Dietary antiaging phytochemicals and mechanisms associated with prolonged survival

Aging is well-known an inevitable process that is influenced by genetic, lifestyle and environmental factors. However, the exact mechanisms underlying the aging process are not well understood. Increasing evidence shows that aging is highly associated with chronic increase in reactive oxygen species (ROS), accumulation of a low-grade proinflammatory phenotype and reduction in age-related autophagy, suggesting that these factors may play important roles in promoting aging. Indeed, reduction of ROS and low-grade inflammation and promotion of autophagy by calorie restriction or other dietary manipulation can extend lifespan in a wide spectrum of model organisms. Interestingly, recent studies show that some food-derived small molecules, also called phytochemicals, can extend lifespan in various animal species. In this paper, we review several recently identified potential antiaging phytochemicals that have been studied in cells, animals and humans and further highlight the cellular and molecular mechanisms underlying the antiaging actions by these molecules.     

Aging and Reproduction: Comparative Endocrinology of the Common Tern and Japanese Quail

SYNOPSIS. The endocrinology of reproductive aging in avian specieshas been described primarily in captive domestic birds, suchas the Japanese quail (Coturnix japonica), which show majorchanges in hormones and reproductive performance. To explorereproductive aging in longer-lived avian species, longitudinalstudies are being conducted on the Common Tern (Sterna hirundo)in which age-related changes in nesting patterns and clutchsize have been monitored. However, little information is availablerelevant to endocrine status of breeding pairs of Common Terns.This review summarizes information pertinent to the breedingbiology and endocrine status of the Common Tern during reproductiveaging and compares these findings to data available from theJapanese quail. Fundamental mechanisms in the process of agingin avian species may become apparent in the comparison of thesedata and data from field species.     

热量限制延长寿命的分子机制

很多研究均发现,热量限制在很多物种中都有延长寿命的作用.这些报道认为,寿命的延长可 能与氧化应激和炎症过程有关.值得注意的是,热量限制调节氧化应激与脂质代谢调控、抑 制细胞凋亡、DNA保护等分子过程有密切关系.最近,有研究者表明,热量限制调控氧化应激和炎症过程是通过胰岛素/胰岛素样生长因子信号通路起作用的.热量限制在所有的动物模型实验中都显示延长寿命,然而,在人类中应用热量限制,可能还存在很多对人体健康问题值得关注.本文就热量限制如何调控寿命的机制的研究进展作一综述.     

Calorie restriction and aging in nonhuman primates

In the 75 years since the seminal observation of Clive McCay that restriction of calorie intake extends the lifespan of rats, a great deal has been learned about the effects of calorie restriction (CR; reduced intake of a nutritious diet) on aging in various short-lived animal models. Studies have demonstrated many beneficial effects of CR on health, the rate of aging, and longevity. Two prospective investigations of the effects of CR on long-lived nonhuman primate (NHP) species began nearly 25 years ago and are still under way. This review presents the design, methods, and main findings of these and other important contributing studies, which have generally revealed beneficial effects of CR on physiological function and the retardation of disease consistent with studies in other species. Specifically, prolonged CR appears to extend the lifespan of rhesus monkeys, which exhibited lower body fat; slower rate of muscle loss with age; lower incidence of neoplasia, cardiovascular disease, type 2 diabetes mellitus, and endometriosis; improved insulin sensitivity and glucose tolerance; and no apparent adverse effect on bone health, as well as a reduction in total energy expenditure. In addition, there are no reports of deleterious effects of CR on reproductive endpoints, and brain morphology is preserved by CR. Adrenal and thyroid hormone profiles are inconsistently affected. More research is needed to delineate the mechanisms of the desirable outcomes of CR and to develop interventions that can produce similar beneficial outcomes for humans. This research offers tremendous potential for producing novel insights into aging and risk of disease.     

Mice as a mammalian model for research on the genetics of aging

Mice are an ideal mammalian model for studying the genetics of aging: considerable resources are available, the generation time is short, and the environment can be easily controlled, an important consideration when performing mapping studies to identify genes that influence lifespan and age-related diseases. In this review we highlight some salient contributions of the mouse in aging research: lifespan intervention studies in the Interventions Testing Program of the National Institute on Aging; identification of the genetic underpinnings of the effects of calorie restriction on lifespan; the Aging Phenome Project at the Jackson Laboratory, which has submitted multiple large, freely available phenotyping datasets to the Mouse Phenome Database; insights from spontaneous and engineered mouse mutants; and complex traits analyses identifying quantitative trait loci that affect lifespan. We also show that genomewide association peaks for lifespan in humans and lifespan quantitative loci for mice map to homologous locations in the genome. Thus, the vast bioinformatic and genetic resources of the mouse can be used to screen candidate genes identified in both mouse and human mapping studies, followed by functional testing, often not possible in humans, to determine their influence on aging.     

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.     

Dietary restriction alters demographic but not behavioral aging in Drosophila

Dietary restriction extends lifespan substantially in numerous species including Drosophila. However, it is unclear whether dietary restriction in flies impacts age-related functional declines in conjunction with its effects on lifespan. Here, we address this issue by assessing the effect of dietary restriction on lifespan and behavioral senescence in two wild-type strains, in our standard white laboratory stock, and in short-lived flies with reduced expression of superoxide dismutase 2. As expected, dietary restriction extended lifespan in all of these strains. The effect of dietary restriction on lifespan varied with genetic background, ranging from 40 to 90% extension of median lifespan in the seven strains tested. Interestingly, despite its robust positive effects on lifespan, dietary restriction had no substantive effects on senescence of behavior in any of the strains in our studies. Our results suggest that dietary restriction does not have a global impact on aging in Drosophila and support the hypothesis that lifespan and behavioral senescence are not driven by identical mechanisms.     

Are farm-reared quails for game restocking really common quails (Coturnix coturnix)?: a genetic approach

The common quail (Coturnix coturnix) is a popular game species for which restocking with farm-reared individuals is a common practice. In some areas, the number of released quails greatly surpasses the number of wild breeding common quail. However, common quail are difficult to raise in captivity and this casts suspicion about a possible hybrid origin of the farmed individuals from crosses with domestic Japanese quail (C. japonica). In this study we used a panel of autosomal microsatellite markers to characterize the genetic origin of quails reared for hunting purposes in game farms in Spain and of quails from an experimental game farm which was founded with hybrids that have been systematically backcrossed with wild common quails. The genotypes of these quail were compared to those of wild common quail and domestic strains of Japanese quail. Our results show that more than 85% of the game farm birds were not common quail but had domestic Japanese quail ancestry. In the experimental farm a larger proportion of individuals could not be clearly separated from pure common quails. We conclude that the majority of quail sold for restocking purposes were not common quail. Genetic monitoring of individuals raised for restocking is indispensable as the massive release of farm-reared hybrids could represent a severe threat for the long term survival of the native species.     

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.     

Negligible senescence in the longest living rodent,the naked mole-rat: insights from a successfully aging species

Aging refers to a gradual deterioration in function that, over time, leads to increased mortality risk, and declining fertility. This pervasive process occurs in almost all organisms, although some long-lived trees and cold water inhabitants reportedly show insignificant aging. Negligible senescence is characterized by attenuated age-related change in reproductive and physiological functions, as well as no observable age-related gradual increase in mortality rate. It was questioned whether the longest living rodent, the naked mole-rat, met these three strict criteria. Naked mole-rats live in captivity for more than 28.3 years, ∼9 times longer than similar-sized mice. They maintain body composition from 2 to 24 years, and show only slight age-related changes in all physiological and morphological characteristics studied to date. Surprisingly breeding females show no decline in fertility even when well into their third decade of life. Moreover, these animals have never been observed to develop any spontaneous neoplasm. As such they do not show the typical age-associated acceleration in mortality risk that characterizes every other known mammalian species and may therefore be the first reported mammal showing negligible senescence over the majority of their long lifespan. Clearly physiological and biochemical processes in this species have evolved to dramatically extend healthy lifespan. The challenge that lies ahead is to understand what these mechanisms are.     

Yeast as a model to understand the interaction between genotype and the response to calorie restriction

Calorie restriction is reported to enhance survival and delay the onset of age-related decline in many different species. Several proteins have been proposed to play a role in mediating the response to calorie restriction, including the target of rapamycin kinase, sirtuins, and AMP kinase. An enhanced mechanistic understanding of calorie restriction has popularized the concept of "calorie restriction mimetics", drugs that mimic the beneficial effects of caloire restriction without requiring a reduction in nutrient intake. In theory, such drugs should delay the onset and progression of multiple age-related diseases, similar to calorie restriction in mammals. Despite the potential benefits of such calorie restriction mimetics, however, relatively little is known about the interaction between genetic variation and individual response to calorie restriction. Limited evidence from model systems indicates that genotype plays a large role in determining both the magnitude and direction of effect that calorie restriction has on longevity. Here we present an overview of these data from the perspective of using yeast as a model to study aging and describe an approach we are taking to further characterize the molecular mechanisms underlying genotype-dependent responses to calorie restriction.     

Lack of introgression of Japanese quail in a captive population of common quail

Farm-reared quails are released to the wild in Europe in vast numbers every year to increase hunting bag quotas. Experimental studies indicate that rather than the native common quail (Coturnix coturnix), the restocking is often done with domestic Japanese quail (Coturnix japonica) or with hybrids of domestic Japanese quail and common quail. Such practices are thought to be a severe threat for the native species as it could lead to introgression of domestic Japanese quail alleles into the wild common quail genome and potentially alter the migratory and reproductive behaviour in wild populations. In this study, we assessed the genetic purity of a captive population of common quail that was established from wild-caught founders caught on the Southern Italian coast in Sicily (Italy). We evaluated the proportion of ancestry to common and Japanese quail in this captive population via genetic screening using nuclear microsatellite markers and mitochondrial DNA analyses. We showed that the captive farm quail in our study had no sign of admixture with domestic Japanese quail and had similar genotype frequencies relative to wild common quail, confirming the success of the breeding programme for the native species. We propose that raising common quails in captivity for restocking purposes rather than domestic Japanese quails or hybrids would be a feasible alternative that could minimise the risk of genetic pollution of wild common quail populations.     

Nicotinamide riboside promotes Sir2 silencing and extends lifespan via Nrk and Urh1/Pnp1/Meu1 pathways to NAD+

Although NAD(+) biosynthesis is required for Sir2 functions and replicative lifespan in yeast, alterations in NAD(+) precursors have been reported to accelerate aging but not to extend lifespan. In eukaryotes, nicotinamide riboside is a newly discovered NAD(+) precursor that is converted to nicotinamide mononucleotide by specific nicotinamide riboside kinases, Nrk1 and Nrk2. In this study, we discovered that exogenous nicotinamide riboside promotes Sir2-dependent repression of recombination, improves gene silencing, and extends lifespan without calorie restriction. The mechanism of action of nicotinamide riboside is totally dependent on increased net NAD(+) synthesis through two pathways, the Nrk1 pathway and the Urh1/Pnp1/Meu1 pathway, which is Nrk1 independent. Additionally, the two nicotinamide riboside salvage pathways contribute to NAD(+) metabolism in the absence of nicotinamide-riboside supplementation. Thus, like calorie restriction in the mouse, nicotinamide riboside elevates NAD(+) and increases Sir2 function.     

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.     

Dietary calorie restriction,DNA-repair and brain aging

It is now well established, in many species, that dietary calorie restriction confers beneficial effects like slowing down many age dependent processes and extending the lifespan. There are indications that this phenomenon may be applicable even in non-human primates and humans. However the precise mechanism through which these effects are achieved is not known. Since decreasing DNA repair has been correlated with increasing age, information available on the effect of dietary calorie restriction on DNA repair potential in different species, including humans, is reviewed with special emphasis on brain in view of its uniqueness and the age related appearance of several neurodegenerative disorders. There is considerable evidence to indicate that calorie restriction reduces the rate of, among other things, the age dependent decrease in DNA repair potential thus leading to a better maintenance of genomic integrity. In brain also dietary calorie restriction is found to improve the activities of some enzymes supposedly involved in DNA repair. It is suggested that one of the lifespan extending mechanisms of calorie restriction may be to channel the limited energy resource available to maintain a process like DNA repair rather than towards reproductive and anabolic activities.     

Neuroendocrine and behavioral implications of endocrine disrupting chemicals in quail

Studies in our laboratory have focused on endocrine, neuroendocrine, and behavioral components of reproduction in the Japanese quail. These studies considered various stages in the life cycle, including embryonic development, sexual maturation, adult reproductive function, and aging. A major focus of our research has been the role of neuroendocrine systems that appear to synchronize both endocrine and behavioral responses. These studies provide the basis for our more recent research on the impact of endocrine disrupting chemicals (EDCs) on reproductive function in the Japanese quail. These endocrine active chemicals include pesticides, herbicides, industrial products, and plant phytoestrogens. Many of these chemicals appear to mimic vertebrate steroids, often by interacting with steroid receptors. However, most EDCs have relatively weak biological activity compared to native steroid hormones. Therefore, it becomes important to understand the mode and mechanism of action of classes of these chemicals and sensitive stages in the life history of various species. Precocial birds, such as the Japanese quail, are likely to be sensitive to EDC effects during embryonic development, because sexual differentiation occurs during this period. Accordingly, adult quail may be less impacted by EDC exposure. Because there are a great many data available on normal development and reproductive function in this species, the Japanese quail provides an excellent model for examining the effects of EDCs. Thus, we have begun studies using a Japanese quail model system to study the effects of EDCs on reproductive endocrine and behavioral responses. In this review, we have two goals: first, to provide a summary of reproductive development and sexual differentiation in intact Japanese quail embryos, including ontogenetic patterns in steroid hormones in the embryonic and maturing quail. Second, we discuss some recent data from experiments in our laboratory in which EDCs have been tested in Japanese quail. The Japanese quail provides an excellent avian model for testing EDCs because this species has well-characterized reproductive endocrine and behavioral responses. Considerable research has been conducted in quail in which the effects of embryonic steroid exposure have been studied relative to reproductive behavior. Moreover, developmental processes have been studied extensively and include investigations of the reproductive axis, thyroid system, and stress and immune responses. We have conducted a number of studies, which have considered long-term neuroendocrine consequences as well as behavioral responses to steroids. Some of these studies have specifically tested the effects of embryonic steroid exposure on later reproductive function in a multigenerational context. A multigenerational exposure provides a basis for understanding potential exposure scenarios in the field. In addition, potential routes of exposure to EDCs for avian species are being considered, as well as differential effects due to stage of the life cycle at exposure to an EDC. The studies in our laboratory have used both diet and egg injection as modes of exposure for Japanese quail. In this way, birds were exposed to a specific dose of an EDC at a selected stage in development by injection. Alternatively, dietary exposure appears to be a primary route of exposure; therefore experimental exposure through the diet mimics potential field situations. Thus, experiments should consider a number of aspects of exposure when attempting to replicate field exposures to EDCs.     

Caenorhabditis elegans integrates food and reproductive signals in lifespan determination

Dietary restriction extends lifespan and inhibits reproduction in many species. In Caenorhabditis elegans, inhibiting reproduction by germline removal extends lifespan. Therefore, we asked whether the effect of dietary restriction on lifespan might proceed via changes in the activity of the germline. We found that dietary restriction could increase the lifespan of animals lacking the entire reproductive system. Thus, dietary restriction can extend lifespan independently of any reproductive input. However, dietary restriction produced little or no increase in the long lifespan of animals that lack germ cells. Thus, germline removal and dietary restriction may potentially activate lifespan-extending pathways that ultimately converge on the same downstream longevity mechanisms. In well-fed animals, the somatic reproductive tissues are generally completely required for germline removal to extend lifespan. We found that this was not the case in animals subjected to dietary restriction. In addition, in these animals, loss of the germline could either further lengthen lifespan or shorten lifespan, depending on the genetic background. Thus, nutrient levels play an important role in determining how the reproductive system influences longevity.     

Genetic and pharmacological factors that influence reproductive aging in nematodes

Age-related degenerative changes in the reproductive system are an important aspect of aging, because reproductive success is the major determinant of evolutionary fitness. Caenorhabditis elegans is a prominent organism for studies of somatic aging, since many factors that extend adult lifespan have been identified. However, mechanisms that control reproductive aging in nematodes or other animals are not well characterized. To use C. elegans to measure reproductive aging, we analyzed mated hermaphrodites that do not become sperm depleted and monitored the duration and level of progeny production. Mated hermaphrodites display a decline of progeny production that culminates in reproductive cessation before the end of the lifespan, demonstrating that hermaphrodites undergo reproductive aging. To identify factors that influence reproductive aging, we analyzed genetic, environmental, and pharmacological factors that extend lifespan. Dietary restriction and reduced insulin/insulin-like growth factor signaling delayed reproductive aging, indicating that nutritional status and a signaling pathway that responds to environmental stress influence reproductive aging. Cold temperature delayed reproductive aging. The anticonvulsant medicine ethosuximide, which affects neural activity, delayed reproductive aging, indicating that neural activity can influence reproductive aging. Some of these factors decrease early progeny production, but there is no consistent relationship between early progeny production and reproductive aging in strains with an extended lifespan. To directly examine the effects of early progeny production on reproductive aging, we used sperm availability to modulate the level of early reproduction. Early progeny production neither accelerated nor delayed reproductive aging, indicating that reproductive aging is not controlled by use-dependent mechanisms. The implications of these findings for evolutionary theories of aging are discussed.     

Calorie restriction mimetics: an emerging research field

When considering all possible aging interventions evaluated to date, it is clear that calorie restriction (CR) remains the most robust. Studies in numerous species have demonstrated that reduction of calories 30-50% below ad libitum levels of a nutritious diet can increase lifespan, reduce the incidence and delay the onset of age-related diseases, improve stress resistance, and decelerate functional decline. A current major focus of this research area is whether this nutritional intervention is relevant to human aging. Evidence emerging from studies in rhesus monkeys suggests that their response to CR parallels that observed in rodents. To assess CR effects in humans, clinical trials have been initiated. However, even if results from these studies could eventually substantiate CR as an effective pro-longevity strategy for humans, the utility of this intervention would be hampered because of the degree and length of restriction required. As an alternative strategy, new research has focused on the development of 'CR mimetics'. The objective of this strategy is to identify compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. For example, drugs that inhibit glycolysis (2-deoxyglucose), enhance insulin action (metformin), or affect stress signaling pathways (resveratrol), are being assessed as CR mimetics (CRM). Promising results have emerged from initial studies regarding physiological responses which resemble those observed in CR (e.g. reduced body temperature and plasma insulin) as well as protection against neurotoxicity (e.g. enhanced dopamine action and up-regulated neurotrophic factors). Ultimately, lifespan analyses in addition to expanded toxicity studies must be accomplished to fully assess the potential of any CRM. Nonetheless, this strategy clearly offers a very promising and expanding research endeavor.