脂肪组织氧化应激与运动干预

脂肪组织在调控代谢稳态和运动适应中扮演着重要的角色。肥胖引起的脂肪组织氧化应激是2型糖尿病与代谢综合征等的重要病理特征,是促进脂肪组织炎症和胰岛素抵抗的重要机制。氧化应激可以引起脂肪细胞趋化因子表达,募集炎症细胞浸润脂肪组织,炎症细胞分泌大量的炎症因子,并促进了局部和系统的胰岛素抵抗与慢性炎症。运动对肥胖相关的慢性代谢病的有效干预与运动的抗氧化效应相关。本文总结了氧化应激在脂肪组织炎症和胰岛素抵抗中的作用,以及运动对脂肪组织氧化应激的调控。     

热量限制对延缓衰老的作用

热量限制（caloric restriction,CR）在很多物种中能够改善健康和延缓衰老,近年来的许多研究发现,热量限制可以减少多种与年龄相关性疾病的发生,但至今热量限制延缓衰老的机制尚未十分清楚.最近有研究表明,热量限制延缓衰老的机制可能与营养调控、生殖滞育等过程有密切的关系,SIRT1、PGC-1α、AMPK、TOR等信号因子也因其在热量限制和营养调控延缓衰老的机制研究中的重要作用而受到极大的关注.     

果蝇衰老的调控机制

衰老是一个复杂的生物学过程,涉及到有害物质的积累导致整体生命功能的下降,生物的生理状况逐渐恶化,最终导致疾病和死亡。黑腹果蝇Drosophila melanogaster作为最重要的遗传学工具之一,近年来常被用于衰老的研究,以阐明衰老的发生与发展机制。本文结合本实验室的研究进展,综述了果蝇寿命调控的生理生化机制,如保幼激素、胰岛素/类胰岛素生长因子、TOR信号网络、腺苷酸活化蛋白激酶信号通路、热量限制和饮食限制、氧化应激、小分子RNA以及鞘脂类代谢都会对果蝇的寿命产生影响。除此之外,基因调控网络研究还能够发现潜在的与长寿相关的基因组区域,将有可能发现更多寿命相关基因。以果蝇为模式生物的研究,对于其他昆虫衰老、存活等种群生物学问题的研究以及天敌、益虫保育和害虫控制,具有十分重要的指导意义。     

去乙酰化酶SIRT1对氧化应激的调控

去乙酰化酶SIRT1在许多生物过程中具有重要的作用,包括氧化应激、能量代谢、细胞分化及基因组稳定等。细胞的存活及其寿命和氧化应激的存在密切相关。氧化应激可引起多种病理表现,如内皮损伤、线粒体损伤、炎症、自噬、凋亡甚至坏死等。近来研究发现,SIRT1在多种氧化应激相关疾病中保护细胞存活。SIRT1可以通过调控不同转录因子而发挥抗氧化应激作用,但研究发现,SIRT1也对氧化应激有负性调控作用。本文就SIRT1对氧化应激的调控进行概述。     

对抗衰老的营养策略:限制性饮食

限制性饮食(restriction diet, RD)是一种被重点关注且已证明有效的抗衰老干预措施,可延长寿命、延缓衰老,并能减少和防止与年龄相关疾病的发生发展。RD已从单纯的热量限制饮食扩展到多元领域,根据禁食时间、频率、营养成分、昼夜节律、介入年龄和性别等控制变量,延伸出限时饮食和限制蛋白质饮食,其可通过与热量限制饮食相似的代谢和分子适应机制达到类似的抗衰老效果并减少衰老生物标志物。mTOR、AMPK、胰岛素/IGF-1、SIRT和FGF21等关键信号通路之间相互作用构成了RD复杂的代谢调控网络。此外,热量限制模拟物作为热量限制饮食的替代方法无需机体长期控制热量摄入,同样能达到抗衰老的作用。作为一种前景较好的健康老龄化策略,可通过分析RD延长健康寿命的分子途径及RD与运动等其他生活因素的相互作用,进行规模更大、时间更长的人体研究,使用个性化饮食方案确定个体如何通过优化饮食成分、摄入量及摄入时间来达到改善健康和延长寿命的最佳效果。因此,本文总结了RD中热量限制饮食、限时饮食和限制蛋白质饮食在对抗衰老方面的作用机制,以期为RD在对抗衰老和健康促进方面的研究提供新的角度和思路。     

内脏蛋白质降低胰岛素水平而延长寿命

胰岛素含量低的蛔虫,趋向于活得更长,有一项新研究鉴定了一种蛋白质,其可解释个中缘由.低胰岛素水平加强了该蛋白质在内脏中的活性,从而因避免细胞损伤而能够延长寿命.研究者说,人类与其他哺乳类有一组类似的蛋白质,提示在人中,胰岛素也很可能影响这些蛋白质的活性.该发现可以帮助解释为什么在动物中限制热卡的饮食能延长寿命,以及为什么糖尿病会减少寿命.该蛋白质与胰岛素的关系是引人感兴趣的.然而,我们需要更多的研究才能证明这种蛋白质与胰岛素的关系对于饮食或是糖尿病能起很大作用.科学家自20世纪30年代以来就已知道,给酵母与许多动物品种喂饲严格限制的饮食时,包括喂饲比正常动物低1/3卡路里的饮食,它们比正常动物多活30%～50%.人们经常观察到这种严格限制的饮食可以改善胰岛素的敏感性.胰岛素的敏感性改善后,可引起身体少产生胰岛素.在另一个极端,2型糠尿病人的胰岛素敏感性低,故而需要产生更多的胰岛素来补偿.研究者研究了蛔虫胰岛素如何调节一种称为SKN-1的蛋白质,该蛋白质与解毒酶相结合为一个家庭来清除自由基而保护细胞—在细胞世界中,自由基的破坏作用可以缩短寿命.研究者发现胰岛素降低SKN-1活性,抑制解毒酶,从而使细胞失去较多保护.加入SKN-1额外的基因拷贝来提高SKN-1水平,可延长蛔虫的寿命达30%～50%,研究者在2008年3月21日Cell上作了报道.增加SKN1足以使寿命延长,这个事实是非常重要的研究成果.这是SKN-1确实与寿命有关的证据.去年Nature上发表一项研究表明,蛔虫头脑神经细胞中的SKN 1对于因限制热卡而延长寿命的作用是至关重要的.而新研究表明,内脏蛋白质的变种以不同的方式影响寿命——其中之一为胰岛素的调节控制作用.为什么胰岛素可以缩短动物的寿命,有一个解释,即胰岛素需要一个氧化的化学环境——即与自由基友好共处——以发挥其调节血糖的基本作用.为了消除自由基,解毒酶创建了相对的环境来减少解毒酶.故而,身体很可能以细胞稍微损伤来换取胰岛素作用的改善.哺乳类的SKN1的译本可能给研究者提供新的药靶来试图开发延长寿命的药物.     

硒蛋白S与2型糖尿病

硒是哺乳动物不可缺少的微量元素,在人体内通过硒蛋白形式发挥多种生物学功能。早期的研究证实硒具有胰岛素样作用,补硒或硒蛋白可预防和治疗2型糖尿病(type 2 diabete mellitus, T2DM)。硒蛋白S (Selenoprotein S, SelS)参与机体内质网相关降解通路、氧化应激、炎症反应,并对血糖、血脂具有调控作用;同时,SelS异常表达于T2DM患者体内,参与胰岛素抵抗,并诱发血管病变。该文综述硒蛋白S基因的表达调控、生物学作用、代谢调节,以及与T2DM相关的研究,为T2DM的治疗提供理论依据。     

节食延缓衰老的分子生物学机理

作为一种复杂的生命过程,衰老既受到自身内部基因的调控,又受到外界环境的影响。节食作为唯一一种通过改变外界环境改变衰老进程的手段,是指在不会造成营养不良的情况下,通过减少正常饮食量的20%~40%的食物限制或者是减少食物中的高热量成分来实现总摄入热量的降低。节食不仅能延长寿命(lifespan),而且能有效预防衰老相关疾病的发生,从而延长健康寿命(healthspan)。节食的分子机理在模式动物线虫、果蝇和小鼠中都得到了很好的阐释,在此将对节食延缓衰老的分子机理进行总结,并对近些年来发现的可以模拟节食对衰老推迟作用的小分子化合物的作用机理进行阐释。     

热量限制延缓衰老的自噬与表观遗传修饰交互关系

衰老是多因素作用下的组织、器官功能性衰退进程。自噬是真核细胞溶酶体介导而降解细胞质成分的过程,参与衰老及相关的各种生理病理过程。环境因素所致衰老则大多数伴随着表观遗传修饰的改变。热量限制被认为是调节衰老、延长寿命的干预措施。本综述围绕自噬与表观遗传修饰,阐述了热量限制引发自噬、通过表观遗传修饰延缓衰老的分子机制,以及两者在热量限制中的交互作用。以期为衰老与延缓衰老的机制研究提供新思路。     

《自然-通讯》:研究表明节食或通过影响肠道菌群促进健康

<正>日前,上海交通大学赵立平团队与中科院上海生命科学研究院营养科学研究所刘勇团队、国家人类基因组南方中心赵国屏团队合作,发现热量限制能促进肠道益菌的生长,从而令小鼠增加寿命。该研究表明,节食或许通过造成一个更健康的菌群来促进宿主健康,相关研究论文发表在《自然-通讯》上。通过减少食物摄入量,从而限制热量摄入在很多动物模型中被证明能够有效延缓衰老和延长寿命。虽然很难在人群中开展全生命周期的节食实验,但以人为对象的短期实验同样证明,不造成营养不良的节食干预对健康有益。关于节食的作用机理,科学家已经进行了大量研究,提出了各种假说、找出了一些相关的基因及调控通路,但是仍然还有许多未知环节需要继续深入研究。     

Calorie restriction delays lipid oxidative damage in Drosophila melanogaster

The oxidative stress hypothesis predicts that the accumulation of oxidative damage to a variety of macromolecules is the molecular trigger driving the process of aging. Although an inverse relationship between oxidative damage and lifespan has been established in several different species, the precise relationship between oxidative damage and aging is not fully understood. Drosophila melanogaster is a favored model organism for aging research. Environmental interventions such as ambient temperature and calorie restriction can alter adult lifespan to provide an excellent system to examine the relationship between oxidative damage, aging and lifespan. We have developed an enzyme-linked immunosorbent assay (ELISA) using commercially available reagents for measuring 4-hydroxy-2-nonenal (HNE) in proteins, a marker for oxidative damage to lipids, and present data in flies to show that HNE adducts accumulate in an age-dependent manner. With immunohistology, we also find the primary site of HNE accumulation is the pericerebral fat body, where induction of dFOXO was recently shown to retard aging. When subjected to environmental interventions that shorten lifespan, such as elevated ambient temperature, the chronological accumulation of HNE adduct is accelerated. Conversely, interventions that extend lifespan, such as lower ambient temperature or low calorie diets, slow the accumulation of HNE adduct. These studies associate damage from lipid peroxidation with aging and lifespan in Drosophila and show that calorie restriction in flies, as in mammals, slows the accumulation of lipid related oxidative damage.     

Longevity genes: insights from calorie restriction and genetic longevity models

In this review, we discuss the genes and the related signal pathways that regulate aging and longevity by reviewing recent findings of genetic longevity models in rodents in reference to findings with lower organisms. We also paid special attention to the genes and signals mediating the effects of calorie restriction (CR), a powerful intervention that slows the aging process and extends the lifespan in a range of organisms. An evolutionary view emphasizes the roles of nutrient-sensing and neuroendocrine adaptation to food shortage as the mechanisms underlying the effects of CR. Genetic and non-genetic interventions without CR suggest a role for single or combined hormonal signals that partly mediate the effect of CR. Longevity genes fall into two categories, genes relevant to nutrient-sensing systems and those associated with mitochondrial function or redox regulation. In mammals, disrupted or reduced growth hormone (GH)-insulin-like growth factor (IGF)-1 signaling robustly favors longevity. CR also suppresses the GH-IGF-1 axis, indicating the importance of this signal pathway. Surprisingly, there are very few longevity models to evaluate the enhanced anti-oxidative mechanism, while there is substantial evidence supporting the oxidative stress and damage theory of aging. Either increased or reduced mitochondrial function may extend the lifespan. The role of redox regulation and mitochondrial function in CR remains to be elucidated.     

Neuroendocrine and immune characteristics of aging in avian species

Avian species show a remarkable diversity in lifespan. The differing lifespan patterns are found across a number of birds, in spite of higher body temperature and apparent increased metabolic rate. These characteristics make study of age-related changes of great interest, especially for understanding the biology of aging associated with surprisingly long lifespan in some birds. Our studies have focused on a short-lived avian model, the Japanese quail in order to describe reproductive aging and the neuroendocrine characteristics leading to reproductive senescence. Biomarkers of aging used in mammalian species include telomere length, oxidative damage, and selected metabolic indicators. These markers provide confirming evidence that the long-lived birds appear to age more slowly. A corollary area of interest is that of immune function and aging. Immune responses have been studied in selected wild birds and there has been a range of studies that have considered the effects of stress in wild and domestic species. Our laboratory studies have specifically tested response to immune challenge relative to aging in the quail model and these studies indicate that there is an age-related change in the qualitative aspects of the response. However, there are also intriguing differences in the ability of the aging quail to respond that differ from mammalian data. Finally, another approach to understanding aging is to attempt to develop or test strategies that may extend lifespan and presumably health. One area of great interest has been to consider the effect of calorie restriction, which is a treatment shown to extend lifespan in a variety of species. This approach is routinely used in domestic poultry as a means for extending reproductive function and enhancing health. Our data indicate that moderate calorie restriction has beneficial effects, and that physiological and endocrine responses reflect these benefits.     

Sirtuin regulation in calorie restriction

The beneficial effects of calorie restriction diet in extending lifespan and preventing diseases have long been recognized. Recent genetic and molecular studies in model organisms began to uncover the molecular regulation of calorie restriction response, with the gene SIR2 playing an essential role. This article summarizes the latest development on how mammalian SIR2 homologs coordinately regulate the calorie restriction response.     

Effect of exercise and calorie restriction on biomarkers of aging in mice

Unlike calorie restriction, exercise fails to extend maximum life span, but the mechanisms that explain this disparate effect are unknown. We used a 24-wk protocol of treadmill running, weight matching, and pair feeding to compare the effects of exercise and calorie restriction on biomarkers related to aging. This study consisted of young controls, an ad libitum-fed sedentary group, two groups that were weight matched by exercise or 9% calorie restriction, and two groups that were weight matched by 9% calorie restriction + exercise or 18% calorie restriction. After 24 wk, ad libitum-fed sedentary mice were the heaviest and fattest. When weight-matched groups were compared, mice that exercised were leaner than calorie-restricted mice. Ad libitum-fed exercise mice tended to have lower serum IGF-1 than fully-fed controls, but no difference in fasting insulin. Mice that underwent 9% calorie restriction or 9% calorie restriction + exercise, had lower insulin levels; the lowest concentrations of serum insulin and IGF-1 were observed in 18% calorie-restricted mice. Exercise resulted in elevated levels of tissue heat shock proteins, but did not accelerate the accumulation of oxidative damage. Thus, failure of exercise to slow aging in previous studies is not likely the result of increased accrual of oxidative damage and may instead be due to an inability to fully mimic the hormonal and/or metabolic response to calorie restriction.     

Could glucose be a proaging factor?

There is an ever-increasing scientific interest for the interplay between cell's environment and the aging process. Although it is known that calorie restriction affects longevity, the exact molecular mechanisms through which nutrients influence various cell signalling/modulators of lifespan remain a largely unresolved issue. Among nutrients, glucose constitutes an evolutionarily stable, precious metabolic fuel, which is catabolized through glycolytic pathway providing energy in the form of ATP and consuming NAD. Accumulating evidence shows that among the important regulators of aging process are autophagy, sirtuin activity and oxidative stress. In light of recent work indicating that glucose availability decreases lifespan whilst impaired glucose metabolism extends life expectancy, the present article deals with the potential role of glucose in the aging process by regulating - directly through its metabolism or indirectly through insulin secretion - autophagy, sirtuins as well as other modulators of aging like oxidative stress and advanced glycation end-products (AGEs).     

Reducing sphingolipid synthesis orchestrates global changes to extend yeast lifespan

Studies of aging and longevity are revealing how diseases that shorten life can be controlled to improve the quality of life and lifespan itself. Two strategies under intense study to accomplish these goals are rapamycin treatment and calorie restriction. New strategies are being discovered including one that uses low‐dose myriocin treatment. Myriocin inhibits the first enzyme in sphingolipid synthesis in all eukaryotes, and we showed recently that low‐dose myriocin treatment increases yeast lifespan at least in part by down‐regulating the sphingolipid‐controlled Pkh1/2‐Sch9 (ortholog of mammalian S6 kinase) signaling pathway. Here we show that myriocin treatment induces global effects and changes expression of approximately forty percent of the yeast genome with 1252 genes up‐regulated and 1497 down‐regulated (P < 0.05) compared with untreated cells. These changes are due to modulation of evolutionarily conserved signaling pathways including activation of the Snf1/AMPK pathway and down‐regulation of the protein kinase A (PKA) and target of rapamycin complex 1 (TORC1) pathways. Many processes that enhance lifespan are regulated by these pathways in response to myriocin treatment including respiration, carbon metabolism, stress resistance, protein synthesis, and autophagy. These extensive effects of myriocin match those of rapamycin and calorie restriction. Our studies in yeast together with other studies in mammals reveal the potential of myriocin or related compounds to lower the incidence of age‐related diseases in humans and improve health span.