial Lon protease is a highly conserved protease found in prokaryotes and the mitochondrial compartment of eukaryotes and is believed to play an important role in the degradation of oxidized mitochondrial matrix proteins. Age-dependent declines in the activity and regulation of this proteolytic system may underlie accumulation of oxidatively modified and dysfunctional protein and loss in mitochondrial viability.     

Changes in parvalbumin immunoreactivity with aging in the central auditory system of the rat

Changes in the levels of calcium binding proteins are known to occur in different parts of the brain during aging. In our study we attempted to define the effect that aging has on the parvalbumin-expressing system of neurons in the higher parts of the central auditory system. Age-related changes in parvalbumin immunoreactivity were investigated in the inferior colliculus (IC), medial geniculate body (MGB) and auditory cortex (AC) in two rat strains, normally aging Long-Evans (LE) and fast aging Fischer 344 (F344). The results demonstrate that the changes in PV-immunoreactivity are strain-dependent with an increase in the number of PV-immunoreactive (PV-ir) neurons occurring in the inferior colliculus of old LE rats and a pronounced decline in the number of PV-ir neurons appearing in the auditory cortex of aged F344 animals. In some parts of the AC of old F344 animals no PV-ir neurons were present at all. The number of PV-ir neurons in the MGB in all examined animals was very low independent of the strain and age. The loss of PV-ir neurons in the auditory cortex of Fischer 344 rats with aging may contribute to the substantial deterioration of hearing function in this strain.     

Presbycusis and auditory brainstem responses: a review

Age-related hearing loss or presbycusis is a complex phenomenon consisting of elevation of hearing levels as well as changes in the auditory processing. It is commonly classified into four categories depending on the cause. Auditory brainstem responses (ABRs) are a type of early evoked potentials recorded within the first 10 ms of stimulation. They represent the synchronized activity of the auditory nerve and the brainstem. Some of the changes that occur in the aging auditory system may significantly influence the interpretation of the ABRs in comparison with the ABRs of the young adults. The waves of ABRs are described in terms of amplitude, latencies and interpeak latency of the different waves. There is a tendency of the amplitude to decrease and the absolute latencies to increase with advancing age but these trends are not always clear due to increase in threshold with advancing age that act a major confounding factor in the interpretation of ABRs.     

Age-related hearing loss: quality of care for quality of life

Age-related hearing loss (ARHL), known as presbycusis, is characterized by progressive deterioration of auditory sensitivity, loss of the auditory sensory cells, and central processing functions associated with the aging process. ARHL is the third most prevalent chronic condition in older Americans, after hypertension and arthritis, and is a leading cause of adult hearing handicaps in the United States. The prevalence of ARHL is expected to rise for the next several decades with the increasing aging Baby Boomer population. Nevertheless, ARHL remains an often undetected, underestimated and neglected condition in the geriatric population due to a slow development process of the disease. If left untreated, the impact of ARHL on patients, significant others, and the society as a whole would be significant. The purpose of this review is to raise the awareness of ARHL, to update our current understanding of ARHL with a focus on age-related deficits in auditory and cognitive processing of speech, and to explore strategies of prevention, identification, amplification, and aural rehabilitation. The ultimate goal is to improve the quality of hearing health care and the overall quality of life of the Baby Boomer generation.     

Apolipoprotein E deficiency and a mouse model of accelerated liver aging

The liver is the central metabolic organ which regulates several key aspects of lipid metabolism. The liver changes with age leading to an impaired ability to respond to hepatic insults and an increased incidence of liver disease in the elderly. Apolipoprotein E (ApoE) null mice have proved to be a very popular model to study spontaneous atherosclerosis, but recently it has been demonstrated that in ApoE?/? mice liver there are enzymatic and structural alterations, normally linked to the age. The purpose of this study was to consider ApoE?/? mice as a model for oxidative stress induced hepatic disease and to clarify how ApoE inactivation accelerates the aging process and causes liver disease.We used ApoE null mice and control mice at different ages (6 weeks and 15 months).Liver morphological damage as well as proteins involved in oxidative stress and liver ageing were all analyzed.Our study showed that ApoE null mice develop important age-related changes including oxidative stress, pseudocapillarization, increased polyploidy, decreased hepatocyte number and increased nuclear size. Our findings provide evidence that hypercholesterolemic ApoE?/? mice are more likely to develop severe liver injury, suggesting that in addition to vascular disease, increased cholesterol products and oxidative stress may also play a role in accelerating the progression of aging in the liver.     

Dizziness in aging: the clinical experience

Dizziness and vertigo occur frequently in aging. Inner ear or nervous system pathology (central or peripheral) may be the cause. Other causes may also be cardiovascular disease, medication, leg pathology, psycho-pathologic processes (psychogenic dizziness), etc. In our Dizziness Clinic, 3427 patients 70 years of age or older were evaluated and an accurate diagnosis was possible in 76.25 percent of cases. Dizziness specific to aging was not identified, although at times dizziness was more serious than in younger patients due either to weakness because of aging or to more than one cause of dizziness. Thus dizziness and vertigo in aging have to be investigated carefully and similarly to other age groups. To this effect, the history, the clinical examination, and the follow-up are the most essential tools available to the practicing physician.