Axenic growth up-regulates mass-specific metabolic rate,stress resistance,and extends life span in Caenorhabditis elegans

Culture in axenic medium causes two-fold increases in the length of development and adult life span in Caenorhabditis elegans. We asked whether axenic medium imposes dietary restriction (ADR), and causes changes in metabolic activity and stress resistance. Eat mutants, which have a reduced food intake, were studied in parallel with wild-type worms to assess potential synergistic actions of axenic culture and food restriction. We found that axenic culture enhances metabolic activity as assessed by mass-specific oxygen consumption rate and heat production. Axenic culture also caused higher activities of the antioxidant enzymes superoxide dismutase and catalase, and led to increased resistance to high temperature, which was further exacerbated by mutation in eat-2. These results show that axenic medium up-regulates a variety of somatic maintenance functions including oxidative and thermal stress resistance and that food restriction due to axenic growth and to mutation in eat-2 are very similar but not identical.     

Caenorhabditis elegans 2007: the premier model for the study of aging

This is the 25th anniversary of the discovery of extended longevity mutants in Caenorhabditis elegans. About one hundred papers describing results from studies on C. elegans in aging research appeared this year. Many themes were pursued including dietary restriction, daf-9 action, the role of proteolysis and autophagy, and the continued search for more Age mutants. I use the word "modulate" not "regulate" so as to be consistent with the evolutionary theory of aging, which is also consistent with the empirical findings of all extended longevity (Age) mutants. These Age mutants universally result from deficits in known physiologic systems, rather than in some process designed to kill the animal in old age.     

Genetic and environmental conditions that increase longevity in Caenorhabditis elegans decrease metabolic rate

Mutations that increase the longevity of the soil nematode Caenorhabditis elegans could define genes involved in a process specific for aging. Alternatively, these mutations could reduce animal metabolic rate and increase longevity as a consequence. In ectotherms, longevity is often negatively correlated with metabolic rate. Consistent with these observations, environmental conditions that reduce the metabolic rate of C. elegans also extend longevity. We found that the metabolic rate of long-lived C. elegans mutants is reduced compared with that of wild-type worms and that a genetic suppressor that restored normal longevity to long-lived mutants restored normal metabolic rate. Thus, the increased longevity of some long-lived C. elegans mutants may be a consequence of a reduction in their metabolic rate, rather than an alteration of a genetic pathway that leads to enhanced longevity while maintaining normal physiology. The actual mechanism responsible for the inverse correlation between metabolic rate and longevity remains unknown.     

Relationship between increased longevity and stress resistance as assessed through gerontogene mutations in Caenorhabditis elegans.

We review the status of the hypothesis that interventions that increase the resistance to stress offer the potential for effective life prolongation and increased health. The work focuses on research in the nematode worm Caenorhabditis elegans and describes both published and unpublished results consistent with this hypothesis. Correlations between stress resistance and longevity among many gerontogene mutants is provided.     

Fertility/longevity trade-offs under limiting-male conditions in mating populations of Caenorhabditis elegans

Evolutionary theories of aging suggest that trade-offs between longevity and fitness should be found under certain conditions. In C. elegans, there is little evidence for the existence of such trade-offs. We asked if fertility/longevity trade-offs exist in populations of randomly mating males and hermaphrodites. We set up a large population of young males and 5-day-old hermaphrodites that were no longer self-fertile. We then allowed them to mate for one day with an equal number young males and then separated hermaphrodites to individual plates and determined daily fertility of individual hermaphrodites. There was a significant negative relationship between late-life fertility and individual longevity.     

淫羊藿苷延长秀丽线虫寿命与机制

目的探讨淫羊藿苷（Icariin,Ica）对秀丽线虫寿命的干预效果与机制,为筛选延缓衰老、延长寿命的药物提供实验依据。方法将秀丽线虫分为空白对照组、Ica5mg／L、10mg／L、15mg／L、20mg／L各剂量干预实验组,观察在Ica不同梯度剂量作用下秀丽线虫寿命的变化,以明确Ica作用的最佳剂量。接着设立秀丽线虫空白对照组和Ica（15mg／L）干预组,评价Ica对秀丽线虫平均寿命、生殖能力的干预效果;同时进行急性热应激和急性氧化应激实验,观察应激时线虫的平均生存时间,探讨Ica延长线虫寿命的机制。结果15mg／L的Ica是延长秀丽线虫寿命的最佳剂量。Ica组线虫的平均寿命明显长于空白对照组[（31．87±4．46）d vs．（20．13±2．81）d]（P〈0．01）;Ica组线虫生殖高峰期子代数目比空白对照组显著增加（151±21．13VS．122±17．09,P〈O．01）;急性热应激实验和急性氧化应激实验发现Ica组线虫平均生存时间均明显长于空白对照组[（9．53±1．34）hVS．（5．97±0．84）h,（8．34±1．17）hvs.（5．77±O．81）h]（P〈0．01）。结论淫羊藿苷能延长秀丽线虫的寿命,其机制可能与淫羊藿苷提高线虫的应激能力有关。     

The longevity effect of cranberry extract in Caenorhabditis elegans is modulated by daf-16 and osr-1

Nutraceuticals are known to have numerous health and disease preventing properties. Recent studies suggest that extracts containing cranberry may have anti-aging benefits. However, little is known about whether and how cranberry by itself promotes longevity and healthspan in any organism. Here we examined the effect of a cranberry only extract on lifespan and healthspan in Caenorhabditis elegans. Supplementation of the diet with cranberry extract (CBE) increased the lifespan in C. elegans in a concentration-dependent manner. Cranberry also increased tolerance of C. elegans to heat shock, but not to oxidative stress or ultraviolet irradiation. In addition, we tested the effect of cranberry on brood size and motility and found that cranberry did not influence these behaviors. Our mechanistic studies indicated that lifespan extension induced by CBE requires the insulin/IGF signaling pathway and DAF-16. We also found that cranberry promotes longevity through osmotic stress resistant-1 (OSR-1) and one of its downstream effectors, UNC-43, but not through SEK-1, a component of the p38 MAP kinase pathway. However, SIR-2.1 and JNK signaling pathways are not required for cranberry to promote longevity. Our findings suggest that cranberry supplementation confers increased longevity and stress resistance in C. elegans through pathways modulated by daf-16 and osr-1. This study reveals the anti-aging property of widely consumed cranberry and elucidates the underpinning mechanisms.     

Two size-selective mechanisms specifically trap bacteria-sized food particles in Caenorhabditis elegans

Caenorhabditis elegans is a filter feeder: it draws bacteria suspended in liquid into its pharynx, traps the bacteria, and ejects the liquid. How pharyngeal pumping simultaneously transports and filters food particles has been poorly understood. Here, we use high-speed video microscopy to define the detailed workings of pharyngeal mechanics. The buccal cavity and metastomal flaps regulate the flow of dense bacterial suspensions and exclude excessively large particles from entering the pharynx. A complex sequence of contractions and relaxations transports food particles in two successive trap stages before passage into the terminal bulb and intestine. Filtering occurs at each trap as bacteria are concentrated in the central lumen while fluids are expelled radially through three apical channels. Experiments with microspheres show that the C. elegans pharynx, in combination with the buccal cavity, is tuned to specifically catch and transport particles of a size range corresponding to most soil bacteria.     

衰老内分泌学：老龄社会内分泌学的重要分支

衰老内分泌学或老年内分泌学是老龄社会新兴的一门内分泌学，研究衰老时各项内分泌激素及疾病的改变及关系。目前初步探明了一些激素水平的变化，但有许多尚不清楚。不少人试图用激素替代方法来延缓衰老或减轻症状，但并不很成功，且近期和远期效果不一，故尚有许多问题值得探讨和进一步研究。     

Lifespan extension of Caenorhabditis elegans following repeated mild hormetic heat treatments

Mild hormetic heat treatments early in life can significantly increase the lifespan of the nematode C. elegans. We have examined the effects of heat treatments at different ages and show that treatments early in life cause the largest increases in lifespan. We also find that repeated mild heat treatments throughout life have a larger effect on lifespan compared to a single mild heat treatment early in life. We hypothesize that the magnitude of the hormetic effect is related to the levels of heat shock protein expression. Following heat treatment young worms show a dramatic increase in the levels of the small heat shock protein HSP-16 whereas old worms are a 100-fold less responsive. The levels of the heat shock proteins HSP-4 and HSP-16 correlate well with the effects on lifespan by the hormetic treatments.     

富含亮氨酸重复序列的G蛋白偶联受体4基因缺陷导致寿命缩短和多器官组织衰老

目的:研究富含亮氨酸重复序列的G蛋白偶联受体4(LGR4)基因缺失对小鼠寿命以及衰老相关表型的影响。方法:在正常繁殖、饲养状态下,观察LGR4基因敲除小鼠与衰老相关的表型,并记录每只小鼠的出生时间和死亡时间,比较LGR4基因敲除小鼠与正常小鼠的自然寿命差异;此外,收集2组老年小鼠的不同组织(如皮肤、眼睛、肺脏、肝脏、脾脏等),进行病理切片和苏木精-伊红(HE)染色,观察各组织形态学改变。结果:LGR4基因敲除小鼠中位生存期为17.25个月,野生型小鼠中位生存期为22.75个月,2组生存率存在明显差异(P20个月的2组小鼠生存率并无统计学差异。组织学结果提示,老龄LGR4基因敲除小鼠的皮肤出现明显的结构异常,包括角质层不平整、毛囊稀少、皮下脂肪层变薄、血管减少。结论:LGR4基因缺失缩短小鼠的全程寿命,但并不影响老龄小鼠的生存率。     

Folic acid supplementation at lower doses increases oxidative stress resistance and longevity in Caenorhabditis elegans

Folic acid (FA) is an essential nutrient that the human body needs but cannot be synthesized on its own. Fortified foods and plant food sources such as green leafy vegetables, beans, fruits, and juices are good sources of FA to meet the daily requirements of the body. The aim was to evaluate the effect of dietary FA levels on the longevity of well-known experimental aging model Caenorhabditis elegans. Here, we show for first time that FA extends organism life span and causes a delay in aging. We observed that FA inhibits mechanistic target of rapamycin (mTOR) and insulin/insulin growth factor 1 (IGF-1) signaling pathways to control both oxidative stress levels and life span. The expression levels of stress- and life span-relevant gerontogenes, viz. daf-16, skn-1, and sir. 2.1, and oxidative enzymes, such as glutathione S-transferase 4 (GST-4) and superoxide dismutase 3 (SOD-3), were also found to be highly enhanced to attenuate the intracellular reactive oxygen species (ROS) damage and to delay the aging process. Our study promotes the use of FA to mitigate abiotic stresses and other aging-related ailments.     

Modulation of longevity and diapause by redox regulation mechanisms under the insulin-like signaling control in Caenorhabditis elegans

In Caenorhabditis elegans, the downregulation of insulin-like signaling induces lifespan extension (Age) and the constitutive formation of dauer larvae (Daf-c). This also causes resistance to oxidative stress (Oxr) and other stress stimuli and enhances the expression of many stress-defense-related enzymes such as Mn superoxide dismutase (SOD) that functions to remove reactive oxygen species in mitochondria. To elucidate the roles of the two isoforms of MnSOD, SOD-2 and SOD-3, in the Age, Daf-c and Oxr phenotypes, we investigated the effects of a gene knockout of MnSODs on them in the daf-2 (insulin-like receptor) mutants that lower insulin-like signaling. In our current report, we demonstrate that double deletions of two MnSOD genes induce oxidative-stress sensitivity and thus ablate Oxr, but do not abolish Age in the daf-2 mutant background. This indicates that Oxr is not the underlying cause of Age and that oxidative stress is not necessarily a limiting factor for longevity. Interestingly, deletions in the sod-2 and sod-3 genes suppressed and stimulated, respectively, both Age and Daf-c. In addition, the sod-2/sod-3 double deletions stimulated these phenotypes in a similar manner to the sod-3 deletion, suggesting that the regulatory pathway consists of two MnSOD isoforms. Furthermore, hyperoxic and hypoxic conditions affected Daf-c in the MnSOD-deleted daf-2 mutants. We thus conclude that the MnSOD systems in C. elegans fine-tune the insulin-like-signaling based regulation of both longevity and dauer formation by acting not as antioxidants but as physiological-redox-signaling modulators.     

Association of exceptional parental longevity and physical function in aging

Offspring of parents with exceptional longevity (OPEL), who are more likely to carry longevity-associated genotypes, may age more successfully than offspring of parents with usual survival (OPUS). Maintenance of physical function is a key attribute of successful aging. While many genetic and non-genetic factors interact to determine physical phenotype in aging, examination of the contribution of exceptional parental longevity to physical function in aging is limited. The LonGenity study recruited a relatively genetically homogenous cohort of Ashkenazi Jewish (AJ) adults age 65 and older, who were defined as either OPEL (having at least one parent who lived to age 95 or older) or OPUS (neither parent survived to age 95). Subjective and objective measures of physical function were compared between the two groups, accounting for potential confounders. Of the 893 LonGenity subjects, 365 were OPEL and 528 were OPUS. OPEL had better objective and subjective measures of physical function than OPUS, especially on unipedal stance (p = 0.009) and gait speed (p = 0.002). Results support the protective role of exceptional parental longevity in preventing decline in physical function, possibly via genetic mechanisms that should be further explored.     

Effect of calorie restriction on the metabolic history of chronologically aging yeast

Aging is a highly complex, multifactorial process. We use the yeast Saccharomyces cerevisiae as a model to study the mechanisms of cellular aging in multicellular eukaryotes. To address the inherent complexity of aging from a systems perspective and to build an integrative model of aging process, we investigated the effect of calorie restriction (CR), a low-calorie dietary regimen, on the metabolic history of chronologically aging yeast. We examined how CR influences the age-related dynamics of changes in the intracellular levels of numerous proteins and metabolites, carbohydrate and lipid metabolism, interorganellar metabolic flow, concentration of reactive oxygen species, mitochondrial morphology, essential oxidation–reduction processes in mitochondria, mitochondrial proteome, cardiolipin in the inner mitochondrial membrane, frequency of mitochondrial DNA mutations, dynamics of mitochondrial nucleoid, susceptibility to mitochondria-controlled apoptosis, and stress resistance. Based on the comparison of the metabolic histories of long-lived CR yeast and short-lived non-CR yeast, we propose that yeast define their long-term viability by designing a diet-specific pattern of metabolism and organelle dynamics prior to reproductive maturation. Thus, our data suggest that longevity in chronologically aging yeast is programmed by the level of metabolic capacity and organelle organization they developed, in a diet-specific fashion, prior to entry into a non-proliferative state.     

Coevolution of exceptional longevity, exceptionally high metabolic rates, and mitochondrial DNA-coded proteins in mammals

Mammals' longevity is inversely related to mass-specific basal metabolic rate because the generation of reactive oxygen species constrains lifespan. Longevity increases with body mass because the latter is inversely related to mass-specific basal metabolic rates. In placental mammals the longevity residuals from the power laws that describe longevity as a function of mass-specific basal metabolic rates, or body mass, are positively correlated with the relative rates of evolution of cytochrome b, a generator of reactive oxygen species. Therefore, longevity is more accurately described as a function of both mass-specific basal metabolic rate and the relative rate of cytochrome b evolution. The longevity residuals from the power law that describe longevity as a function of body mass are positively correlated with the relative rate of evolution of most other mtDNA-coded proteins. In taxa with very high rate of cytochrome b evolution exceptional longevity is associated with an increase, rather than the predicted decrease, of basal metabolic rates. These finding are compatible with the hypothesis that, in placental mammals, the accelerated evolution of mtDNA-coded proteins, allowed the extension of lifespan by selecting mutations that reduce the generation of reactive oxygen species, mostly by increasing internal proton leak, that accelerates mitochondrial electron transport.     

Adaptive evolution in the SRZ chemoreceptor families of Caenorhabditis elegans and Caenorhabditis briggsae

We investigated the possibility of positive selection acting on members of the putative seven-pass chemoreceptor superfamily in Caenorhabditis elegans, which comprises approximately 1,300 genes encoding seven-pass G protein-coupled receptors (GPCRs). Using a maximum-likelihood approach, we conducted statistical tests for evidence of codon sites where the ratio of nonsynonymous substitutions per nonsynonymous site to synonymous substitutions per synonymous site (d(N)/d(S)) was >1. Evidence for positive selection was found only for the srz family, about which virtually nothing specific is known. We extended the annotation of the srz gene family, establishing gene models for 60 srz genes in C. elegans and 28 srz genes in Caenorhabditis briggsae. d(N)/d(S) ratios varied dramatically in different regions of the SRZ proteins, peaking in predicted extracellular regions. These regions included 23 sites where evidence of positive selection was highly significant, corresponding remarkably well with regions implicated in ligand binding in other GPCR family members. We interpret these results as indicating that the srz family is under positive selection, probably driven by ligand binding.