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Search Results: 1 - 10 of 1616 matches for " Matt Kaeberlein "
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Genome-wide approaches to understanding human ageing
Matt Kaeberlein
Human Genomics , 2006, DOI: 10.1186/1479-7364-2-6-422
Abstract:
mTOR Inhibition: From Aging to Autism and Beyond
Matt Kaeberlein
Scientifica , 2013, DOI: 10.1155/2013/849186
Abstract: The mechanistic target of rapamycin (mTOR) is a highly conserved protein that regulates growth and proliferation in response to environmental and hormonal cues. Broadly speaking, organisms are constantly faced with the challenge of interpreting their environment and making a decision between “grow or do not grow.” mTOR is a major component of the network that makes this decision at the cellular level and, to some extent, the tissue and organismal level as well. Although overly simplistic, this framework can be useful when considering the myriad functions ascribed to mTOR and the pleiotropic phenotypes associated with genetic or pharmacological modulation of mTOR signaling. In this review, I will consider mTOR function in this context and attempt to summarize and interpret the growing body of literature demonstrating interesting and varied effects of mTOR inhibitors. These include robust effects on a multitude of age-related parameters and pathologies, as well as several other processes not obviously linked to aging or age-related disease. 1. Introduction mTOR regulates a diverse array of cellular processes through its catalytic function as a serine/threonine protein kinase of the phosphoinositide-3-kinase-related family [1]. It acts within at least two distinct molecular complexes: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) [2]. The composition of each complex is highly studied, and many of the distinct components of each complex have been characterized [3, 4]. mTORC1 consists of mTOR, the regulatory-associated protein of mTOR (raptor), the mammalian lethal with Sec13 protein 8 (mLST8), the DEP domain containing mTOR-interacting protein (deptor), and the proline-rich Akt substrate of 40?kDa (PRAS40). mTORC2 also contains mTOR and mLST8, but the remaining mTORC2 components are distinct from mTORC1. These include the rapamycin-insensitive companion of mTOR (rictor), protein observed with rictor (protor), mammalian stress-activated protein kinase-interacting protein 1 (mSin1), and proline-rich protein 5 (PRR5). Both mTOR complexes are essential, as loss of either raptor or rictor results in loss of viability [5, 6]. mTOR was first identified from studies in the budding yeast Saccharomyces cerevisiae of mutations that conferred altered sensitivity to the macrolide antibiotic rapamycin (also known as sirolimus) [7, 8]. Analysis of rapamycin resistant mutants led to the identification of two yeast genes, TOR1 and TOR2, that both encode mTOR kinases. Yeast Tor1 is found exclusively in mTORC1, while yeast Tor2 functions in both mTOR complexes. Thus,
YODA: Software to facilitate high-throughput analysis of chronological life span, growth rate, and survival in budding yeast
Brady Olsen, Christopher J Murakami, Matt Kaeberlein
BMC Bioinformatics , 2010, DOI: 10.1186/1471-2105-11-141
Abstract: Here we describe the Yeast Outgrowth Data Analyzer (YODA), an automated system for analyzing population survival of yeast cells based on the kinetics of outgrowth measured by optical density over time. YODA has been designed specifically for quantification of yeast chronological life span, but can also be used to quantify growth rate and survival of yeast cells in response to a variety of different conditions, including temperature, nutritional composition of the growth media, and chemical treatments. YODA is optimized for use with a Bioscreen C MBR shaker/incubator/plate reader, but is also amenable to use with any standard plate reader or spectrophotometer.We estimate that use of YODA as described here reduces the effort and resources required to measure chronological life span and analyze the resulting data by at least 15-fold.The ability to accurately monitor survival and growth rate of cells is essential for many assays employed in studies of the budding yeast. Changes in growth rate and survival over time are often monitored in response to a chemical treatment, environmental change (e.g. temperature, starvation, etc.), or genetic variant. For example, the yeast ORF deletion collection, which consists of >5000 unique single-gene deletion strains in an isogenic background, has been queried for more than 100 unique phenotypes by monitoring growth or viability under different conditions [1]. Growth rate (doubling time) of yeast cells can be quantified by monitoring the change in optical density at 600 nm (OD600) of a yeast culture under specified conditions. Survival of yeast cells has traditionally been quantified by plating the cells onto rich growth medium (yeast peptone dextrose, YPD) and counting colony forming units (CFUs) before and after treatment.One important assay that involves monitoring survival of yeast cells over time is measurement of chronological life span (CLS), which is defined as the length of time a yeast cell is able to maintain viability du
Sir2-Independent Life Span Extension by Calorie Restriction in Yeast
Matt Kaeberlein,Kathryn T. Kirkland,Stanley Fields,Brian K. Kennedy
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0020296
Abstract: Calorie restriction slows aging and increases life span in many organisms. In yeast, a mechanistic explanation has been proposed whereby calorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independent pathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of these genetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reported thus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes.
Recent Developments in Yeast Aging
Matt Kaeberlein ,Christopher R Burtner,Brian K Kennedy
PLOS Genetics , 2007, DOI: 10.1371/journal.pgen.0030084
Abstract: In the last decade, research into the molecular determinants of aging has progressed rapidly and much of this progress can be attributed to studies in invertebrate eukaryotic model organisms. Of these, single-celled yeast is the least complicated and most amenable to genetic and molecular manipulations. Supporting the use of this organism for aging research, increasing evidence has accumulated that a subset of pathways influencing longevity in yeast are conserved in other eukaryotes, including mammals. Here we briefly outline aging in yeast and describe recent findings that continue to keep this “simple” eukaryote at the forefront of aging research.
Composition and Acidification of the Culture Medium Influences Chronological Aging Similarly in Vineyard and Laboratory Yeast
Christopher J. Murakami, Valerie Wall, Nathan Basisty, Matt Kaeberlein
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024530
Abstract: Chronological aging has been studied extensively in laboratory yeast by culturing cells into stationary phase in synthetic complete medium with 2% glucose as the carbon source. During this process, acidification of the culture medium occurs due to secretion of organic acids, including acetic acid, which limits survival of yeast cells. Dietary restriction or buffering the medium to pH 6 prevents acidification and increases chronological life span. Here we set out to determine whether these effects are specific to laboratory-derived yeast by testing the chronological aging properties of the vineyard yeast strain RM11. Similar to the laboratory strain BY4743 and its haploid derivatives, RM11 and its haploid derivatives displayed increased chronological life span from dietary restriction, buffering the pH of the culture medium, or aging in rich medium. RM11 and BY4743 also displayed generally similar aging and growth characteristics when cultured in a variety of different carbon sources. These data support the idea that mechanisms of chronological aging are similar in both the laboratory and vineyard strains.
The MDT-15 Subunit of Mediator Interacts with Dietary Restriction to Modulate Longevity and Fluoranthene Toxicity in Caenorhabditis elegans
Jennifer Schleit, Valerie Z. Wall, Marissa Simko, Matt Kaeberlein
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028036
Abstract: Dietary restriction (DR), the limitation of calorie intake while maintaining proper nutrition, has been found to extend life span and delay the onset of age-associated disease in a wide range of species. Previous studies have suggested that DR can reduce the lethality of environmental toxins. To further examine the role of DR in toxin response, we measured life spans of the nematode Caenorhabditis elegans treated with the mutagenic polyaromatic hydrocarbon, fluoranthene (FLA). FLA is a direct byproduct of combustion, and is one of U.S. Environmental Protection Agency's sixteen priority environmental toxins. Treatment with 5 μg/ml FLA shortened the life spans of ad libitum fed nematodes, and DR resulted in increased sensitivity to FLA. To determine the role of detoxifying enzymes in the toxicity of FLA, we tested nematodes with mutations in the gene encoding the MDT-15 subunit of mediator, a transcriptional coactivator that regulates genes involved in fatty acid metabolism and detoxification. Mutation of mdt-15 increased the life span of FLA treated animals compared to wild-type animals with no difference observed between DR and ad libitum fed mdt-15 animals. We also examined mutants with altered insulin-IGF-1-like signaling (IIS), which is known to modulate life span and stress resistance in C. elegans independently of DR. Mutation of the genes coding for the insulin-like receptor DAF-2 or the FOXO-family transcription factor DAF16 did not alter the animals' susceptibility to FLA compared to wild type. Taken together, our results suggest that certain compounds have increased toxicity when combined with a DR regimen through increased metabolic activation. This increased metabolic activation appears to be mediated through the MDT-15 transcription factor and is independent of the IIS pathway.
Author's Reply.
Kaeberlein Matt,Hu Di,Kerr Emily O,Tsuchiya Mitsuhiro
PLOS Genetics , 2006,
Abstract:
Sir2-Independent Life Span Extension by Calorie Restriction in Yeast
Matt Kaeberlein,Kathryn T Kirkland,Stanley Fields,Brian K Kennedy
PLOS Biology , 2004, DOI: 10.1371/journal.pbio.0020296
Abstract: Calorie restriction slows aging and increases life span in many organisms. In yeast, a mechanistic explanation has been proposed whereby calorie restriction slows aging by activating Sir2. Here we report the identification of a Sir2-independent pathway responsible for a majority of the longevity benefit associated with calorie restriction. Deletion of FOB1 and overexpression of SIR2 have been previously found to increase life span by reducing the levels of toxic rDNA circles in aged mother cells. We find that combining calorie restriction with either of these genetic interventions dramatically enhances longevity, resulting in the longest-lived yeast strain reported thus far. Further, calorie restriction results in a greater life span extension in cells lacking both Sir2 and Fob1 than in cells where Sir2 is present. These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes.
Age- and calorie-independent life span extension from dietary restriction by bacterial deprivation in Caenorhabditis elegans
Erica D Smith, Tammi L Kaeberlein, Brynn T Lydum, Jennifer Sager, K Linnea Welton, Brian K Kennedy, Matt Kaeberlein
BMC Developmental Biology , 2008, DOI: 10.1186/1471-213x-8-49
Abstract: Using bacterial food deprivation as a means of DR in C. elegans, we show that transient DR confers long-term benefits including stress resistance and increased longevity. Consistent with studies in the fruit fly and in mice, we demonstrate that DR also enhances survival when initiated late in life. DR by bacterial food deprivation significantly increases life span in worms when initiated as late as 24 days of adulthood, an age at which greater than 50% of the cohort have died. These survival benefits are, at least partially, independent of food consumption, as control fed animals are no longer consuming bacterial food at this advanced age. Animals separated from the bacterial lawn by a barrier of solid agar have a life span intermediate between control fed and food restricted animals. Thus, we find that life span extension from bacterial deprivation can be partially suppressed by a diffusible component of the bacterial food source, suggesting a calorie-independent mechanism for life span extension by dietary restriction.Based on these findings, we propose that dietary restriction by bacterial deprivation increases longevity in C. elegans by a combination of reduced food consumption and decreased food sensing.Dietary restriction (DR), also referred to as calorie restriction, is an intervention that extends life span and delays the onset of age-related phenotypes in nearly all eukaryotic organisms in which it has been tested [1]. Simplistically, it is defined as a significant reduction in dietary intake in the absence of malnutrition. Many different approaches can be used to achieve DR. In mice and rats for example, life span extension is observed by either reducing the amount of food consumed daily (compared to an ad libitum control group) or by imposing an intermittent fasting regimen [2,3].In addition to simply reducing the amount of food intake, the effects of altering dietary composition has also been examined in different organisms. Methionine-restricted mice [4
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