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Valter D Longo

Publications and source records attributed to Valter D Longo.

17 recordsLinked to original sources
PubMed2006

Sirtuins in aging and age-related disease.

Sirtuins have been the focus of intense scrutiny since the discovery of Sir2 as a yeast longevity factor. Functioning as either deacetylases or ADP ribosylases, Sirtuins are regulated by the cofactor NAD and thus may serve as sensors of the metabolic state of the cell and organism. Here we examine the roles of Sirtuins in diverse eukaryotic species, with special emphasis on their links to aging and age-related diseases including cancer, diabetes, and neurodegenerative disorders.

ADP Ribose Transferases↗
PubMed2005

Sir2 blocks extreme life-span extension.

Sir2 is a conserved deacetylase that modulates life span in yeast, worms, and flies and stress response in mammals. In yeast, Sir2 is required for maintaining replicative life span, and increasing Sir2 dosage can delay replicative aging. We address the role of Sir2 in regulating chronological life span in yeast. Lack of Sir2 along with calorie restriction and/or mutations in the yeast AKT homolog, Sch9, or Ras pathways causes a dramatic chronological life-span extension. Inactivation of Sir2 causes uptake and catabolism of ethanol and upregulation of many stress-resistance and sporulation genes. These changes while sufficient to extend chronological life span in wild-type yeast require severe calorie restriction or additional mutations to extend life span of sir2Delta mutants. Our results demonstrate that effects of SIR2 on chronological life span are opposite to replicatve life span and suggest that the relevant activities of Sir2-like deacetylases may also be complex in higher eukaryotes.

Adenylyl Cyclases↗
PubMed2005

Analysis of gene expression profile in yeast aging chronologically.

The use of simple model systems such as Saccharomyces cerevisiae and Caenorhabditis elegans has played a primary role in the identification of proteins and pathways that regulate the aging process in eukaryotes. Recent findings have shown that analogous pathways regulate aging in higher eukaryotes and suggest a conserved origin for the molecular mechanisms that regulate stress-resistance and longevity. Genomics approaches that allow the simultaneous monitoring of the expression of thousands of genes are beginning to reveal the complexity of the molecular changes required to extend life span. Here we describe how analysis of the gene expression profiles of wild-type and long-lived yeast aging chronologically can be used to identify proteins that increase stress-resistance and longevity. We also discuss a novel genomics method for the identification of chronologically long-lived yeast mutants.

Gene Expression Regulation, Fungal↗
PubMed2005

Programmed and altruistic ageing.

Ageing is widely believed to be a non-adaptive process that results from a decline in the force of natural selection. However, recent studies in Saccharomyces cerevisiae are consistent with the existence of a programme of altruistic ageing and death. We suggest that the similarities between the molecular pathways that regulate ageing in yeast, worms, flies and mice, together with evidence that is consistent with programmed death in salmon and other organisms, raise the possibility that programmed ageing or death can also occur in higher eukaryotes.

Aging↗
PubMed2005

Aging as a mitochondria-mediated atavistic program: can aging be switched off?

Programmed death phenomena have been demonstrated on subcellular (mitoptosis), cellular (apoptosis), and supracellular (collective apoptosis) levels. There are numerous examples of suicide mechanisms at the organismal level (phenoptosis). In yeast, it was recently shown that the death of aging cells is programmed. Many of the steps of programmed cell death are shown to be common for yeast and animals, including mammals. In particular, generation of the mitochondrial reactive oxygen species (ROS) is involved in the suicide programs. Aging of higher animals is accompanied by an increase in damage induced by mitochondrial ROS. Perhaps prevention of such damage by scavenging of mitochondrial ROS might slow down or even switch off the aging programs.

Aging↗
PubMed2004

Ras: the other pro-aging pathway.

Studies in worms, flies, and mice point to the insulin/insulin-like growth factor-1 (IGF-1)/phosphatidylinositol 3-kinase/Akt-like pathway as a central regulator of longevity. A similar pathway, which includes Sch9, a functional mammalian Akt/protein kinase B homolog, regulates longevity in yeast. Chronological aging in yeast is also regulated by a second pathway that includes Ras, adenylate cyclase, protein kinase A, the transcription factors Msn2 and Msn4, and Sod2. Although Ras proteins have not been implicated in longevity regulation in worms or flies, the major role of Ras in mammalian IGF-1 signaling raises the possibility that homologs of yeast Ras2 might accelerate aging in mammals. Here I review the data from experiments at both the organismal and cellular levels that support a role for Ras in the regulation of stress resistance and life span in eukaryotes.

Aging↗
PubMed2004

Superoxide is a mediator of an altruistic aging program in Saccharomyces cerevisiae.

Aging is believed to be a nonadaptive process that escapes the force of natural selection. Here, we challenge this dogma by showing that yeast laboratory strains and strains isolated from grapes undergo an age- and pH-dependent death with features of mammalian programmed cell death (apoptosis). After 90-99% of the population dies, a small mutant subpopulation uses the nutrients released by dead cells to grow. This adaptive regrowth is inversely correlated with protection against superoxide toxicity and life span and is associated with elevated age-dependent release of nutrients and increased mutation frequency. Computational simulations confirm that premature aging together with a relatively high mutation frequency can result in a major advantage in adaptation to changing environments. These results suggest that under conditions that model natural environments, yeast organisms undergo an altruistic and premature aging and death program, mediated in part by superoxide. The role of similar pathways in the regulation of longevity in organisms ranging from yeast to mice raises the possibility that mammals may also undergo programmed aging.

Adaptation, Physiological↗
PubMed2004

Superoxide inhibits 4Fe-4S cluster enzymes involved in amino acid biosynthesis. Cross-compartment protection by CuZn-superoxide dismutase.

Among the phenotypes of Saccharomyces cerevisiae mutants lacking CuZn-superoxide dismutase (Sod1p) is an aerobic lysine auxotrophy; in the current work we show an additional leaky auxotrophy for leucine. The lysine and leucine biosynthetic pathways each contain a 4Fe-4S cluster enzyme homologous to aconitase and likely to be superoxide-sensitive, homoaconitase (Lys4p) and isopropylmalate dehydratase (Leu1p), respectively. We present evidence that direct aerobic inactivation of these enzymes in sod1 Delta yeast results in the auxotrophies. Located in the cytosol and intermembrane space of the mitochondria, Sod1p likely provides direct protection of the cytosolic enzyme Leu1p. Surprisingly, Lys4p does not share a compartment with Sod1p but is located in the mitochondrial matrix. The activity of a second matrix protein, the tricarboxylic acid cycle enzyme aconitase, was similarly lowered in sod1 Delta mutants. We measured only slight changes in total mitochondrial iron and found no detectable difference in mitochondrial "free" (EPR-detectable) iron making it unlikely that a gross defect in mitochondrial iron metabolism is the cause of the decreased enzyme activities. Thus, we conclude that when Sod1p is absent a lysine auxotrophy is induced because Lys4p is inactivated in the matrix by superoxide that originates in the intermembrane space and diffuses across the inner membrane.

Amino Acids↗
PubMed2004

Search for methuselah genes heats up.

In a recent article, Morley and Morimoto confirm previous studies suggesting that the transcriptional activator heat shock factor 1 (HSF-1) regulates stress resistance genes that extend longevity independently of DAF-16. They also show that overexpression of HSF-1 in neurons or body-wall muscle cells is sufficient to extend longevity. The role of multiple transcription factors in extending life span in yeast and worms raises the possibility that many transcriptional regulators can contribute to longevity extension.

Animals↗
PubMed2003

Evolutionary medicine: from dwarf model systems to healthy centenarians?

Restriction of the number of calories consumed extends longevity in many organisms. In rodents, caloric restriction decreases the levels of plasma glucose and insulin-like growth factor I (IGF-1) and postpones or attenuates cancer, immunosenescence, and inflammation without irreversible side effects. In organisms ranging from yeast to mice, mutations in glucose or IGF-I-like signaling pathways extend life-span but also cause glycogen or fat accumulation and dwarfism. This information suggests a new category of drugs that could prevent or postpone diseases of aging with few adverse effects.

Aging↗
PubMed2003

Biodemographic trajectories of age-specific reproliferation from stationary phase in the yeast Saccharomyces cerevisiae seem multiphasic.

Ageing is usually seen as a monotonic decline of functions and survival. However, recent studies reported that age-specific mortality rates increased and then leveled off or even declined at later ages in several species including humans. Preliminary data using the yeast, Saccharomyces cerevisiae, demonstrated an even more complicated, non-monotonic pattern of reproliferation after stationary phase (i.e. the ability of a cell to exit stationary phase and form a colony). In the present article, we conducted a study of the age-specific reproliferation rates of yeast populations. Stationary phase yeast cells were maintained in water and the reproliferation rates were estimated by the number of yeast able to exit stationary phase on rich growth media. We showed that the age-specific reproliferation rates in yeast seem to rise, fall and rise again. Furthermore, we observed this pattern in different experiments and in different genotypes and established that this pattern was not due to genetic heterogeneity of the populations.

Aging↗
PubMed2003

The Ras and Sch9 pathways regulate stress resistance and longevity.

Depending on the availability of extracellular nutrients, yeast can enter either high or low metabolism survival phases. We have identified two pathways that regulate longevity and stress resistance in both the low and high metabolism phases. The deletion of SCH9, which encodes for a serine threonine kinase, triples the mean life span and increases resistance to oxidative and thermal stress. Mutations that decrease the activity of the Ras/Cyr1/PKA pathway also extend longevity and increase stress resistance by activating transcription factors Msn2/Msn4 and the mitochondrial antioxidant enzyme superoxide dismutase (Sod2). Although only one intracellular pathway that includes genes homologous to SCH9 and SOD2 has been identified in worms, our studies in yeast suggest that longevity in higher eukaryotes may also be negatively regulated by the Ras pathway.

DNA-Binding Proteins↗
PubMed2003

The chronological life span of Saccharomyces cerevisiae.

Simple model systems have played an important role in the discovery of fundamental mechanisms of aging. Studies in yeast, worms and fruit flies have resulted in the identification of proteins and signalling pathways that regulate stress resistance and longevity. New findings indicate that these pathways may have evolved to prevent damage and postpone aging during periods of starvation and may be conserved from yeast to mammals. We will review the yeast S. cerevisiae model system with emphasis on the chronological life span as a model system to study aging and the regulation of stress resistance in eukaryotes.

Animals↗
PubMed2003

SOD2 functions downstream of Sch9 to extend longevity in yeast.

Signal transduction pathways inactivated during periods of starvation are implicated in the regulation of longevity in organisms ranging from yeast to mammals, but the mechanisms responsible for life-span extension are poorly understood. Chronological life-span extension in S. cerevisiae cyr1 and sch9 mutants is mediated by the stress-resistance proteins Msn2/Msn4 and Rim15. Here we show that mitochondrial superoxide dismutase (Sod2) is required for survival extension in yeast. Deletion of SOD2 abolishes life-span extension in sch9Delta mutants and decreases survival in cyr1:mTn mutants. The overexpression of Sods--mitochondrial Sod2 and cytosolic CuZnSod (Sod1)--delays the age-dependent reversible inactivation of mitochondrial aconitase, a superoxide-sensitive enzyme, and extends survival by 30%. Deletion of the RAS2 gene, which functions upstream of CYR1, also doubles the mean life span by a mechanism that requires Msn2/4 and Sod2. These findings link mutations that extend chronological life span in S. cerevisiae to superoxide dismutases and suggest that the induction of other stress-resistance genes regulated by Msn2/4 and Rim15 is required for maximum longevity extension.

Aconitate Hydratase↗
PubMed2002

Oxygen? No thanks, I'm on a diet.

In yeast and worms, mutations that extend longevity appear to simulate starvation conditions. The daf-2 pathway in worms plays a major role in life-span extension and in entry into the starvation-resistant and low-metabolism dauer phase. In a recent study published in Science Express on 13 June 2002, researchers screened for Caenorhabditis elegans mutants that survive in a low-oxygen environment and identified a number of daf-2 mutants that are resistant to hypoxia. The implications of these results are discussed in this Perspective.

Animals↗
PubMed2002

Peroxynitrite mediates neurotoxicity of amyloid beta-peptide1-42- and lipopolysaccharide-activated microglia.

The amyloid beta-peptide (Abeta) activates microglia and promotes the generation of cytokines and oxygen species, including nitric oxide (NO) and tumor necrosis factor alpha (TNF-alpha), which can be either neurotoxic or neuroprotective. We show that neuron death in cocultures of rat cortical microglia and neurons activated by lipopolysaccharide (LPS) or Abeta1-42 plus interferon gamma (IFNgamma) is caused by short-lived diffusible molecules and follows the generation of superoxide and/or peroxynitrite as determined by electron paramagnetic spectroscopy. Neurotoxicity induced by LPS or Abeta1-42 plus IFNgamma is blocked by inhibitors of NO synthesis and by the peroxynitrite (ONOO-) decomposition catalysts FeTMPyP [5,10,15,20-tetrakis(n-methyl-4'-pyridyl)porphinato iron (III) chloride] and FeTPPS [5,10,15,20-tetrakis(4-sulfonatophenyl)prophyrinato iron (III) chloride] but not by the TNF-alpha inhibitor pentoxifylline. The specificity of FeTMPyP for ONOO- was confirmed by its ability to block the toxicity of a peroxynitrite donor but not of NO donors or of high levels of superoxide in a yeast mutant lacking superoxide dismutase 1. These results implicate peroxynitrite as a mediator of the toxicity of activated microglia, which may play a major role in Abeta1-42 neurotoxicity and Alzheimer's disease.

Amyloid beta-Peptides↗