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MSN2 and MSN4 Link Calorie Restriction and TOR to Sirtuin-Mediated Lifespan Extension in Saccharomyces cerevisiae  [PDF]
Oliver Medvedik,Dudley W. Lamming,Keyman D. Kim,David A. Sinclair
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0050261
Abstract: Calorie restriction (CR) robustly extends the lifespan of numerous species. In the yeast Saccharomyces cerevisiae, CR has been proposed to extend lifespan by boosting the activity of sirtuin deacetylases, thereby suppressing the formation of toxic repetitive ribosomal DNA (rDNA) circles. An alternative theory is that CR works by suppressing the TOR (target of rapamycin) signaling pathway, which extends lifespan via mechanisms that are unknown but thought to be independent of sirtuins. Here we show that TOR inhibition extends lifespan by the same mechanism as CR: by increasing Sir2p activity and stabilizing the rDNA locus. Further, we show that rDNA stabilization and lifespan extension by both CR and TOR signaling is due to the relocalization of the transcription factors Msn2p and Msn4p from the cytoplasm to the nucleus, where they increase expression of the nicotinamidase gene PNC1. These findings suggest that TOR and sirtuins may be part of the same longevity pathway in higher organisms, and that they may promote genomic stability during aging.
MSN2 and MSN4 Link Calorie Restriction and TOR to Sirtuin-Mediated Lifespan Extension in Saccharomyces cerevisiae  [PDF]
Oliver Medvedik equal contributor,Dudley W Lamming equal contributor,Keyman D Kim,David A Sinclair
PLOS Biology , 2007, DOI: 10.1371/journal.pbio.0050261
Abstract: Calorie restriction (CR) robustly extends the lifespan of numerous species. In the yeast Saccharomyces cerevisiae, CR has been proposed to extend lifespan by boosting the activity of sirtuin deacetylases, thereby suppressing the formation of toxic repetitive ribosomal DNA (rDNA) circles. An alternative theory is that CR works by suppressing the TOR (target of rapamycin) signaling pathway, which extends lifespan via mechanisms that are unknown but thought to be independent of sirtuins. Here we show that TOR inhibition extends lifespan by the same mechanism as CR: by increasing Sir2p activity and stabilizing the rDNA locus. Further, we show that rDNA stabilization and lifespan extension by both CR and TOR signaling is due to the relocalization of the transcription factors Msn2p and Msn4p from the cytoplasm to the nucleus, where they increase expression of the nicotinamidase gene PNC1. These findings suggest that TOR and sirtuins may be part of the same longevity pathway in higher organisms, and that they may promote genomic stability during aging.
Aging and Calorie Restriction Oppositely Affect Mitochondrial Biogenesis through TFAM Binding at Both Origins of Mitochondrial DNA Replication in Rat Liver  [PDF]
Anna Picca, Vito Pesce, Flavio Fracasso, Anna-Maria Joseph, Christiaan Leeuwenburgh, Angela M. S. Lezza
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074644
Abstract: Aging affects mitochondria in a tissue-specific manner. Calorie restriction (CR) is, so far, the only intervention able to delay or prevent the onset of several age-related changes also in mitochondria. Using livers from middle age (18-month-old), 28-month-old and 32-month-old ad libitum-fed and 28-month-old calorie-restricted rats we found an age-related decrease in mitochondrial DNA (mtDNA) content and mitochondrial transcription factor A (TFAM) amount, fully prevented by CR. We revealed also an age-related decrease, completely prevented by CR, for the proteins PGC-1α NRF-1 and cytochrome c oxidase subunit IV, supporting the efficiency of CR to forestall the age-related decrease in mitochondrial biogenesis. Furthermore, CR counteracted the age-related increase in oxidative damage to proteins, represented by the increased amount of oxidized peroxiredoxins (PRX-SO3) in the ad libitum-fed animals. An unexpected age-related decrease in the mitochondrial proteins peroxiredoxin III (Prx III) and superoxide dismutase 2 (SOD2), usually induced by increased ROS and involved in mitochondrial biogenesis, suggested a prevailing relevance of the age-reduced mitochondrial biogenesis above the induction by ROS in the regulation of expression of these genes with aging. The partial prevention of the decrease in Prx III and SOD2 proteins by CR also supported the preservation of mitochondrial biogenesis in the anti-aging action of CR. To investigate further the age- and CR-related effects on mitochondrial biogenesis we analyzed the in vivo binding of TFAM to specific mtDNA regions and demonstrated a marked increase in the TFAM-bound amounts of mtDNA at both origins of replication with aging, fully prevented by CR. A novel, positive correlation between the paired amounts of TFAM-bound mtDNA at these sub-regions was found in the joined middle age ad libitum-fed and 28-month-old calorie-restricted groups, but not in the 28-month-old ad libitum-fed counterpart suggesting a quite different modulation of TFAM binding at both origins of replication in aging and CR.
Calorie restriction and stroke
Silvia Manzanero, Mathias Gelderblom, Tim Magnus, Thiruma V Arumugam
Experimental & Translational Stroke Medicine , 2011, DOI: 10.1186/2040-7378-3-8
Abstract: In the western world the average calorie intake has steadily risen as have associated diseases. Calorie restriction (CR) is defined as a decrease in energy intake without lowering nutritional value. This simple intervention has shown, in a wide range of laboratory animals, to extend lifespan and decrease the incidence of several age-related diseases [1]. In humans, CR can reduce markers of oxidative stress and inflammation [2,3], and can lower cardiovascular disease risk [4]. Dietary energy restriction also benefits neurons, as suggested by data showing that CR protects neurons against dysfunction and degeneration in animal models of epileptic seizure, stroke and neurodegenerative diseases [5,6].The risk of ischemic stroke, the second major cause of morbidity and mortality worldwide, can be reduced through diet and lifestyle modification [7]. The mechanisms responsible for neuronal death caused by stroke are believed to involve metabolic compromise, over activation of glutamate receptors, cellular calcium overload, oxidative stress and inflammation [8]. Studies using in vivo and in vitro stroke models have identified several proteins and signalling pathways that can protect neurons against ischemic injury, including: neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF); protein chaperones, including heat shock protein 70 (Hsp70) and glucose regulated protein 78 (GRP78); antioxidant enzymes, such as heme oxygenase-1 (HO-1) and the regulator of mitochondrial biogenesis PGC-1α. Several studies suggest CR may promote neuronal survival and plasticity in ischemic stroke, by inducing neuroprotective factors and suppressing inflammatory pathways. The present article reviews findings supporting the neuroprotective effects of CR and discusses the mechanisms activated by CR in ischemic stroke.Experiments performed seven decades ago showed that CR increases the lifespan of rodents [9,10], and this has been
Calorie Restriction the Fountain of Youth  [PDF]
Bashir Ahmed Dar, Manzoor Ahmed Dar, Sheeba Bashir
Food and Nutrition Sciences (FNS) , 2012, DOI: 10.4236/fns.2012.311198
Abstract: Calorie restriction (CR) is as close to a real fountain of youth as any known technique is. Caloric restriction known to extend the human lifespan by up to five years has quietly become accepted among leading researchers. Even scientists who are cautious about anti-aging hype say it works. The formula is simple: Eat less. It could add years to your life. In the context of health and longevity, I analyzed data documenting proofs which suggest that the caloric restriction extends life span and retards age-related chronic diseases in a variety of species, including rats, mice, fish, flies, worms, and yeast as well as improve biomarkers of aging in humans. Research has shown that not only does it result in a longer lifespan, but it also lowers blood pressure, oxidative damage, cardiovascular disease, modifies insulin sensitivity, reduces loss of central nervous system cells, strengthens the immune system, lowers cholesterol, diminishes the rate of heart disease, reduces muscle oxygen loss, improves muscle function, reduces free radical damage to body tissue and helps stabilize blood sugar in adult-onset diabetes. Caloric restriction the most widely recognized life span-extending intervention has shown that it does indeed have age-slowing effects in humans like it has been shown to work in animals and Dr. Fontana has already made medical history in studying anti aging effects of caloric restriction.
Artemisinin mimics calorie restriction to initiate antioxidative responses and compromise telomere shortening  [PDF]
Da-Ting Wang,Ming Wu,Si-ming Li,Qian Gao,Qing-Ping Zeng
PeerJ , 2015, DOI: 10.7287/peerj.preprints.565v1
Abstract: Calorie restriction (CR) is known to extend lifespan among organisms with the putative mechanism underlying nitric oxide (NO)-enhanced mitochondrial biogenesis. However, whether NO maintains telomere intact that is implicated in life expectancy remains unknown. We report here the artemisinin derivative artesunate in a low concentration up-regulates mitochondrial SIRT3-SOD2 expression among global activation of antioxidative networks via the NO signaling cascade AMPK→Akt→eNOS→SIRT1→PGC-1α. While the NO donor sodium nitroprusside and the NO precursor L-arginine replicate the antioxidative responses, exogenous low-dose hydrogen peroxide also leads to attenuated oxidative stress. The tumor suppressor BRCA1 and other DNA repair partners are down-regulated after scavenging of reactive oxygen species. Upon treatment, telomere shortening is damped without telomerase up-regulation, highlighting telomere maintenance rather than telomere elongation. In conclusion, artesunate can mimic CR to activate antioxidative responses and alleviate telomere attrition via NO signaling, thereby maintaining the stability and integrity of chromosomes, which are the hallmarks of longevity.
Entropy Generation and Human Aging: Lifespan Entropy and Effect of Diet Composition and Caloric Restriction Diets  [PDF]
Carlos A. Silva,Kalyan Annamalai
Journal of Thermodynamics , 2009, DOI: 10.1155/2009/186723
Abstract: The first and second laws of thermodynamic were applied to statistical databases on nutrition and human growth in order to estimate the entropy generation over the human lifespan. The calculations were performed for the cases of variation in the diet composition and calorie restriction diets; and results were compared to a base case in which lifespan entropy generation was found to be 11 404 kJ/K per kg of body mass, predicting a lifespan of 73.78 and 81.61 years for the average male and female individuals respectively. From the analysis of the results, it was found that changes of diet % of fat and carbohydrates do not have a significant impact on predicted lifespan, while the diet % of proteins has an important effect. Reduction of diet protein % to the minimum recommended in nutrition literature yields an average increase of 3.3 years on the predicted lifespan. Changes in the calorie content of the diet also have an important effect, yielding a % increase in lifespan equal or higher than the % reduction in the diet caloric content. This correlates well experimental data on small mammal and insects, in which lifespan has been increased by diet restriction.
Sir2-Independent Life Span Extension by Calorie Restriction in Yeast  [PDF]
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.
Sir2-Independent Life Span Extension by Calorie Restriction in Yeast  [PDF]
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.
RNAP-II Molecules Participate in the Anchoring of the ORC to rDNA Replication Origins  [PDF]
Maria D. Mayan
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0053405
Abstract: The replication of genomic DNA is limited to a single round per cell cycle. The first component, which recognises and remains bound to origins from recognition until activation and replication elongation, is the origin recognition complex. How origin recognition complex (ORC) proteins remain associated with chromatin throughout the cell cycle is not yet completely understood. Several genome-wide studies have undoubtedly demonstrated that RNA polymerase II (RNAP-II) binding sites overlap with replication origins and with the binding sites of the replication components. RNAP-II is no longer merely associated with transcription elongation. Several reports have demonstrated that RNAP-II molecules affect chromatin structure, transcription, mRNA processing, recombination and DNA repair, among others. Most of these activities have been reported to directly depend on the interaction of proteins with the C-terminal domain (CTD) of RNAP-II. Two-dimensional gels results and ChIP analysis presented herein suggest that stalled RNAP-II molecules bound to the rDNA chromatin participate in the anchoring of ORC proteins to origins during the G1 and S-phases. The results show that in the absence of RNAP-II, Orc1p, Orc2p and Cdc6p do not bind to origins. Moreover, co-immunoprecipitation experiments suggest that Ser2P-CTD and hypophosphorylated RNAP-II interact with Orc1p. In the context of rDNA, cryptic transcription by RNAP-II did not negatively interfere with DNA replication. However, the results indicate that RNAP-II is not necessary to maintain the binding of ORCs to the origins during metaphase. These findings highlight for the first time the potential importance of stalled RNAP-II in the regulation of DNA replication.
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