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Search Results: 1 - 10 of 146940 matches for " Brian K. Kennedy "
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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.
Evidence that Proteasome-Dependent Degradation of the Retinoblastoma Protein in Cells Lacking A-Type Lamins Occurs Independently of Gankyrin and MDM2
Ryan T. Nitta, Catherine L. Smith, Brian K. Kennedy
PLOS ONE , 2007, DOI: 10.1371/journal.pone.0000963
Abstract: Background A-type lamins, predominantly lamins A and C, are nuclear intermediate filaments believed to act as scaffolds for assembly of transcription factors. Lamin A/C is necessary for the retinoblastoma protein (pRB) stabilization through unknown mechanism(s). Two oncoproteins, gankyrin and MDM2, are known to promote pRB degradation in other contexts. Consequently, we tested the hypothesis that gankyrin and/or MDM2 are required for enhanced pRB degradation in Lmna?/? fibroblasts. Principal Findings. To determine if gankyrin promotes pRB destabilization in the absence of lamin A/C, we first analyzed its protein levels in Lmna?/? fibroblasts. Both gankyrin mRNA levels and protein levels are increased in these cells, leading us to further investigate its role in pRB degradation. Consistent with prior reports, overexpression of gankyrin in Lmna+/+ cells destabilizes pRB. This decrease is functionally significant, since gankyrin overexpressing cells are resistant to p16ink4a-mediated cell cycle arrest. These findings suggest that lamin A-mediated degradation of pRB would be gankyrin-dependent. However, effective RNAi-enforced reduction of gankyrin expression in Lmna?/? cells was insufficient to restore pRB stability. To test the importance of MDM2, we disrupted the MDM2-pRB interaction by transfecting Lmna?/? cells with p14arf. p14arf expression was also insufficient to stabilize pRB or confer cell cycle arrest, suggesting that MDM2 also does not mediate pRB degradation in Lmna?/? cells. Conclusions/Significance Our findings suggest that pRB degradation in Lmna?/? cells occurs by gankyrin and MDM2-independent mechanisms, leading us to propose the existence of a third proteasome-dependent pathway for pRB degradation. Two findings from this study also increase the likelihood that lamin A/C functions as a tumor suppressor. First, protein levels of the oncoprotein gankyrin are elevated in Lmna?/? fibroblasts. Second, Lmna?/? cells are refractory to p14arf-mediated cell cycle arrest, as was previously shown with p16ink4a. Potential roles of lamin A/C in the suppression of tumorigenesis are discussed.
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.
Cell-Extrinsic Defective Lymphocyte Development in Lmna-/- Mice
J. Scott Hale,Richard L. Frock,Sara A. Mamman,Pamela J. Fink,Brian K. Kennedy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0010127
Abstract: Mutations in the LMNA gene, which encodes all A-type lamins, result in a variety of human diseases termed laminopathies. Lmna-/- mice appear normal at birth but become runted as early as 2 weeks of age and develop multiple tissue defects that mimic some aspects of human laminopathies. Lmna-/- mice also display smaller spleens and thymuses. In this study, we investigated whether altered lymphoid organ sizes are correlated with specific defects in lymphocyte development.
Decreased Proliferation Kinetics of Mouse Myoblasts Overexpressing FRG1
Steven C. Chen,Ellie Frett,Joseph Marx,Darko Bosnakovski,Xylena Reed,Michael Kyba,Brian K. Kennedy
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019780
Abstract: Although recent publications have linked the molecular events driving facioscapulohumeral muscular dystrophy (FSHD) to expression of the double homeobox transcription factor DUX4, overexpression of FRG1 has been proposed as one alternative causal agent as mice overexpressing FRG1 present with muscular dystrophy. Here, we characterize proliferative defects in two independent myoblast lines overexpressing FRG1. Myoblasts isolated from thigh muscle of FRG1 transgenic mice, an affected dystrophic muscle, exhibit delayed proliferation as measured by decreased clone size, whereas myoblasts isolated from the unaffected diaphragm muscle proliferated normally. To confirm the observation that overexpression of FRG1 could impair myoblast proliferation, we examined C2C12 myoblasts with inducible overexpression of FRG1, finding increased doubling time and G1-phase cells in mass culture after induction of FRG1 and decreased levels of pRb phosphorylation. We propose that depressed myoblast proliferation may contribute to the pathology of mice overexpressing FRG1 and may play a part in FSHD.
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
Author's Reply
Matt Kaeberlein,Di Hu,Emily O. Kerr,Mitsuhiro Tsuchiya,Eric A. Westman,Nick Dang,Stanley Fields,Brian K. Kennedy
PLOS Genetics , 2006, DOI: 10.1371/journal.pgen.0020034
Abstract:
Shortest-Path Network Analysis Is a Useful Approach toward Identifying Genetic Determinants of Longevity
J. R. Managbanag, Tarynn M. Witten, Danail Bonchev, Lindsay A. Fox, Mitsuhiro Tsuchiya, Brian K. Kennedy, Matt Kaeberlein
PLOS ONE , 2008, DOI: 10.1371/journal.pone.0003802
Abstract: Background Identification of genes that modulate longevity is a major focus of aging-related research and an area of intense public interest. In addition to facilitating an improved understanding of the basic mechanisms of aging, such genes represent potential targets for therapeutic intervention in multiple age-associated diseases, including cancer, heart disease, diabetes, and neurodegenerative disorders. To date, however, targeted efforts at identifying longevity-associated genes have been limited by a lack of predictive power, and useful algorithms for candidate gene-identification have also been lacking. Methodology/Principal Findings We have utilized a shortest-path network analysis to identify novel genes that modulate longevity in Saccharomyces cerevisiae. Based on a set of previously reported genes associated with increased life span, we applied a shortest-path network algorithm to a pre-existing protein–protein interaction dataset in order to construct a shortest-path longevity network. To validate this network, the replicative aging potential of 88 single-gene deletion strains corresponding to predicted components of the shortest-path longevity network was determined. Here we report that the single-gene deletion strains identified by our shortest-path longevity analysis are significantly enriched for mutations conferring either increased or decreased replicative life span, relative to a randomly selected set of 564 single-gene deletion strains or to the current data set available for the entire haploid deletion collection. Further, we report the identification of previously unknown longevity genes, several of which function in a conserved longevity pathway believed to mediate life span extension in response to dietary restriction. Conclusions/Significance This work demonstrates that shortest-path network analysis is a useful approach toward identifying genetic determinants of longevity and represents the first application of network analysis of aging to be extensively validated in a biological system. The novel longevity genes identified in this study are likely to yield further insight into the molecular mechanisms of aging and age-associated disease.
Increased Life Span due to Calorie Restriction in Respiratory-Deficient Yeast
Matt Kaeberlein ,Di Hu,Emily O Kerr,Mitsuhiro Tsuchiya,Eric A Westman,Nick Dang,Stanley Fields,Brian K Kennedy
PLOS Genetics , 2005, DOI: 10.1371/journal.pgen.0010069
Abstract: A model for replicative life span extension by calorie restriction (CR) in yeast has been proposed whereby reduced glucose in the growth medium leads to activation of the NAD+–dependent histone deacetylase Sir2. One mechanism proposed for this putative activation of Sir2 is that CR enhances the rate of respiration, in turn leading to altered levels of NAD+ or NADH, and ultimately resulting in enhanced Sir2 activity. An alternative mechanism has been proposed in which CR decreases levels of the Sir2 inhibitor nicotinamide through increased expression of the gene coding for nicotinamidase, PNC1. We have previously reported that life span extension by CR is not dependent on Sir2 in the long-lived BY4742 strain background. Here we have determined the requirement for respiration and the effect of nicotinamide levels on life span extension by CR. We find that CR confers robust life span extension in respiratory-deficient cells independent of strain background, and moreover, suppresses the premature mortality associated with loss of mitochondrial DNA in the short-lived PSY316 strain. Addition of nicotinamide to the medium dramatically shortens the life span of wild type cells, due to inhibition of Sir2. However, even in cells lacking both Sir2 and the replication fork block protein Fob1, nicotinamide partially prevents life span extension by CR. These findings (1) demonstrate that respiration is not required for the longevity benefits of CR in yeast, (2) show that nicotinamide inhibits life span extension by CR through a Sir2-independent mechanism, and (3) suggest that CR acts through a conserved, Sir2-independent mechanism in both PSY316 and BY4742.
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