Biomedical subjects

Scott D Pletcher

Publications and source records attributed to Scott D Pletcher.

16 recordsLinked to original sources

PubMed2006

Trade-offs between longevity and pathogen resistance in Drosophila melanogaster are mediated by NFkappaB signaling.

The innate immune response protects numerous organisms, including humans, from the universe of pathogenic molecules, viruses and micro-organisms. Despite its role in promoting pathogen resistance, inappropriate activation and expression of NFkappaB and other immunity-related effector molecules can lead to cancer, inflammation, and other diseases of aging. Understanding the mechanisms leading to immune system activation as well as the short- and long-term consequences of such activation on health and lifespan is therefore critical for the development of beneficial immuno-modulating and longevity-promoting interventions. Mechanisms of innate immunity are highly conserved across species, and we take advantage of genetic tools in the model organism, Drosophila melanogaster, to study the effects of acute and chronic activation of immunity pathways on pathogen resistance and general fitness of adult flies. Our findings indicate that fat body specific overexpression of a putative pathogen recognition molecule, peptidoglycan recognition protein (PGRP-LE), is sufficient for constitutive up-regulation of the immune response and for enhanced pathogen resistance. Primary components of fitness are unaffected by acute activation, but chronic activation leads to an inflammatory state and reduced lifespan. These phenotypes are dependent on the NFkappaB-related transcriptional factor, Relish, and they establish a mechanistic basis for a link between immunity, inflammation, and longevity.

Animals↗

PubMed2005

Flies and their golden apples: the effect of dietary restriction on Drosophila aging and age-dependent gene expression.

Reduced nutrient availability (dietary restriction) extends lifespan in species as diverse as yeast, nematode worms, Daphnia, Drosophila, and mammals. Recent demographic experiments have shown that moderate nutrient manipulation in adult Drosophila affects current mortality rate in a completely reversible manner, which suggests that dietary restriction in Drosophila increases lifespan through a reduction of the current risk of death rather than a slowing of aging-related damage. When examined in the light of the new demographic data, age-dependent changes in gene expression in normal and diet-restricted flies can provide unique insight into the biological processes affected by aging and may help identify molecular pathways that regulate it.

Aging↗

PubMed2005

Genome-wide gene expression in response to parasitoid attack in Drosophila.

BACKGROUND: Parasitoids are insect parasites whose larvae develop in the bodies of other insects. The main immune defense against parasitoids is encapsulation of the foreign body by blood cells, which subsequently often melanize. The capsule sequesters and kills the parasite. The molecular processes involved are still poorly understood, especially compared with insect humoral immunity. RESULTS: We explored the transcriptional response to parasitoid attack in Drosophila larvae at nine time points following parasitism, hybridizing five biologic replicates per time point to whole-genome microarrays for both parasitized and control larvae. We found significantly different expression profiles for 159 probe sets (representing genes), and we classified them into 16 clusters based on patterns of co-expression. A series of functional annotations were nonrandomly associated with different clusters, including several involving immunity and related functions. We also identified nonrandom associations of transcription factor binding sites for three main regulators of innate immune responses (GATA/srp-like, NF-kappaB/Rel-like and Stat), as well as a novel putative binding site for an unknown transcription factor. The appearance or absence of candidate genes previously associated with insect immunity in our differentially expressed gene set was surveyed. CONCLUSION: Most genes that exhibited altered expression following parasitoid attack differed from those induced during antimicrobial immune responses, and had not previously been associated with defense. Applying bioinformatic techniques contributed toward a description of the encapsulation response as an integrated system, identifying putative regulators of co-expressed and functionally related genes. Genome-wide studies such as ours are a powerful first approach to investigating novel genes involved in invertebrate immunity.

Animals↗

PubMed2005

Differential patterns of apoptosis in response to aging in Drosophila.

Several lines of evidence suggest that programmed cell death may play a role in the aging process and the age-related functional declines of multicellular organisms. To pave the way for the use of Drosophila to rigorously test this hypothesis in a genetic model organism, this work examines the pattern of apoptosis in the adult fly during aging. The analysis across the lifespan of caspase activity and DNA fragmentation shows that apoptosis occurs in adult flies at all ages and that it is linked to physiological age. The results establish that under normal conditions, fly aging is coupled with a lifelong gradual increase of apoptosis within muscle cells and an activation of apoptosis in fat cells of old flies. The nervous system does not show signs of apoptosis. These time- and tissue-specific changes indicate that aging influences the levels and the nature of the cells that commit to apoptosis. The comparison with the apoptotic response to starvation and oxidative stresses strongly suggests that the lifelong increase in flight and leg muscles results from the accumulation of oxidative damage associated with aging. This finding presents an attractive mechanism to account for the decline of locomotor functions and muscle loss in the elderly and opens the way for the genetic analysis of sarcopenia in Drosophila.

Adipose Tissue↗

PubMed2005

Dietary restriction, mortality trajectories, risk and damage.

Restriction of food intake extends lifespan in evolutionarily diverse organisms, including mammals. Dietary restriction (DR) also delays the appearance of ageing-related damage and pathology and keeps organisms in a youthful state for longer. DR has hence been suggested to lower the rate of ageing. Analysis of mortality rates can be used to test this idea. During ageing, mortality rates in general increase, approximately exponentially. Lifespan can be extended either by a reduction in the rate of increase in mortality rate with age or a lowering of the initial rate of mortality. A reduction in the slope of a mortality trajectory has generally been taken to indicate that the rate of ageing has been lowered. Data on the effects of temperature on mortality in Drosophila are in accordance with this idea. Lowered temperature extends lifespan solely by lowering the slope of the mortality trajectory and flies with a hotter thermal history have permanently elevated death rates. In contrast, lowering of the initial rate of mortality has been taken to leave the rate of ageing unaffected. In Drosophila and in mice, but not in rats, DR extends lifespan by lowering the initial mortality rate. In Drosophila, the effect of DR is acute, and mortality rate switches rapidly between DR and control values with the corresponding changes in nutritional regime. DR in Drosophila therefore has no impact upon the rate of ageing. Possible mechanisms by which DR can both delay damage and pathology and yet act acutely to determine mortality rates are discussed. In rodents, some phenotypes associated with DR, including microarray profiles, show rapid switching with changed nutritional regime, pointing to potentially acute effects of DR in mammals.

Animals↗

PubMed2004

Vital connections.

Scientists are currently exploring the structure and behavior of complex biological systems, which consist of networks of interacting entities. A recent paper in Proceedings of the Royal Society of London Series B Biological Sciences describes the distinctive characteristics of aging-related proteins in the yeast protein-protein interaction network. In this Perspective, I discuss the implications of these findings for longevity research.

Protein Interaction Mapping↗

PubMed2004

Comparing genomic expression patterns across species identifies shared transcriptional profile in aging.

We developed a method for systematically comparing gene expression patterns across organisms using genome-wide comparative analysis of DNA microarray experiments. We identified analogous gene expression programs comprising shared patterns of regulation across orthologous genes. Biological features of these patterns could be identified as highly conserved subpatterns that correspond to Gene Ontology categories. Here, we demonstrate these methods by analyzing a specific biological process, aging, and show that similar analysis can be applied to a range of biological processes. We found that two highly diverged animals, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, implement a shared adult-onset expression program of genes involved in mitochondrial metabolism, DNA repair, catabolism, peptidolysis and cellular transport. Most of these changes were implemented early in adulthood. Using this approach to search databases of gene expression data, we found conserved transcriptional signatures in larval development, embryogenesis, gametogenesis and mRNA degradation.

Age Factors↗

PubMed2004

Multivariate character process models for the analysis of two or more correlated function-valued traits.

Various methods, including random regression, structured antedependence models, and character process models, have been proposed for the genetic analysis of longitudinal data and other function-valued traits. For univariate problems, the character process models have been shown to perform well in comparison to alternative methods. The aim of this article is to present an extension of these models to the simultaneous analysis of two or more correlated function-valued traits. Analytical forms for stationary and nonstationary cross-covariance functions are studied. Comparisons with the other approaches are presented in a simulation study and in an example of a bivariate analysis of genetic covariance in age-specific fecundity and mortality in Drosophila. As in the univariate case, bivariate character process models with an exponential correlation were found to be quite close to first-order structured antedependence models. The simulation study showed that the choice of the most appropriate methodology is highly dependent on the covariance structure of the data. The bivariate character process approach proved to be able to deal with quite complex nonstationary and nonsymmetric cross-correlation structures and was found to be the most appropriate for the real data example of the fruit fly Drosophila melanogaster.

Age Factors↗

PubMed2003

Demography of dietary restriction and death in Drosophila.

Dietary restriction (DR) increases life-span in organisms from yeast to mammals, presumably by slowing the accumulation of aging-related damage. Here we show that in Drosophila, DR extends life-span entirely by reducing the short-term risk of death. Two days after the application of DR at any age for the first time, previously fully fed flies are no more likely to die than flies of the same age that have been subjected to long-term DR. DR of mammals may also reduce short-term risk of death, and hence DR instigated at any age could generate a full reversal of mortality.

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↗

PubMed2002

Mitigating the tithonus error: genetic analysis of mortality phenotypes.

Summarizing an organism's age at death in terms of the mean or maximum life-span is the most popular way to describe genetic effects on aging. In this Perspective, the author describes a new study with the fly Drosophila melanogaster, in which another type of measure is also used: the age-dependent risk of death, or age-specific mortality. Changes in age-specific mortality reflect the underlying physiological deterioration of an organism as it ages. Thus, the author argues that these changes provide a phenotype that is ideal for the genetic analysis of aging.

Aging↗

PubMed2002

Advice to an aging scientist.

Fifty years ago, Peter Medawar and George Williams developed two now-classic theories for the evolution of senescence. In the past 20 years, evolutionary biologists studying aging have developed explicit mathematical models of these theories, used these models to derive explicit predictions, and tested these predictions using a variety of approaches. But, we argue here, our singular focus on these models may have hindered progress in evolutionary studies of aging. Research in this area has not kept pace with dramatic advances in evolutionary theory and molecular genetics. Progress in evolutionary studies of aging will depend on a bold, integrative approach, incorporating evolutionary and molecular advances from other fields, along with the powerful statistical and mathematical tools now available. We discuss several specific examples where we may gain new insight into the causes of aging by looking to other evolutionary phenomena, including sexual conflict and the evolution of social behavior. In addition, we present new results which suggest that the analysis of gene networks may lend particular insight into the genetic underpinnings of the aging process.

Aging↗

PubMed2002

Genome-wide transcript profiles in aging and calorically restricted Drosophila melanogaster.

BACKGROUND: We characterized RNA transcript levels for the whole Drosophila genome during normal aging. We compared age-dependent profiles from animals aged under full-nutrient conditions with profiles obtained from animals maintained on a low-calorie medium to determine if caloric restriction slows the aging process. Specific biological functions impacted by caloric restriction were identified using the Gene Ontology annotation. We used the global patterns of expression profiles to test if particular genomic regions contribute differentially to changes in transcript profiles with age and if global disregulation of gene expression occurs during aging. RESULTS: Whole-genome transcript profiles contained a statistically powerful genetic signature of normal aging. Nearly 23% of the genome changed in transcript representation with age. Caloric restriction was accompanied by a slowing of the progression of normal, age-related changes in transcript levels. Many genes, including those associated with stress response and oogenesis, showed age-dependent transcript representation. Caloric restriction resulted in the downregulation of genes primarily involved in cell growth, metabolism, and reproduction. We found no evidence that age-dependent changes in transcription level were confined to genes localized to specific regions of the genome and found no support for widespread disregulation of gene expression with age. CONCLUSIONS: Aging is characterized by highly dynamic changes in the expression of many genes, which provides a powerful molecular description of the normal aging process. Caloric restriction extends life span by slowing down the rate of normal aging. Transcription levels of genes from a wide variety of biological functions and processes are impacted by age and dietary conditions.

Aging↗

PubMed2002

Population genomics: ageing by association.

Mutations in the gene Klotho lead to premature ageing in mice. Recent work on human genetic variation has identified an association between a particular allele of Klotho and human lifespan. A harbinger of things to come, this work illustrates the power and growth potential for association studies of human ageing.

Adolescent↗

PubMed2002

Non-parametric exploratory analysis of the covariance structure for genetic analysis of repeated measures and other function-value traits.

In the analysis of longitudinal data, before assuming a parametric model, an idea of the shape of the variance and correlation functions for both the genetic and environmental parts should be known. When a small number of observations is available for each subject at a fixed set of times, it is possible to estimate unstructured covariance matrices, but not when the number of observations over time is large and when individuals are not measured at all times. The non-parametric approach, based on the variogram, presented by Diggle & Verbyla (1998), is specially adapted for exploratory analysis of such data. This paper presents a generalization of their approach to genetic analyses. The methodology is applied to daily records for milk production in dairy cattle and data on age-specific fertility in Drosophila.

Animals↗

PubMed2002

Generalized character process models: estimating the genetic basis of traits that cannot be observed and that change with age or environmental conditions.

The genetic analysis of characters that change as a function of some independent and continuous variable has received increasing attention in the biological and statistical literature. Previous work in this area has focused on the analysis of normally distributed characters that are directly observed. We propose a framework for the development and specification of models for a quantitative genetic analysis of function-valued characters that are not directly observed, such as genetic variation in age-specific mortality rates or complex threshold characters. We employ a hybrid Markov chain Monte Carlo algorithm involving a Monte Carlo EM algorithm coupled with a Markov chain approximation to the likelihood, which is quite robust and provides accurate estimates of the parameters in our models. The methods are investigated using simulated data and are applied to a large data set measuring mortality rates in the fruit fly, Drosophila melanogaster.

Age Factors↗