Biomedical subjects

S M Jazwinski

Publications and source records attributed to S M Jazwinski.

At least 19 recordsLinked to original sources

PubMed2001

Profiles of random change during aging contain hidden information about longevity and the aging process.

Many different morphological and physiological changes occur during the yeast replicative lifespan. It has been proposed that change is a cause rather than an effect of aging. It is difficult to ascribe causality to processes that manifest themselves at the level of the entire organism, because of their global nature. Although causal connections can be established for processes that occur at the molecular level, their exact contributions are obscured, because they are immersed in a highly interactive network of processes. A top-down approach that can isolate crucial features of aging processes for further study may be a productive avenue. We have mathematically depicted the complicated and random changes that occur in cellular spatial organization during the lifespan of individual yeast cells. We call them budding profiles. This has allowed us to demonstrate that budding profiles are a highly individual characteristic, and that they are correlated with an individual cell's longevity. Additional information can be extracted from our model, indicating that random budding is associated with longevity. This expectation was confirmed, providing new avenues for exploring causal factors in yeast aging. The methodology described here can be readily applied to other aspects of aging in yeast and in higher organisms.

Animals↗

PubMed2001

New clues to old yeast.

The yeast Saccharomyces cerevisiae has been used as an experimental model for the genetic and molecular dissecton of the aging process for the past decade. This period has seen the implication of some 30 genes in yeast aging. These genes encode a wide array of biochemical functions, suggesting the participation of multiple molecular mechanisms of aging. However, four principles appear to be at play: metabolism, stress resistance, gene dysregulation, and genetic instability. They unite the broad physiological aspects of yeast aging with those in other species. Genes and environment are not the only players; stochastic change also appears important in determining life span. This element of chance provides opportunities for an integrative approach, which is beginning to appear in yeast aging research.

Animals↗

PubMed2001

C26-CoA-dependent ceramide synthesis of Saccharomyces cerevisiae is operated by Lag1p and Lac1p.

Lag1p and Lac1p are two highly homologous membrane proteins of the endoplasmic reticulum (ER). When both genes are deleted, cells cannot transport glycosylphosphatidylinositol (GPI)-anchored proteins from the ER to the Golgi at a normal rate. Here we show that microsomes or detergent extracts from lag1lac1 double mutants lack an activity transferring C26 fatty acids from C26-coenzyme A onto dihydrosphingosine or phytosphingosine. As a consequence, in intact cells, the normal ceramides and inositolphosphorylceramides are drastically reduced. lag1lac1 cells compensate for the lack of normal sphingolipids by making increased amounts of C26 fatty acids, which become incorporated into glycerophospholipids. They also contain 20- to 25-fold more free long chain bases than wild type and accumulate very large amounts of abnormally polar ceramides. They make small amounts of abnormal mild base-resistant inositolphospholipids. The lipid remodelling of GPI-anchored proteins is severely compromised in lag1lac1 double mutants since only few and mostly abnormal ceramides are incorporated into the GPI anchors. The participation of Lag1p and Lac1p in ceramide synthesis may explain their role in determining longevity.

Acyl Coenzyme A↗

PubMed2000

Coordination of metabolic activity and stress resistance in yeast longevity.

The genetic analysis of longevity in yeast has revealed the importance of metabolic control and resistance to stress in aging. It has also shown that these two physiological processes are interwoven. Molecular mechanisms underlying the longevity effects of metabolic control and stress resistance, as well as genetic stability, are emerging. The yeast RAS genes play a substantial role in coordinating at least the first two of these processes. Numerous correlates can be found between the physiological processes involved in yeast aging and aging in Caenorhabditis elegans and in Drosophila, and the dietary restriction paradigm in mammals.

Aging↗

PubMed2000

Metabolic control and ageing.

There appear to be multiple processes that are limiting for longevity and the associated mechanisms of ageing. Among these processes, metabolic control is coming to the forefront, because it has surfaced in studies in several model systems and because of its relevance to mammalian ageing. The genetic and molecular dissection of ageing in yeast points to mechanisms involving three aspects of metabolism. First, dysfunctional mitochondria signal many changes in nuclear gene expression that result in metabolic adjustments that extend life span. Second, manipulation of nutritional status can also increase longevity in a separate caloric-restriction pathway. Finally, protein synthesis is a third aspect, which depends on the transcriptional state of chromatin and the histone deacetylases that modulate it.

Aging↗

PubMed2000

Metabolic mechanisms of yeast ageing.

The genetic analysis of ageing of the yeast Saccharomyces cerevisiae points to several processes important in determining life span. Among these, metabolic control plays a leading role. An examination of the molecular mechanisms underlying metabolic control of longevity has revealed two separate pathways. The retrograde response signals mitochondrial dysfunction to the nucleus resulting in gene regulatory changes that compensate. Nutritional status also modulates life span, adjusting metabolism to efficiently utilize energy resources, in a response that closely resembles the caloric restriction paradigm described in rodents. Although the retrograde response and caloric restriction are distinct pathways of life span extension, there appears to be some overlap of the longevity effectors under their control.

Nutritional Physiological Phenomena↗

PubMed2000

Does a retrograde response in human aging and longevity exist?

The retrograde response (RR) is a compensatory mechanism by which mutant strains of yeast are able to cope with mitochondrial DNA (mtDNA) impairments by up-regulating the expression of the stress-responder nuclear genes and significantly increasing lifespan. Starting from the observation that both mtDNA variability and Tyrosine hydroxylase (THO, stress-responder gene) variability are correlated with human longevity, we asked ourselves whether mechanisms similar to RR may exist in humans. As a first investigative step we have analyzed the distribution of the mtDNA inherited variants (haplogroups) according to THO genotypes in three sample groups of increasing ages (20-49 years; 50-80 years; centenarians). We found that the mtDNA haplogroups and the THO genotypes are associated randomly in the first group, while in the second group, and particularly in the centenarians, a non-random association is observed between the mtDNA and nuclear DNA variability. Moreover, in centenarians the U haplogroup is over-represented (p=0.012) in subjects carrying the THO genotype unfavorable to longevity. On the whole these findings are in line with the hypothesis that longevity requires particular interactions between mtDNA and nuclear DNA and do not exclude the possibility that an RR has been maintained throughout evolution and it is present in higher organisms.

Adult↗

PubMed2000

An intervention resembling caloric restriction prolongs life span and retards aging in yeast.

The yeast Saccharomyces cerevisiae has a finite life span that is measured by the number of daughter cells an individual produces. The 20 genes known to determine yeast life span appear to function in more than one pathway, implicating a variety of physiological processes in yeast longevity. Less attention has been focused on environmental effects on yeast aging. We have examined the role that nutritional status plays in determining yeast life span. Reduction of the glucose concentration in the medium led to an increase in life span and to a delay in appearance of an aging phenotype. The increase in life span was the more extensive the lower the glucose levels. Life extension was also elicited by decreasing the amino acids content of the medium. This suggests that it is the decline in calories and not a particular nutrient that is responsible, in striking similarity to the effect on aging of caloric restriction in mammals. The caloric restriction effect did not require the induction of the retrograde response pathway, which signals the functional status of the mitochondrion and determines longevity. Furthermore, deletion of RTG3, a downstream mediator in this pathway, and caloric restriction had an additive effect, resulting in the largest increase (123%) in longevity described thus far in yeast. Thus, retrograde response and caloric restriction operate along distinct pathways in determining yeast longevity. These pathways may be exclusive, at least in part. This provides evidence for multiple mechanisms of metabolic control in yeast aging. Inasmuch as caloric restriction lowers blood glucose levels, this study raises the possibility that reduced glucose alters aging at the cellular level in mammals.

Amino Acids↗

PubMed2000

Metabolic control and gene dysregulation in yeast aging.

Life span in the yeast Saccharomyces cerevisiae is usually measured by the number of divisions individual cells complete. Four broad physiologic processes that determine yeast life span have been identified: metabolic control, resistance to stress, chromatin-dependent gene regulation, and genetic stability. A pathway of interorganelle communication involving mitochondria, the nucleus, and peroxisomes has provided a molecular mechanism of aging based on metabolic control. This pathway functions continuously, rather than as an on-off switch, in determining life span. The longevity gene RAS2 modulates this pathway. RAS2 also modulates a variety of other cellular processes, including stress responses and chromatin-dependent gene regulation. An optimal level of Ras2p activity is required for maximum longevity. This may be due to the integration of life maintenance processes by RAS2, which functions as a homeostatic device in yeast longevity. Loss of transcriptional silencing of heterochromatic regions of the genome is a mark of yeast aging. It is now clear that the functional status of chromatin plays an important role in aging. Changes in this functional status result in gene dysregulation, which can be altered by manipulation of the histone deacetylase genes. Silencing of ribosomal DNA appears to be of particular importance. Extrachromosomal ribosomal DNA circles are neither sufficient nor necessary for yeast aging.

Animals↗

PubMed2000

Aging and longevity genes.

The genetics of aging has made substantial strides in the past decade. This progress has been confined primarily to model organisms, such as filamentous fungi, yeast, nematodes, fruit flies, and mice, in which some thirty-five genes that determine life span have been cloned. These genes encode a wide array of cellular functions, indicating that there must be multiple mechanisms of aging. Nevertheless, some generalizations are already beginning to emerge. It is now clear that there are at least four broad physiological processes that play a role in aging: metabolic control, resistance to stress, gene dysregulation, and genetic stability. The first two of these at least are common themes that connect aging in yeast, nematodes, and fruit flies, and this convergence extends to caloric restriction, which postpones senescence and increases life span in rodents. Many of the human homologs of the longevity genes found in model organisms have been identified. This will lead to their use as candidate human longevity genes in population genetic studies. The urgency for such studies is great: The population is graying, and this research holds the promise of improvement in the quality of the later years of life.

Aging↗

PubMed1999

Longevity, genes, and aging: a view provided by a genetic model system.

The genetic analysis of aging in the yeast Saccharomyces cerevisiae has revealed the importance of metabolic capacity, resistance to stress, integrity of gene regulation, and genetic stability for longevity. A balance between these life maintenance processes is sustained by the RAS2 gene, which channels cellular resources among them. This gene cooperates with mitochondria and PHB1 in metabolic adjustments important for longevity. It also modulates stress responses. Transcriptional silencing of heterochromatic regions of the genome is lost during aging, suggesting that gene dysregulation accompanies the aging process. There is evidence that this age change plays a causal role. Aging possesses features of a nonlinear process, and it is likely that application of nonlinear system methodology to aging will be productive.

Aging↗

PubMed1999

Molecular mechanisms of yeast longevity.

The genetic analysis of yeast longevity has illuminated the underlying molecular mechanisms of aging that invoke the importance of metabolic regulation, genetic stability and stress resistance in determination of life span. The RAS genes have emerged as important modulators of life-maintenance processes and of life span itself.

Gene Expression Regulation, Fungal↗

PubMed1999

Modulation of life-span by histone deacetylase genes in Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae has a limited life-span, which is measured by the number of divisions that individual cells complete. Among the many changes that occur as yeasts age are alterations in chromatin-dependent transcriptional silencing. We have genetically manipulated histone deacetylases to modify chromatin, and we have examined the effect on yeast longevity. Deletion of the histone deacetylase gene RPD3 extended life-span. Its effects on chromatin functional state were evidenced by enhanced silencing at the three known heterochromatic regions of the genome, the silent mating type (HM), subtelomeric, and rDNA loci, which occurred even in the absence of SIR3. Similarly, the effect of the rpd3Delta on life-span did not depend on an intact Sir silencing complex. In fact, deletion of SIR3 itself had little effect on life-span, although it markedly accelerated the increase in cell generation time that is observed during yeast aging. Deletion of HDA1, another histone deacetylase gene, did not result in life-span extension, unless it was combined with deletion of SIR3. The hda1Delta sir3Delta resulted in an increase in silencing, but only at the rDNA locus. Deletion of RPD3 suppressed the loss of silencing in rDNA in a sir2 mutant; however, the silencing did not reach the level found in the rpd3Delta single mutant, and RPD3 deletion did not overcome the life-span shortening seen in the sir2 mutant. Deletion of both RPD3 and HDA1 caused a decrease in life-span, which resulted from a substantial increase in initial mortality of the population. The expression of both of these genes declines with age, providing one possible explanation for the increase in mortality during the life-span. Our results are consistent with the loss of rDNA silencing leading to aging in yeast. The functions of RPD3 and HDA1 do not overlap entirely. RPD3 exerts its effect on chromatin at additional sites in the genome, raising the possibility that events at loci other than rDNA play a role in the aging process.

Aging↗

PubMed1999

Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae.

Replicative capacity, which is the number of times an individual cell divides, is the measure of longevity in the yeast Saccharomyces cerevisiae. In this study, a process that involves signaling from the mitochondrion to the nucleus, called retrograde regulation, is shown to determine yeast longevity, and its induction resulted in postponed senescence. Activation of retrograde regulation, by genetic and environmental means, correlated with increased replicative capacity in four different S. cerevisiae strains. Deletion of a gene required for the retrograde response, RTG2, eliminated the increased replicative capacity. RAS2, a gene previously shown to influence longevity in yeast, interacts with retrograde regulation in setting yeast longevity. The molecular mechanism of aging elucidated here parallels the results of genetic studies of aging in nematodes and fruit flies, as well as the caloric restriction paradigm in mammals, and it underscores the importance of metabolic regulation in aging, suggesting a general applicability.

Antifungal Agents↗

PubMed1998

Role of RAS2 in recovery from chronic stress: effect on yeast life span.

The replicative life span of Saccharomyces cerevisiae was previously shown to be modulated by the homologous signal transducers Ras1p and Ras2p in a reciprocal manner. We have used thermal stress as a life span modulator in order to uncover functional differences between the RAS genes that may contribute to their divergent effects on life span. Chronic exposure of cells throughout life to recurring heat shocks at sublethal temperatures decreased their replicative life span. ras2 mutants, however, suffered the largest decrease compared to wild-type and ras1 mutant cells. The decrease was correlated with a substantial delay in resumption of budding upon recovery from these heat shocks, indicating an impaired renewal of cell cycling. Detailed analysis of gene expression showed that, during recovery, ras2 mutants were selectively impaired in down-regulation of stress-responsive genes and up-regulation of growth-promoting genes. Our results suggest that one of the functions of RAS2 in maintaining life span, for which RAS1 does not substitute, is to ensure renewal of growth and cell division after bouts of stress that cells encounter during their life. This activity of RAS2 is effected by the cyclic AMP pathway. Overexpression of RAS2, but not RAS2(ser42) which is deficient in the activation of adenylate cyclase, completely reversed the effect of chronic stress on life span. Thus, RAS2 is limiting for longevity in the face of chronic stress. Since RAS2 is known to down-regulate stress responses, this demonstrates that for longevity the ability to recover from stress is at least as important as the ability to mount a stress response.

Blotting, Northern↗

PubMed1998

Heat stress-induced life span extension in yeast.

The yeast Saccharomyces cerevisiae has a limited life span that can be measured by the number of times individual cells divide. Several genetic manipulations have been shown to prolong the yeast life span. However, environmental effects that extend longevity have been largely ignored. We have found that mild, nonlethal heat stress extended yeast life span when it was administered transiently early in life. The increased longevity was due to a reduction in the mortality rate that persisted over many cell divisions (generations) but was not permanent. The genes RAS1 and RAS2 were necessary to observe this effect of heat stress. The RAS2 gene is consistently required for maintenance of life span when heat stress is chronic or in its extension when heat stress is transient or absent altogether. RAS1, on the other hand, appears to have a role in signaling life extension induced by transient, mild heat stress, which is distinct from its life-span-curtailing effect in the absence of stress and its lack of involvement in the response to chronic heat stress. This distinction between the RAS genes may be partially related to their different effects on growth-promoting genes and stress-responsive genes. The ras2 mutation clearly hindered resumption of growth and recovery from stress, while the ras1 mutation did not. The HSP104 gene, which is largely responsible for induced thermotolerance in yeast, was necessary for life extension induced by transient heat stress. An interaction between mitochondrial petite mutations and heat stress was found, suggesting that mitochondria may be necessary for life extension by transient heat stress. The results raise the possibility that the RAS genes and mitochondria may play a role in the epigenetic inheritance of reduced mortality rate afforded by transient, mild heat stress.

Blotting, Northern↗

PubMed1998

Epigenetic stratification: the role of individual change in the biological aging process.

Aging is a complex process. It consists of a diverse assortment of seemingly random manifestations that occur in the individual, the mutual relationship and impact on mortality of which is frequently obscure. We derive a simple equation to model the aging process based on scale invariant and increasing change. The solution to this equation indicates that this change itself, irrespective of its quality, is the cause and not simply the effect of aging. This model establishes loss of homeostasis as a fundamental feature of aging. The model is deterministic, but it supports the stochastic nature of age changes. Paradoxically, this model states that a sufficient augmentation of aging processes results in a lack of aging. Experimental evidence in support of this model is presented that spans the levels of population mortality rates, cellular spatial organization, and gene dysregulation.

Aging↗

PubMed1998

Homologs of the yeast longevity gene LAG1 in Caenorhabditis elegans and human.

LAG1 is a longevity gene, the first such gene to be identified and cloned from the yeast Saccharomyces cerevisiae. A close homolog of this gene, which we call LAC1, has been found in the yeast genome. We have cloned the human homolog of LAG1 with the ultimate goal of examining its possible function in human aging. In the process, we have also cloned a homolog from the nematode worm Caenorhabditis elegans. Both of these homologs, LAG1Hs and LAG1Ce-1, functionally complemented the lethality of a lag1delta lac1delta double deletion, despite low overall sequence similarity to the yeast proteins. The proteins shared a short sequence, the Lag1 motif, and a similar transmembrane domain profile. Another, more distant human homolog, TRAM, which lacks this motif, did not complement. LAG1Hs also restored the life span of the double deletion, demonstrating that it functions in establishing the longevity phenotype in yeast. LAG1Hs mapped to 19p12, and it was expressed in only three tissues: brain, skeletal muscle, and testis. This gene possesses a trinucleotide (CTG) repeat within exon 1. This and its expression profile raise the possibility that it may be involved in neurodegenerative disease. This possibility suggests at least one way in which LAG1Hs might be involved in human aging.

Aging↗