Aging yeast gain a competitive advantage on non‐optimal carbon sources

Animals, plants and fungi undergo an aging process with remarkable physiological and molecular similarities, suggesting that aging has long been a fact of life for eukaryotes and one to which our unicellular ancestors were subject. Key biochemical pathways that impact longevity evolved prior to multicellularity, and the interactions between these pathways and the aging process therefore emerged in ancient single‐celled eukaryotes. Nevertheless, we do not fully understand how aging impacts the fitness of unicellular organisms, and whether such cells gain a benefit from modulating rather than simply suppressing the aging process. We hypothesized that age‐related loss of fitness in single‐celled eukaryotes may be counterbalanced, partly or wholly, by a transition from a specialist to a generalist life‐history strategy that enhances adaptability to other environments. We tested this hypothesis in budding yeast using competition assays and found that while young cells are more successful in glucose, highly aged cells outcompete young cells on other carbon sources such as galactose. This occurs because aged yeast divide faster than young cells in galactose, reversing the normal association between age and fitness. The impact of aging on single‐celled organisms is therefore complex and may be regulated in ways that anticipate changing nutrient availability. We propose that pathways connecting nutrient availability with aging arose in unicellular eukaryotes to capitalize on age‐linked diversity in growth strategy and that individual cells in higher eukaryotes may similarly diversify during aging to the detriment of the organism as a whole.     

Slowing down aging from within: mechanistic aspects of anti-aging hormetic effects of mild heat stress on human cells

Since aging is primarily the result of a failure of maintenance and repair mechanisms, various approaches are being developed in order to stimulate these pathways and modulate the process of aging. One such approach, termed hormesis, involves challenging cells and organisms by mild stress that often results in anti-aging and life prolonging effects. In a series of experimental studies, we have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These beneficial effects of repeated challenge include the maintenance of stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the proteasomal activities for the degradation of abnormal proteins, improved cellular resistance to other stresses, and enhanced levels of cellular antioxidant ability. In order to elucidate the molecular mechanisms of hormetic effects of RMHS, we are now undertaking studies on signal transduction pathways, energy production and utilisation kinetics, and the proteomic analysis of patterns of proteins synthesised and their posttranslational modifications in various types of human cells undergoing cellular aging in vitro. Human applications of hormesis include early intervention and modulation of the aging process to prevent or delay the onset of age-related conditions, such as sarcopenia, Alzheimer's disease, Parkinson's disease, cataracts and osteoporosis.     

The plasticity of aging: insights from long-lived mutants

Mutations in genes affecting endocrine signaling, stress responses, metabolism, and telomeres can all increase the life spans of model organisms. These mutations have revealed evolutionarily conserved pathways for aging, some of which appear to extend life span in response to sensory cues, caloric restriction, or stress. Many mutations affecting longevity pathways delay age-related disease, and the molecular analysis of these pathways is leading to a mechanistic understanding of how these two processes--aging and disease susceptibility--are linked.     

Age to survive: DNA damage and aging

Aging represents the progressive functional decline and increased mortality risk common to nearly all metazoans. Recent findings experimentally link DNA damage and organismal aging: longevity-regulating genetic pathways respond to the accumulation of DNA damage and other stress conditions and conversely influence the rate of damage accumulation and its impact for cancer and aging. This novel insight has emerged from studies on human progeroid diseases and mouse models that have deficient DNA repair pathways. Here we discuss a unified concept of an evolutionarily conserved 'survival' response that shifts the organism's resources from growth to maintenance as an adaptation to stresses, such as starvation and DNA damage. This shift protects the organism from cancer and promotes healthy aging.     

Respiratory Chains in the Last Common Ancestor of Living Organisms

Sequences in current databases show that a number of proteins involved in respiratory processes are homologous in archaeal and bacterial species. In particular, terminal oxidases belonging to oxygen, nitrate, sulfate, and sulfur respiratory pathways have been sequenced in members of both domains. They include cytochrome oxidase, nitrate reductase, adenylylsulfate reductase, sulfite reductase, and polysulfide reductase. These proteins can be assigned to the last common ancestor of living organisms assuming that the deepest split of the three domains of life occurred between Archaea and Bacteria and that they were not acquired through lateral gene transfer by one of these domains. These molecular data indicate that several of the most important respiratory pathways arose early in evolution and that the last common ancestor of living organisms was not a simple organism in its energetic metabolism. Rather, it may have been able to gain energy by means of at least four electron transport chains, and therefore it may have been prepared to face a wide range of environmental conditions.     

Emerging role of sirtuins on tumorigenesis: possible link between aging and cancer

Aging is the strongest risk factor for cancer development, suggesting that molecular crosstalks between aging and tumorigenesis exist in many cellular pathways. Recently, Sirtuins (Sirt1-7), the mammalian homologues of aging-related sir2α in yeast, have been shown to modulate several major cellular pathways, such as DNA repair, inflammation, metabolism, cell death, and proliferation in response to diverse stresses, and may serve as a possible molecular link between aging and tumorignenesis. In addition, growing evidence suggests that sirtuins are directly implicated in the development of cancer, and they can act as either a tumor suppressor or promoter, depending on the cellular context and tumor types. While the functions of Sirt1 in tumorigenesis have been reported and reviewed in many studies, the connection between sirtuins 2-7 and the development of cancer is less established. Thus, this review will present the recent updates on the emerging roles of Sirt2-7 members in carcinogenesis. [BMB Reports 2013; 46(9): 429-438]     

Working harder to stay alive: metabolic rate increases with age in Drosophila simulans but does not correlate with life span

The hypothesis that metabolic rate is inversely correlated with life span has long been debated. Another area of controversy has been the relationship between metabolic rate and aging. In most molecular studies key aspects of cellular metabolism have been shown to decline with age. Less attention has been focused on metabolic rate as an organism ages. We studied the survival of three Drosophila simulans fly lines and measured whole organism metabolic rate, mitochondrial DNA copy number and walking speed. Metabolic rate as assayed by CO(2) production did not correlate with median lifespan but increased by 0.43-1.14%/d. In contrast, mitochondrial DNA copy number decreased by 0.56-1.06%/d. Physical activity, as assayed by mean walking speed, did not change with age but was positively correlated with mitochondrial DNA copy number. One explanation for these data is that metabolic rate was increased, in the face of a reduced mitochondrial DNA copy number and capacity for oxidative metabolism, to maintain a constant bioenergetic demand (physical activity). Alternatively, metabolic rate may increase to provide energy for the repair of cellular damage or due to a shift in metabolic substrate use over time.     

Longevity regulation in Saccharomyces cerevisiae: linking metabolism, genome stability, and heterochromatin.

When it was first proposed that the budding yeast Saccharomyces cerevisiae might serve as a model for human aging in 1959, the suggestion was met with considerable skepticism. Although yeast had proved a valuable model for understanding basic cellular processes in humans, it was difficult to accept that such a simple unicellular organism could provide information about human aging, one of the most complex of biological phenomena. While it is true that causes of aging are likely to be multifarious, there is a growing realization that all eukaryotes possess surprisingly conserved longevity pathways that govern the pace of aging. This realization has come, in part, from studies of S. cerevisiae, which has emerged as a highly informative and respected model for the study of life span regulation. Genomic instability has been identified as a major cause of aging, and over a dozen longevity genes have now been identified that suppress it. Here we present the key discoveries in the yeast-aging field, regarding both the replicative and chronological measures of life span in this organism. We discuss the implications of these findings not only for mammalian longevity but also for other key aspects of cell biology, including cell survival, the relationship between chromatin structure and genome stability, and the effect of internal and external environments on cellular defense pathways. We focus on the regulation of replicative life span, since recent findings have shed considerable light on the mechanisms controlling this process. We also present the specific methods used to study aging and longevity regulation in S. cerevisiae.     

Longevity Regulation in Saccharomyces cerevisiae: Linking Metabolism, Genome Stability, and Heterochromatin

When it was first proposed that the budding yeast Saccharomyces cerevisiae might serve as a model for human aging in 1959, the suggestion was met with considerable skepticism. Although yeast had proved a valuable model for understanding basic cellular processes in humans, it was difficult to accept that such a simple unicellular organism could provide information about human aging, one of the most complex of biological phenomena. While it is true that causes of aging are likely to be multifarious, there is a growing realization that all eukaryotes possess surprisingly conserved longevity pathways that govern the pace of aging. This realization has come, in part, from studies of S. cerevisiae, which has emerged as a highly informative and respected model for the study of life span regulation. Genomic instability has been identified as a major cause of aging, and over a dozen longevity genes have now been identified that suppress it. Here we present the key discoveries in the yeast-aging field, regarding both the replicative and chronological measures of life span in this organism. We discuss the implications of these findings not only for mammalian longevity but also for other key aspects of cell biology, including cell survival, the relationship between chromatin structure and genome stability, and the effect of internal and external environments on cellular defense pathways. We focus on the regulation of replicative life span, since recent findings have shed considerable light on the mechanisms controlling this process. We also present the specific methods used to study aging and longevity regulation in S. cerevisiae.     

Autophagy links lipid metabolism to longevity in C. elegans

The cellular recycling process of autophagy is emerging as a central player in many of the conserved longevity pathways in C. elegans, but the underlying mechanisms that link autophagy and life span remain unclear. In a recent study, we provided evidence to suggest that autophagy modulates aging through an effect on lipid homeostasis. Specifically, we identified a role for autophagy in a longevity model in which germline removal in C. elegans extends life span. Life-span extension in these animals is achieved, at least in part, through increased expression of the lipase LIPL-4. We found that autophagy and LIPL-4-dependent lipolysis are both upregulated in germline-less animals and work interdependently to prolong life span. While these genetic results lend further support to a growing link between autophagy and lipid metabolism, our findings are the first to suggest a possible molecular mechanism by which autophagy modulates organismal aging.     

Human premature aging, DNA repair and RecQ helicases

Genomic instability leads to mutations, cellular dysfunction and aberrant phenotypes at the tissue and organism levels. A number of mechanisms have evolved to cope with endogenous or exogenous stress to prevent chromosomal instability and maintain cellular homeostasis. DNA helicases play important roles in the DNA damage response. The RecQ family of DNA helicases is of particular interest since several human RecQ helicases are defective in diseases associated with premature aging and cancer. In this review, we will provide an update on our understanding of the specific roles of human RecQ helicases in the maintenance of genomic stability through their catalytic activities and protein interactions in various pathways of cellular nucleic acid metabolism with an emphasis on DNA replication and repair. We will also discuss the clinical features of the premature aging disorders associated with RecQ helicase deficiencies and how they relate to the molecular defects.     

Age‐related AMP‐activated protein kinase alterations: From cellular energetics to longevity

5’ adenosine monophosphate‐activated protein kinase (AMPK) is a key regulator of energy in the cell, which allows the cell/organism to survive with deficit of ATP. Since AMPK is involved in the adaptation to caloric restriction, the role of age‐related changes in AMPK activity in both the aging organism and the aging cell is actively investigated in gerontology. Studies on yeast, worms, flies, rodents, and primates have demonstrated an important effect of this regulator on key signalling pathways involved in the aging process. In some cases, researchers conclude that AMPK promotes aging. However, in our opinion, in such cases, we observe a disturbance in the adaptive ability because of the prolonged cell/organism presence in stressful conditions because the functional capacity of any adaptation system is limited. Interestingly, AMPK can regulate metabolic processes in noncell‐autonomous manner. The main effects of AMPK activation in the cell are realized in restriction of proliferation and launching autophagy. In tissues of an aging organism, the ability of AMPK to respond to energy deficit decreases; this fact is especially critical for organs that contain postmitotic cells. In this review, we have tried to consider the involvement of AMPK in age‐related changes in the cell and in the organism.     

Longevity and skeletal muscle mass: the role of IGF signalling,the sirtuins,dietary restriction and protein intake

Advancing age is associated with a progressive loss of skeletal muscle (SkM) mass and function. Given the worldwide aging demographics, this is a major contributor to morbidity, escalating socio‐economic costs and ultimately mortality. Previously, it has been established that a decrease in regenerative capacity in addition to SkM loss with age coincides with suppression of insulin/insulin‐like growth factor signalling pathways. However, genetic or pharmacological modulations of these highly conserved pathways have been observed to significantly enhance life and healthspan in various species, including mammals. This therefore provides a controversial paradigm in which reduced regenerative capacity of skeletal muscle tissue with age potentially promotes longevity of the organism. This paradox will be assessed and considered in the light of the following: (i) the genetic knockout, overexpression and pharmacological models that induce lifespan extension (e.g. IRS‐1/s6K KO, mTOR inhibition) versus the important role of these signalling pathways in SkM growth and adaptation; (ii) the role of the sirtuins (SIRTs) in longevity versus their emerging role in SkM regeneration and survival under catabolic stress; (iii) the role of dietary restriction and its impact on longevity versus skeletal muscle mass regulation; (iv) the crosstalk between cellular energy metabolism (AMPK/TSC2/SIRT1) and survival (FOXO) versus growth and repair of SkM (e.g. AMPK vs. mTOR); and (v) the impact of protein feeding in combination with dietary restriction will be discussed as a potential intervention to maintain SkM mass while increasing longevity and enabling healthy aging.     

Molecular signaling involved in regulating feeding and other motivated behaviors

The metabolic and nutritional status of an organism influences multiple behaviors in addition to food intake. When an organism is hungry, it employs behaviors that help it locate and ingest food while suppressing behaviors that are not associated with this goal. Alternatively, when an organism is satiated, food-seeking behaviors are repressed so that the animal can direct itself to other goal-oriented tasks such as reproductive behaviors. Studies in both vertebrate and invertebrate model systems have revealed that food-deprived and -satiated behaviors are differentially executed and integrated via common molecular signaling mechanisms. This article discusses cellular and molecular mechanisms for how insulin, neuropeptide Y (NPY), and serotonin utilize common signaling pathways to integrate feeding and metabolic state with other motivated behaviors. Insulin, NPY, and serotonin are three of the most well-studied molecules implicated in regulating such behaviors. Overall, insulin signaling allows an organism to coordinate proper behavioral output with changes in metabolism, NPY activates behaviors required for locating and ingesting food, and serotonin modulates behaviors performed when an organism is satiated. These three molecules work to ensure that the proper behaviors are executed in response to the feeding state of an organism.