Iron,glucose and intrinsic factors alter sphingolipid composition as yeast cells enter stationary phase

Survival of Saccharomyces cerevisiae cells, like most microorganisms, requires switching from a rapidly dividing to a non-dividing or stationary state. To further understand how cells navigate this switch, we examined sphingolipids since they are key structural elements of membranes and also regulate signaling pathways vital for survival. During and after the switch to a non-dividing state there is a large increase in total free and sphingolipid-bound long chain-bases and an even larger increase in free and bound C20-long-chain bases, which are nearly undetectable in dividing cells. These changes are due to intrinsic factors including Orm1 and Orm2, ceramide synthase, Lcb4 kinase and the Tsc3 subunit of serine palmitoyltransferase as well as extrinsic factors including glucose and iron. Lowering the concentration of glucose, a form of calorie restriction, decreases the level of LCBs, which is consistent with the idea that reducing the level of some sphingolipids enhances lifespan. In contrast, iron deprivation increases LCB levels and decreases long term survival; however, these phenomena may not be related because iron deprivation disrupts many metabolic pathways. The correlation between increased LCBs and shorter lifespan is unsupported at this time. The physiological rise in LCBs that we observe may serve to modulate nutrient transporters and possibly other membrane phenomena that contribute to enhanced stress resistance and survival in stationary phase.     

Reducing signs of aging and increasing lifespan by drug synergy

Disease incidence rises rapidly with age and increases both human suffering and economic hardship while shortening life. Advances in understanding the signaling pathways and cellular processes that influence aging support the possibility of reducing the incidence of age‐related diseases and increasing lifespan by pharmacological intervention. Here, we demonstrate a novel pharmacological strategy that both reduces signs of aging in the budding yeast Saccharomyces cerevisiae and generates a synergistic increase in lifespan. By combining a low dose of rapamycin, to reduce activity of the target of rapamycin complex 1 (TORC1) protein kinase, and myriocin, to reduce sphingolipid synthesis, we show enhancement of autophagy, genomic stability, mitochondrial function, and AMP kinase pathway activity. These processes are controlled by evolutionarily conserved signal transduction pathways that are vital for maintaining a healthy state and promoting a long life. Thus, our data show that it ought to be possible to find pharmacological approaches to generate a synergistic reduction in the incidence of human age‐related diseases to improve health quality in the elderly and enhance lifespan.     

植物鞘脂的结构、代谢途径及其功能

众所周知,鞘脂是生物膜结构的重要组成成分,随着鞘脂在动物和酵母中的深入研究发现,鞘脂及其代谢产物是一类很重要的活性分子,它们参与调节细胞的生长、分化、衰老和细胞程序性死亡等许多重要的信号转导过程。鞘脂在植物中的研究最近几年才开始,植物鞘脂的功能还不十分清楚。最近的研究发现,鞘脂及其代谢产物在植物中也起着很重要的信号分子作用。该文详细总结了鞘脂在植物中的结构、代谢途径和主要生物学功能,并结合实验室的工作对植物鞘脂的功能研究进行了展望。     

Subacute calorie restriction and rapamycin discordantly alter mouse liver proteome homeostasis and reverse aging effects

Calorie restriction (CR) and rapamycin (RP) extend lifespan and improve health across model organisms. Both treatments inhibit mammalian target of rapamycin (mTOR) signaling, a conserved longevity pathway and a key regulator of protein homeostasis, yet their effects on proteome homeostasis are relatively unknown. To comprehensively study the effects of aging, CR, and RP on protein homeostasis, we performed the first simultaneous measurement of mRNA translation, protein turnover, and abundance in livers of young (3 month) and old (25 month) mice subjected to 10‐week RP or 40% CR. Protein abundance and turnover were measured in vivo using ²H₃–leucine heavy isotope labeling followed by LC‐MS/MS, and translation was assessed by polysome profiling. We observed 35–60% increased protein half‐lives after CR and 15% increased half‐lives after RP compared to age‐matched controls. Surprisingly, the effects of RP and CR on protein turnover and abundance differed greatly between canonical pathways, with opposite effects in mitochondrial (mt) dysfunction and eIF2 signaling pathways. CR most closely recapitulated the young phenotype in the top pathways. Polysome profiles indicated that CR reduced polysome loading while RP increased polysome loading in young and old mice, suggesting distinct mechanisms of reduced protein synthesis. CR and RP both attenuated protein oxidative damage. Our findings collectively suggest that CR and RP extend lifespan in part through the reduction of protein synthetic burden and damage and a concomitant increase in protein quality. However, these results challenge the notion that RP is a faithful CR mimetic and highlight mechanistic differences between the two interventions.     

The TOR pathway comes of age

Studies in a variety of model organisms indicate that nutrient signaling is tightly coupled to longevity. In nutrient replete conditions, organisms develop, grow, and age quickly. When nutrients become sparse as with dietary restriction, growth and development decline, stress response pathways become induced and organisms live longer. Considerable effort has been devoted to understanding the molecular events mediating lifespan extension by dietary restriction. One central focus has been on nutrient-responsive signal transduction pathways including insulin/IGF-1, AMP kinase, protein kinase A and the TOR pathway. Here we describe the increasingly prominent links between TOR signaling and aging in invertebrates. Longevity studies in mammals are not published to date. Instead, we highlight studies in mouse models, which indicate that dampening the TOR pathway leads to widespread protection from an array of age-related diseases.     

DO‐SRS imaging of diet regulated metabolic activities in Drosophila during aging processes

Lipid metabolism plays crucial roles during aging processes, but how it is regulated by diets and how it interplays with aging still remain unclear. We proposed a new optical imaging platform by integrating heavy water (D₂O) probing with stimulated Raman scattering (DO‐SRS) microscopy, for the first time, to directly visualize and quantify lipid metabolism regulated by different diets and insulin signaling pathway in Drosophila fat body during aging. We found that calorie restriction, low protein diet, and (moderately) high protein and high sucrose diets enhanced lipid turnover in flies at all ages, while (moderately) high fructose and glucose diets only promoted lipid turnover in aged flies. The measured lipid turnover enhancements under diverse diets were due to different mechanisms. High protein diet shortened the lifespan while all other diets extended the lifespan. Downregulating the insulin signaling pathway enhanced lipid turnover, which is likely related to lifespan increase, while upregulating insulin signaling pathway decreased lipid turnover that would shorten the lifespan. Our study offers the first approach to directly visualize spatiotemporal alterations of lipid turnover in aging Drosophila in situ, for a better understanding of the interconnections between lipid metabolism, diets, and aging.     

Nutrigerontology: why we need a new scientific discipline to develop diets and guidelines to reduce the risk of aging‐related diseases

Many diets and nutritional advice are circulating, often based on short‐ or medium‐term clinical trials and primary outcomes, like changes in LDL cholesterol or weight. It remains difficult to assess which dietary interventions can be effective in the long term to reduce the risk of aging‐related disease and increase the (healthy) lifespan. At the same time, the scientific discipline that studies the aging process has identified some important nutrient‐sensing pathways that modulate the aging process, such as the mTOR and the insulin/insulin‐like growth factor signaling pathway. A thorough understanding of the aging process can help assessing the efficacy of dietary interventions aimed at reducing the risk of aging‐related diseases. To come to these insights, a synthesis of biogerontological, nutritional, and medical knowledge is needed, which can be framed in a new discipline called ‘nutrigerontology’.     

Resveratrol and rapamycin: are they anti‐aging drugs?

Studies of the basic biology of aging have advanced to the point where anti‐aging interventions, identified from experiments in model organisms, are beginning to be tested in people. Resveratrol and rapamycin, two compounds that target conserved longevity pathways and may mimic some aspects of dietary restriction, represent the first such interventions. Both compounds have been reported to slow aging in yeast and invertebrate species, and rapamycin has also recently been found to increase life span in rodents. In addition, both compounds also show impressive effects in rodent models of age‐associated diseases. Clinical trials are underway to assess whether resveratrol is useful as an anti‐cancer treatment, and rapamycin is already approved for use in human patients. Compounds such as these, identified from longevity studies in model organisms, hold great promise as therapies to target multiple age‐related diseases by modulating the molecular causes of aging.     

Endocrine targets for pharmacological intervention in aging in Caenorhabditis elegans

Studies in the nematode Caenorhabditis elegans have been instrumental in defining genetic pathways that are involved in modulating lifespan. Multiple processes such as endocrine signaling, nutritional sensing and mitochondrial function play a role in determining lifespan in the worm and these mechanisms appear to be conserved across species. These discoveries have identified a range of novel targets for pharmacological manipulation of lifespan and it is likely that the nematode model will now prove useful in the discovery of compounds that slow aging. This review will focus on the endocrine targets for intervention in aging and the use of C. elegans as a system for high throughput screens of compounds for their effects on aging.     

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.     

Temperature affects longevity and age-related locomotor and cognitive decay in the short-lived fish Nothobranchius furzeri

Temperature variations are known to modulate aging and life-history traits in poikilotherms as different as worms, flies and fish. In invertebrates, temperature affects lifespan by modulating the slope of age-dependent acceleration in death rate, which is thought to reflect the rate of age-related damage accumulation. Here, we studied the effects of temperature on aging kinetics, aging-related behavioural deficits, and age-associated histological markers of senescence in the short-lived fish Nothobranchius furzeri. This species shows a maximum captive lifespan of only 3 months, which is tied with acceleration in growth and expression of aging biomarkers. These biological peculiarities make it a very convenient animal model for testing the effects of experimental manipulations on life-history traits in vertebrates. Here, we show that (i) lowering temperature from 25 degrees C to 22 degrees C increases both median and maximum lifespan; (ii) life extension is due to reduction in the slope of the age-dependent acceleration in death rate; (iii) lowering temperature from 25 degrees C to 22 degrees C retards the onset of age-related locomotor and learning deficits; and (iv) lowering temperature from 25 degrees C to 22 degrees C reduces the accumulation of the age-related marker lipofuscin. We conclude that lowering water temperature is a simple experimental manipulation which retards the rate of age-related damage accumulation in this short-lived species.     

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.     

Sphingolipids in colon cancer

Colorectal cancer is one of the major causes of death in the western world. Despite increasing knowledge of the molecular signaling pathways implicated in colon cancer, therapeutic outcomes are still only moderately successful. Sphingolipids, a family of N-acyl linked lipids, have not only structural functions but are also implicated in important biological functions. Ceramide, sphingosine and sphingosine-1-phosphate are the most important bioactive lipids, and they regulate several key cellular functions. Accumulating evidence suggests that many cancers present alterations in sphingolipids and their metabolizing enzymes. The aim of this review is to discuss the emerging roles of sphingolipids, both endogenous and dietary, in colon cancer and the interaction of sphingolipids with WNT/β-catenin pathway, one of the most important signaling cascades that regulate development and homeostasis in intestine. This article is part of a Special Issue entitled New Frontiers in Sphingolipid Biology.     

Drug Synergy Drives Conserved Pathways to Increase Fission Yeast Lifespan

Aging occurs over time with gradual and progressive loss of physiological function. Strategies to reduce the rate of functional loss and mitigate the subsequent onset of deadly age-related diseases are being sought. We demonstrated previously that a combination of rapamycin and myriocin reduces age-related functional loss in the Baker’s yeast Saccharomyces cerevisiae and produces a synergistic increase in lifespan. Here we show that the same drug combination also produces a synergistic increase in the lifespan of the fission yeast Schizosaccharomyces pombe and does so by controlling signal transduction pathways conserved across a wide evolutionary time span ranging from yeasts to mammals. Pathways include the target of rapamycin complex 1 (TORC1) protein kinase, the protein kinase A (PKA) and a stress response pathway, which in fission yeasts contains the Sty1 protein kinase, an ortholog of the mammalian p38 MAP kinase, a type of Stress Activated Protein Kinase (SAPK). These results along with previous studies in S. cerevisiae support the premise that the combination of rapamycin and myriocin enhances lifespan by regulating signaling pathways that couple nutrient and environmental conditions to cellular processes that fine-tune growth and stress protection in ways that foster long term survival. The molecular mechanisms for fine-tuning are probably species-specific, but since they are driven by conserved nutrient and stress sensing pathways, the drug combination may enhance survival in other organisms.     

Haploinsufficiency of Akt1 Prolongs the Lifespan of Mice

There is increasing evidence that nutrient-sensing machinery is critically involved in the regulation of aging. The insulin/insulin-like growth factor-1 signaling pathway is the best-characterized pathway with an influence on longevity in a variety of organisms, ranging from yeast to rodents. Reduced expression of the receptor for this pathway has been reported to prolong the lifespan; however, the underlying mechanisms are largely unknown. Here we show that haploinsufficiency of Akt1 leads to an increase of the lifespan in mice. Akt1 ^+/– mice had a lower body weight than their littermates with less fat mass and normal glucose metabolism. Ribosomal biogenesis and the mitochondrial DNA content were significantly reduced in these mice, along with a decrease of oxidative stress. Consistent with the results obtained in mice, inhibition of Akt-1 promoted longevity in nematodes (Caenorhabditis elegans), whereas activation of Akt-1 shortened the lifespan. Inhibition of Akt-1 led to a decrease of ribosomal gene expression and the mitochondrial DNA content in both human cells and nematodes. Moreover, deletion of ribosomal gene expression resulted in a decrease of the mitochondrial DNA content and normalized the lifespan shortened by Akt-1 activation in nematodes. These results suggest that an increase of mitochondrial amount and energy expenditure associated with enhanced protein synthesis accelerates both aging and the onset of age-associated diseases.     

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.     

The aging lysosome: An essential catalyst for late-onset neurodegenerative diseases

Lysosomes figure prominently in theories of aging as the proteolytic system most responsible for eliminating growing burdens of damaged proteins and organelles in aging neurons and other long lived cells. Newer evidence shows that diverse experimental measures known to extend lifespan in invertebrate aging models share the property of boosting lysosomal clearance of substrates through the autophagy pathway. Maintaining an optimal level of lysosome acidification is particularly crucial for these anti-aging effects. The exceptional dependence of neurons on fully functional lysosomes is reflected by the neurological phenotypes that develop in congenital lysosomal storage disorders, which commonly present as severe neurodevelopmental or neurodegenerative conditions even though the lysosomal deficit maybe systemic. Similar connections are now being appreciated between primary lysosomal deficit and the risk for late age-onset neurodegenerative disorders. In diseases such as Alzheimer's and Parkinson's, as in aging alone, primary lysosome dysfunction due to acidification impairment is emerging as a frequent theme, supported by the growing list of familial neurodegenerative disorders that involve primary vATPase dysfunction. The additional cellular roles played by intraluminal pH in sensing nutrient and stress and modulating cellular signaling have further expanded the possible ways that lysosomal pH dysregulation in aging and disease can disrupt neuronal function. Here, we consider the impact of cellular aging on lysosomes and how the changes during aging may create the tipping point for disease emergence in major late-age onset neurodegenerative disorders.