Celecoxib extends C. elegans lifespan via inhibition of insulin-like signaling but not cyclooxygenase-2 activity

One goal of aging research is to develop interventions that combat age-related illnesses and slow aging. Although numerous mutations have been shown to achieve this in various model organisms, only a handful of chemicals have been identified to slow aging. Here, we report that celecoxib, a nonsteroidal anti-inflammatory drug widely used to treat pain and inflammation, extends Caenorhabditis elegans lifespan and delays the age-associated physiological changes, such as motor activity decline. Celecoxib also delays the progression of age-related proteotoxicity as well as tumor growth in C. elegans. Celecoxib was originally developed as a potent cyclooxygenase-2 (COX-2) inhibitor. However, the result from a structural-activity analysis demonstrated that the antiaging effect of celecoxib might be independent of its COX-2 inhibitory activity, as analogs of celecoxib that lack COX-2 inhibitory activity produce a similar effect on lifespan. Furthermore, we found that celecoxib acts directly on 3'-phosphoinositide-dependent kinase-1, a component of the insulin/IGF-1 signaling cascade to increase lifespan.     

维尔康对家蝇(Musca domestica)寿命和飞翔肌线粒体年龄变化的影响

本文观察了中药复方维尔康对雄蝇寿命、飞翔肌线粒体能量转换ATP酶(以下简称ATP(?))活性及线粒体超微结构衰老变化的影响。实验表明维尔康可使(?)的群体平均寿命和5％存活时的日龄分别增加11.4％和13.7％,用losrank检验比较对黑组和维尔序组家蝇的生存数据,结果差异极(?)著,P<0.001。对照组家蝇孵化后6日龄ATP酶水解活性最高,随即开始下降。维尔康组家蝇的要(?)活性则一直维持到15日龄以后才开始下降,但其ATP酶活性的年龄交化规律仍与对照组家蝇类似。维尔康组家蝇飞翔肌线粒体超微结构的退化也有较对照组家蝇推迟的趋向。这些现象提示维尔康似可延缓家蝇的衰老过程。     

Estrogen and mitochondria: a new paradigm for vascular protection?

Mitochondrial dysfunction has been implicated as a cause of age-related disorders, and the mitochondrial theory of aging links aging, exercise, and diet. Endothelial dysfunction is a key paradigm for vascular disease and aging, and there is considerable evidence that exercise and dietary restriction protect against cardiovascular disease. Recent studies demonstrate that estrogen receptors are present in mitochondria and that estrogen promotes mitochondrial efficiency and decreases oxidative stress in the cerebral vasculature. Chronic estrogen treatment increases mitochondrial capacity for oxidative phosphorylation while decreasing production of reactive oxygen species. The effectiveness of estrogen against age-related cardiovascular disorders, including stroke, may thus arise in part from hormonal effects on mitochondrial function. Estrogen-mediated mitochondrial efficiency may also be a contributing factor to the longer lifespan of women.     

Epigenetic perturbations in aging stem cells

Stem cells maintain homeostasis in all regenerating tissues during the lifespan of an organism. Thus, age-related functional decline of such tissues is likely to be at least partially explained by molecular events occurring in the stem cell compartment. Some of these events involve epigenetic changes, which may dictate how an aging genome can lead to differential gene expression programs. Recent technological advances have made it now possible to assess the genome-wide distribution of an ever-increasing number of epigenetic marks. As a result, the hypothesis that there may be a causal role for an altered epigenome contributing to the functional decline of cells, tissues, and organs in aging organisms can now be explored. In this paper, we review recent developments in the field of epigenetic regulation of stem cells, and how this may contribute to aging.     

Oxidative stress and aging: beyond correlation

The oxidative stress theory of aging has become increasingly accepted as playing a role in the aging process, based primarily on a substantial accumulation of circumstantial evidence. In recent years, the hypothesis that mitochondrially generated reactive oxygen species play a role in organismal aging has been directly tested in both invertebrate and mammalian model systems. Initial results imply that oxidative damage, specifically the level of superoxide, does play a role in limiting the lifespans of invertebrates such as Drosophila melanogaster and Caenorhabditis elegans. In mammalian model systems, the effect of oxidative stress on lifespan is less clear, but there is evidence that antioxidant treatment protects against age-related dysfunction, including cognitive decline.     

Delayed behavioural aging and altered mortality in Drosophila beta integrin mutants

The genetic basis for aging is being intensely investigated in a variety of model systems. Much of the focus in Drosophila has been on the molecular-genetic determinants of lifespan, whereas the molecular-genetic basis for age-related functional declines has been less vigorously explored. We evaluated behavioural aging and lifespan in flies harbouring loss-of-function mutations in myospheroid, the gene that encodes betaPS, a beta integrin. Integrins are adhesion molecules that regulate a number of cellular processes and developmental events. Their role in aging, however, has received limited attention. We report here that age-related declines in locomotor activity are ameliorated and that mean lifespan is increased in myospheroid mutants. The delayed functional senescence and altered mortality in myospheroid flies are independent of changes in body size, reproduction or stress resistance. Our data indicate that functional senescence and age-dependent mortality are influenced by beta integrins in Drosophila.     

Adipose tissue aging: mechanisms and therapeutic implications

Adipose tissue, which is the crucial energy reservoir and endocrine organ for the maintenance of systemic glucose, lipid, and energy homeostasis, undergoes significant changes during aging. These changes cause physiological declines and age-related disease in the elderly population. Here, we review the age-related changes in adipose tissue at multiple levels and highlight the underlying mechanisms regulating the aging process. We also discuss the pathogenic pathways of age-related fat dysfunctions and their systemic negative consequences, such as dyslipidemia, chronic general inflammation, insulin resistance, and type 2 diabetes (T2D). Age-related changes in adipose tissue involve redistribution of deposits and composition, in parallel with the functional decline of adipocyte progenitors and accumulation of senescent cells. Multiple pathogenic pathways induce defective adipogenesis, inflammation, aberrant adipocytokine production, and insulin resistance, leading to adipose tissue dysfunction. Changes in gene expression and extracellular signaling molecules regulate the aging process of adipose tissue through various pathways. In addition, adipose tissue aging impacts other organs that are infiltrated by lipids, which leads to systemic inflammation, metabolic system disruption, and aging process acceleration. Moreover, studies have indicated that adipose aging is an early onset event in aging and a potential target to extend lifespan. Together, we suggest that adipose tissue plays a key role in the aging process and is a therapeutic target for the treatment of age-related disease, which deserves further study to advance relevant knowledge.Subject terms: Senescence, Endocrine system and metabolic diseases     

Aging of the hypothalamo-pituitary-ovarian axis: hormonal influences and cellular mechanisms

Longitudinal studies employing heterochronic ovarian grafts and long-term ovariectomy indicate that there is no single pacemaker of reproductive aging. Neuroendocrine dysfunction, the declining follicular reserve, and ovarian secretions all contribute to reproductive decline, and their relative importance to the different stages of reproductive aging varies markedly. Moreover, although ovarian secretions during adulthood potentiate certain aspects of the reproductive aging process, their behavior does not fit a simple model of cumulative steroidal damage incurred over the lifespan. Current data are more consistent with temporally distinct windows of steroidal vulnerability for the events affected: cycle lengthening is affected by ovarian secretions during the period of cyclicity, and post-cyclic neuroendocrine failure is potentiated by ovarian secretions during the peri- and post-cyclic period of the lifespan. Recent examination of estradiol receptor dynamics reveals multiple, albeit selective, changes during aging that may contribute to the age-related impairments of tissue sensitivity to estrogen. These changes vary qualitatively and quantitatively among target tissues. Thus, aging of the hypothalamo-pituitary-ovarian axis at the cellular level mirrors, in its multifactorial nature, aging at the organismic level.     

Large Differences in Aging Phenotype between Strains of the Short-Lived Annual Fish Nothobranchius furzeri

Background

A laboratory inbred strain of the annual fish Nothobranchius furzeri shows exceptionally short life expectancy and accelerated expression of age markers. In this study, we analyze new wild-derived lines of this short-lived species.

Methodology/Principal Findings

We characterized captive survival and age-related traits in F1 and F2 offspring of wild-caught N. furzeri. Wild-derived N. furzeri lines showed expression of lipofuscin and neurodegeneration at age 21 weeks. Median lifespan in the laboratory varied from to 20 to 23 weeks and maximum lifespan from 25 to 32 weeks. These data demonstrate that rapid age-dependent decline and short lifespan are natural characteristics of this species. The N. furzeri distribution range overlaps with gradients in altitude and aridity. Fish from more arid habitats are expected to experience a shorter survival window in the wild. We tested whether captive lines stemming from semi-arid and sub-humid habitats differ in longevity and expression of age-related traits. We detected a clear difference in age-dependent cognitive decline and a slight difference in lifespan (16% for median, 15% for maximum lifespan) between these lines. Finally, we observed shorter lifespan and accelerated expression of age-related markers in the inbred laboratory strain compared to these wild-derived lines.

Conclusions/Significance

Owing to large differences in aging phenotypes in different lines, N. furzeri could represent a model system for studying the genetic control of life-history traits in natural populations.     

Total aneuploidy and age-related sex chromosome aneuploidy in cultured lymphocytes of normal men and women

Summary In PHA-cultured lymphocytes, about 8% of metaphases from 32 women were aneuploid compared to 4% of metaphases from 35 men. A significant part of this aneuploidy was characterized by sex chromosome involvement: in women, the loss or gain of X chromosomes; in men, the gain of X chromosomes and the loss or gain of Y chromosomes. The incidence of this aneuploidy was positively age-related for both sexes. Premature division of the X-chromosome centromere was closely associated with X-chromosome aneuploidy in women and men, and appeared to be the mechanism of nondisjunction causing this aneuploidy. Premature centromere division (PCD) indicated a dysfunction of the X-chromosome centromere with aging, and this dysfunction was the basic cause of age-related aneuploidy. A similar mechanism of nondisjunction may operate for the Y chromosome of men, but could not be clearly demonstrated because of the low incidence of Y-chromosome aneuploidy.The balance of the aneuploidy was characterized by chromosome loss and the involvement of all chromosome groups. It was consistent with chromosome loss from metaphase cells damaged during preparation for cytogenetic examination.     

Mitochondrial longevity pathways

Average lifespan has increased over the last centuries, as a consequence of medical and environmental factors, but maximal life span remains unchanged. Better understanding of the underlying mechanisms of aging and determinants of life span will help to reduce age-related morbidity and facilitate healthy aging. Extension of maximal life span is currently possible in animal models with measures such as genetic manipulations and caloric restriction (CR). CR appears to prolong life by reducing oxidative damage. Reactive oxygen species (ROS) have been proposed to cause deleterious effects on DNA, proteins, and lipids, and generation of these highly reactive molecules takes place in the mitochondria. But ROS is positively implicated in cellular stress defense mechanisms and formation of ROS a highly regulated process controlled by a complex network of intracellular signaling pathways. There are endogenous anti-oxidant defense systems that have the potential to partially counteract ROS impact. In this review, we will describe pathways contributing to the regulation of the age-related decline in mitochondrial function and their impact on longevity. This article is part of a Special Issue entitled Mitochondria: the deadly organelle.     

Déficit Androgénique Lié à l’Age

In contrast with the abrupt cessation of ovarian function at menopause in women, alteration of testicular functions in aging males is partial and progressive. Several cross-sectional studies have demonstrated an age-related decrease of testosterone levels in men. This decrease has also been observed when only men in good health are included in such studies. This age-related decline of testosterone levels has been recently confirmed by a longitudinal study including a large number of subjects. The progressive decline begins early, from the late thirties, and continues at a constant rate throughout the subject’s lifetime. Since SHBG increases with age, free testosterone and non-SHBG-bound testosterone (referred to as bioavailable testosterone) decrease more markedly than total testosterone. As variations of SHBG levels (mainly a decrease in obese and/or insulin-resistant subjects) are often encountered in clinical practice and as it is difficult to reliably measure free testosterone, bioavailable testosterone appears to be the better index to diagnose androgen deficiency in the aging male. Elevation of basal LH levels, decrease of hCG-induced testosterone levels and reduction of Leydig cell number demonstrate the testicular origin of hypogonadism. However, gonadotropic function is also relatively altered with aging. As a result of this alteration of gonadotropic function, LH level is not a reliable index of hypogonadism in the aging male. None of the androgen-dependent functions that are altered with aging, i.e. libido, erectile function, sense of well-being, muscle mass, muscle strength, fat mass, bone mass, etc., are exclusively controlled by androgens. In clinical practice, the indication for androgen replacement therapy must therefore be based on a combination of clinical symptoms and a reduction of bioavailable testosterone below a certain cut-off value, indicating “significant” hypogonadism.     

Rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice

The nutrient-sensing TO R (target of rapamycin) pathway is involved in cellular and organismal aging. Rapamycin, an inhibitor of TO R, extends lifespan in yeast, fruit flies and genetically heterogeneous mice. Here, we demonstrate that lifelong administration of rapamycin extends lifespan in female 129/Sv mice characterized by normal mean lifespan of 2 y. Importantly, rapamycin was administrated intermittently (2 weeks per month) starting from the age of 2 mo. Rapamycin inhibited age-related weight gain, decreased aging rate, increased lifespan (especially in the last survivors) and delayed spontaneous cancer. 22.9% of rapamycin-treated mice survived the age of death of the last mouse in control group. Thus we demonstrated for the first time in normal inbred mice that lifespan can be extended by rapamycin. This opens an avenue to develop optimal doses and schedules of rapamycin as an anti-aging modality.     

Exploring the physiology and pathology of aging in the intestine of Drosophila melanogaster

The gastrointestinal tract, due to its role as a digestive organ and as a barrier between the exterior and interior milieus, is critically impacted by dietary, environmental, and inflammatory conditions that influence health and lifespan. Work in flies is now uncovering the multifaceted molecular mechanisms that control homeostasis in this tissue, and establishing its central role in health and lifespan of metazoans. The Drosophila intestine has thus emerged as a productive, genetically accessible model to study various aspects of the pathophysiology of aging. Studies in flies have characterized the maintenance of regenerative homeostasis, the development of immune senescence, the loss of epithelial barrier function, the decline in metabolic homeostasis, as well as the maintenance of epithelial diversity in this tissue. Due to its fundamental similarity to vertebrate intestines, it can be anticipated that findings obtained in this system will have important implications for our understanding of age-related changes in the human intestine. Here, I review recent studies exploring age-related changes in the fly intestine, and their insight into the regulation of health and lifespan of the animal.     

Target of rapamycin activation predicts lifespan in fruit flies

Aging and age-related diseases are one of the most important health issues that the world will confront during the 21^st century. Only by understanding the proximal causes will we be able to find treatments to reduce or delay the onset of degenerative diseases associated with aging. Currently, the prevalent paradigm in the field is the accumulation of damage. However, a new theory that proposes an alternative explanation is gaining momentum. The hyperfunction theory proposes that aging is not a consequence of a wear and tear process, but a result of the continuation of developmental programs during adulthood. Here we use Drosophila melanogaster, where evidence supporting both paradigms has been reported, to identify which parameters that have been previously related with lifespan best predict the rate of aging in wild type flies cultured at different temperatures. We find that mitochondrial function and mitochondrial reactive oxygen species (mtROS) generation correlates with metabolic rate, but not with the rate of aging. Importantly, we find that activation of nutrient sensing pathways (i.e. insulin-PI3K/Target of rapamycin (Tor) pathway) correlates with lifespan, but not with metabolic rate. Our results, dissociate metabolic rate and lifespan in wild type flies and instead link nutrient sensing signaling with longevity as predicted by the hyperfunction theory.     

Role of the neuroendocrine system in aging

The study involves 3 aspects of neuroendocrine control over the organism functions in aging: the decline in reproductive functions, the reduction of growth hormone secretion and the decrease in thymic functional activity and the altered relationship between neuroendocrine and immune systems. The role that an age-related decrease in dopamine and noradrenaline production by hypothalamic neurones plays in the above age changes in neuroendocrine control has been traced. The age-related decrease in functions of hypothalamic catecholaminergic neurones is apparently caused by the damaging effect of hormones (prolactin, glucocorticoids and, especially, estrogen), free radicals and toxins, both of the endogenous and exogenous origin. The restrained nutrition increases lifespan of the experimental animal owing to reduced "wear out" of the neuroendocrine system and organs and tissues that are controlled by this system.     

Lifelong rapamycin administration ameliorates age-dependent cognitive deficits by reducing IL-1β and enhancing NMDA signaling

Understanding the factors that contribute to age-related cognitive decline is imperative, particularly as age is the major risk factor for several neurodegenerative disorders. Levels of several cytokines increase in the brain during aging, including IL-1β, whose levels positively correlate with cognitive deficits. Previous reports show that reducing the activity of the mammalian target of rapamycin (mTOR) extends lifespan in yeast, nematodes, Drosophila, and mice. It remains to be established, however, whether extending lifespan with rapamycin is accompanied by an improvement in cognitive function. In this study, we show that 18-month-old mice treated with rapamycin starting at 2 months of age perform significantly better on a task measuring spatial learning and memory compared to age-matched mice on the control diet. In contrast, rapamycin does not improve cognition when given to 15-month-old mice with pre-existing, age-dependent learning and memory deficits. We further show that the rapamycin-mediated improvement in learning and memory is associated with a decrease in IL-1β levels and an increase in NMDA signaling. This is the first evidence to show that a small molecule known to increase lifespan also ameliorates age-dependent learning and memory deficits.     

Skeletal muscle oxidative capacity in young and older women and men.

It has been suggested that a decline in skeletal muscle oxidative capacity is a general consequence of aging in humans. However, previous studies have not always controlled for the effects of varying levels of physical activity on muscle oxidative capacity. To test the hypothesis that, when matched for comparable habitual physical activity levels, there would be no age-related decline in the oxidative capacity of a locomotor muscle, the postexercise recovery time of phosphocreatine was compared in the tibialis anterior muscle of young [n = 19; 33.8 +/- 4.8 (SD) yr] and older [n = 18; 75.5 +/- 4.5 yr] healthy women and men of similar, relatively low, activity levels. The intramuscular metabolic measurements were accomplished by using phosphorus magnetic resonance spectroscopy. The results indicate that there was no age effect on the postexercise recovery time of phosphocreatine recovery, thus supporting the stated hypothesis. These data suggest that there is no requisite decline in skeletal muscle oxidative capacity with aging in humans, at least through the seventh decade.