Brian Kennedy

..Here we compare and contrast the results from genome-wide aging screens and assess the likelihood that there are "public" aging mechanisms...

..Second, Lmna-/- cells are refractory to p14(arf)-mediated cell cycle arrest, as was previously shown with p16(ink4a). Potential roles of lamin A/C in the suppression of tumorigenesis are discussed...

..These findings indicate that Sir2 and calorie restriction act in parallel pathways to promote longevity in yeast and, perhaps, higher eukaryotes...

..Dietary restriction (DR) increases life span and delays age-associated disease in many organisms. The mechanism by which DR enhances longevity is not well understood...

..Often, the mammalian factor retains function in yeast, and this allows investigators to exploit the experimental tractability of yeast to ask a diverse set of questions...

..In this review, I discuss data from genome-wide screens in the context of evolutionary theories of ageing and raise issues regarding the increasing complexity associated with the genetics of longevity...

..These findings do link lamin A/C to the functional activation of a critical tumor suppressor pathway and further the possibility that somatic mutations in LMNA contribute to tumor progression...

..Recently, Zid et al. (Zid et al., 2009) linked the benefits of dietary restriction in flies to increased levels of the downstream TOR target 4E-BP1 and corresponding changes in the relative translation rates of classes of mRNAs...

..Here we discuss the links between nutrient reduction and enhanced longevity with emphasis on evolutionarily conserved nutrient response signaling...

..Other significant findings have connected translation control with other known longevity pathways and provided fodder for mechanistic hypotheses. Here, we summarize advances in this emerging field and raise questions for future studies...

..Thus, we propose that lifespan extension by CR is independent of sirtuins and that nicotinamide has sirtuin-independent effects on lifespan extension by CR...

..We propose that up-regulation of a highly conserved response to starvation-induced stress is important for life span extension by decreased TOR signaling in yeast and higher eukaryotes...

..Genetic epistasis analyses suggest that dietary restriction, reduced 60S subunit abundance, and Gcn4 activation extend yeast life span by similar mechanisms...

..In contrast to measurements of aging for mitotic cells, cell survival in the nonmitotic state is decreased by Sir2 activity under conditions that mimic calorie restriction...

..Removal of bacterial food also increases lifespan when initiated in postreproductive adults, suggesting that dietary restriction started during middle age can result in a substantial longevity benefit that is independent of reproduction...

..In light of these findings, the mechanism accounting for putative longevity effects of resveratrol should be reexamined...

..We also report that life-span extension from dietary restriction does not require any of the five yeast sirtuins (Sir2, Hst1, Hst2, Hst3, or Hst4) either alone or in combination...

..This Hot Topic article discusses papers published in the last year related to the importance of translation and its regulation by signaling through the target of rapamycin kinase, in modulating aging and age-associated diseases...

..Contradictory to this, we find that CR greatly increases life span in cells lacking Sir2, Hst1, and Hst2, which suggests that CR is not mediated by Sir2, Hst2, or Hst1...

..These findings demonstrate that dietary restriction confers a general protective effect against proteotoxicity and promotes longevity by a mechanism involving hsf-1...

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..We propose that the TOR and Sch9 kinases define a primary conduit through which excess nutrient intake limits longevity in yeast...

..Together, these findings indicate that the genetic component of life span determination is significantly conserved between divergent eukaryotic species, and suggest pathways that are likely to play a similar role in mammalian aging...

..Importantly, studies published this year also began to provide insights into specific mechanisms by which altered mRNA translation does (and in some cases does not) slow aging in invertebrate model organisms...

..Here we briefly outline aging in yeast and describe recent findings that continue to keep this "simple" eukaryote at the forefront of aging research...

..In summary, this study underscores and elaborates upon predicted pathways by which mutations restore mating function to yeast diploids and identifies new mutants warranting further study...

..These findings indicate that A-type lamins can promote transcriptional repression when in proximity of a promoter...

..Longevity studies in mammals are not published to date. Instead, we highlight studies in mouse models, which indicate that dampening the TOR pathway leads to widespread protection from an array of age-related diseases...

..These results define a limited number of genes likely to regulate replicative life span in a strain-independent manner, and create a basis for future epistasis analysis to determine genetic pathways of aging...

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..The delayed differentiation kinetics and decreased differentiation potential of lamin A/C-deficient and emerin-deficient myoblasts may in part underlie the dystrophic phenotypes observed in patients with EDMD...

..These observations, coupled with genetic studies of longevity, lead to a hypothesis whereby progeria syndromes accelerate a subset of the pathological changes that together drive the normal ageing process...

..We propose that yeast deficient in peroxisomal and other functions are sensitive to oleate perhaps because of an inability to effectively control the fatty acid composition of membrane phospholipids...

..Here, we compare and contrast the LMNA mutations leading to laminopathies with emphasis on progerias, and discuss possible functional roles for A-type lamins in the maintenance of healthy tissues...

..These findings have relevant pharmacological implications because aging in mammals is characterized by metabolic decline associated with obesity, altered body fat distribution, and insulin resistance...

..We conclude that acetic acid induced mortality is the primary mechanism of chronological aging in yeast under standard conditions...

..A recent study finds that LMNA, a gene targeted for mutation in Hutchinson Gilford Progeria Syndrome, may control the onset of aging-associated decline in normal fibroblasts...

..When compared to WRN-mutant WS, LMNA-mutant atypical WS patients appear to show earlier onset and possibly more severe ageing-related symptoms...

..Furthermore, lamin A/C plays a minimal role in the differentiation of 3T3-L1...

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..Some features of this disorder are also present in laminopathies caused by mutant LMNA encoding nuclear lamin A/C. Because of this similarity, we sequenced LMNA in individuals with atypical Werner's syndrome (wild-type WRN)...

..They further raise the possibility that altered pRB function may be a contributing factor in dystrophic syndromes arising from LMNA mutation...

..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...

..These results suggest that mammalian cells undergo a large-scale reorganization of chromatin during the rounds of DNA replication that precede cell cycle exit...

..Here, we describe several recent studies that promote the view that regulated association with subcompartments of the nucleus is inherent to tumor-suppressor function...

..Through achieving a better understand of the modulatory role played by regulated protein translation in aging, we will be able to pinpoint key targets for pharmacological interventions. ..

..Findings from these studies will identify and test potential mechanistic underpinnings that underlie Hutchinson-Gilford progeria syndrome and other A-type lamin-associated diseases. ..

..We have determined that reduced S6 kinase function leads to lifespan extension in organisms ranging from yeast to mice. In this proposal, we will dissect the mechanisms by which S6 kinase activity accelerates the aging process. ..

..When completed, this study will dramatically improve our understanding of aging in yeast and lead to models of caloric restriction that can be tested in mammalian systems. ..

..Myoblast cell lines, generated from Lmna-/- mice, exhibit differentiation defects. These defects will be studied at the molecular level to better understand how aberrant A-type lamin function leads to tissue degeneration. ..

..When completed, this study will dramatically improve our understanding of aging in yeast and lead to models of caloric restriction that can be tested in mammalian systems. ..