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Caenorhabditis elegans PI3K mutants reveal novel genes underlying exceptional stress resistance and lifespanEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Two age-1 nonsense mutants, truncating the class-I phosphatidylinositol 3-kinase catalytic subunit (PI3KCS) before its kinase domain, confer extraordinary longevity and stress-resistance to Caenorhabditis elegans. These traits, unique to second-generation homozygotes, are blunted at the first generation and are largely reversed by additional mutations to DAF-16/FOXO, a transcription factor downstream of AGE-1 in insulin-like signaling. The strong age-1 alleles (mg44, m333) were compared with the weaker hx546 allele on expression microarrays, testing four independent cohorts of each allele. Among 276 genes with significantl...
Source: Aging Cell - October 29, 2009 Category: Cytology Authors: Srinivas Ayyadevara, Çagdaþ Tazearslan, Puneet Bharill, Ramani Alla, Eric Siegel, Robert J. Shmookler Reis Source Type: journals

Exploring mechanisms of sex differences in longevity: lifetime ovary exposure and exceptional longevity in dogsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To move closer to understanding the mechanistic underpinnings of sex differences in human longevity, we studied pet dogs to determine whether lifetime duration of ovary exposure was associated with exceptional longevity. This hypothesis was tested by collecting and analyzing lifetime medical histories, age at death, and cause of death for a cohort of canine 'centenarians'[ndash] exceptionally long-lived Rottweiler dogs that lived more than 30% longer than average life expectancy for the breed. Sex and lifetime ovary exposure in the oldest-old Rottweilers (age at death, [ge] 13 years) were compared to a cohort of Rottweiler...
Source: Aging Cell - October 27, 2009 Category: Cytology Authors: David J. Waters, Seema S. Kengeri, Beth Clever, Julie A. Booth, Aimee H Maras, Deborah L. Schlittler, Michael G. Hayek Source Type: journals

Hot topics in aging research: protein translation, 2009Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In the last few years, links between regulation of mRNA translation and aging have been firmly established in invertebrate model organisms. This year, a possible relationship between mRNA translation and aging in mammals has been established with the report that rapamycin increases lifespan in mice. 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. (Source: Aging Cell)
Source: Aging Cell - October 16, 2009 Category: Cytology Authors: Brian K. Kennedy, Matt Kaeberlein Source Type: journals

Hedgehog signaling maintains hair follicle stem cell phenotype in young and aged human skinEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Skin hair follicles (HF) contain bulge stem cells (SC) that regenerate HFs during hair cycles, and repair skin epithelia following injury. As natural aging is associated with decreased skin repair capacity in humans, we have investigated the impact of age on human scalp HF bulge cell number and function. Here, we isolated human bulge cells, characterized as CD200+/KRT15+/KRT19+ cells of the HF, by dissection-combined CD200 selection in young and aged human skin. Targeted transcriptional profiling indicates that KRT15, KRT19, Dkk3, Dkk4, Tcf3, S100A4, Gas1, EGFR and CTGF/CCN2 are also preferentially expressed by human bulge...
Source: Aging Cell - October 8, 2009 Category: Cytology Authors: Laure Rittié, Stefan W. Stoll, Sewon Kang, John J. Voorhees, Gary J. Fisher Source Type: journals

Calorie restriction effects on silencing and recombination at the yeast rDNAEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aging research has developed rapidly over the past decade, identifying individual genes and molecular mechanisms of the aging process through the use of model organisms and high throughput technologies. Calorie restriction (CR) is the most widely researched environmental manipulation that extends lifespan. Activation of the NAD+-dependent protein deacetylase Sir2 (Silent Information Regulator 2) has been proposed to mediate the beneficial effects of CR in the budding yeast Saccharomyces cerevisiae, as well as other organisms. Here, we show that in contrast to previous reports, Sir2 is not stimulated by CR to strengthen sil...
Source: Aging Cell - October 6, 2009 Category: Cytology Authors: Daniel L. Smith Jr, Chonghua Li, Mirela Matecic, Nazif Maqani, Mary Bryk, Jeffrey S. Smith Source Type: journals

Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathwayEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We report that oxaloacetate supplementation increased lifespan in Caenorhabditis elegans. The increase was dependent on the transcription factor, FOXO/DAF-16, and the energy sensor, AMP-activated protein kinase, indicating involvement of a pathway that is also required for lifespan extension through dietary restriction. These results demonstrate that supplementation of the citric acid cycle metabolite, oxaloacetate, influences a longevity pathway, and suggest a tractable means of introducing the health-related benefits of dietary restriction. (Source: Aging Cell)
Source: Aging Cell - September 30, 2009 Category: Cytology Authors: David S. Williams, Alan Cash, Lara Hamadani, Tanja Diemer Source Type: journals

Relative roles of TGF-β1 and Wnt in the systemic regulation and aging of satellite cell responsesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Muscle stem (satellite) cells are relatively resistant to cell-autonomous aging. Instead, their endogenous signaling profile and regenerative capacity is strongly influenced by the aged P-Smad3, differentiated niche, and by the aged circulation. With respect to muscle fibers, we previously established that a shift from active Notch to excessive transforming growth factor-beta (TGF-[beta]) induces CDK inhibitors in satellite cells, thereby interfering with productive myogenic responses. In contrast, the systemic inhibitor of muscle repair, elevated in old sera, was suggested to be Wnt. Here, we examined the age-dependent my...
Source: Aging Cell - September 24, 2009 Category: Cytology Authors: Morgan E. Carlson, Michael J. Conboy, Michael Hsu, Laurel Barchas, Jaemin Jeong, Anshu Agrawal, Amanda J. Mikels, Smita Agrawal, David V. Schaffer, Irina M. Conboy Source Type: journals

Ambient temperature influences aging in an annual fish (Nothobranchius rachovii)Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we examined the survivorship and the aging process of the annual fish (Nothobranchius rachovii) reared under high (30 °C), moderate (25 °C) and low (20 °C) ambient temperatures. The results showed that low ambient temperatures prolong survivorship, whereas high ambient temperatures shorten survivorship. At low ambient temperature, expression of senescence-associated [beta]-galactosidase, lipofuscin, reactive oxygen species, lipid peroxidation, protein oxidation, mitochondrial density and ADP/ATP ratio were reduced compared with those reared at high and moderate temperatures, whereas catalase activity, Mn-...
Source: Aging Cell - September 24, 2009 Category: Cytology Authors: Chin-Yuan Hsu, Ya-Chi Chiu Source Type: journals

Epigenetic gambling and epigenetic drift as an antagonistic pleiotropic mechanism of agingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Generations of biogerontologists have been puzzled by the marked intraspecific variations in lifespan of their experimental model organisms despite all efforts to control both genotype and environment. The most cogent example comes from life table studies of wild-type Caenorhabditis elegans when grown in suspension cultures using axenic media. While nuclear and mitochondrial somatic mutations and 'thermodynamic noise' likely contribute to such lifespan variegations, I raise an additional hypothetical mechanism, one that may have evolved as a mechanism of phenotypic variation which could have preceded the evolution of meiot...
Source: Aging Cell - September 17, 2009 Category: Cytology Authors: George M. Martin Source Type: journals

Methionine sulfoxide reductase A expression is regulated by the DAF-16/FOXO pathway in Caenorhabditis elegansEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The methionine sulfoxide reductase system has been implicated in aging and protection against oxidative stress. This conserved system reverses the oxidation of methionine residues within proteins. We analyzed one of the components of this system, the methionine sulfoxide reductase A gene, in Caenorhabditis elegans. We found that the msra-1 gene is expressed in most tissues, particularly in the intestine and the nervous system. Worms carrying a deletion of the msra-1 gene are more sensitive to oxidative stress, show chemotaxis and locomotory defects, and a 30% decrease in median survival. We established that msra-1 expressi...
Source: Aging Cell - September 10, 2009 Category: Cytology Authors: Alicia N. Minniti, Romina Cataldo, Carla Trigo, Luis Vasquez, Patricio Mujica, Federico Leighton, Nibaldo C. Inestrosa, Rebeca Aldunate Source Type: journals

Dysfunction of the unfolded protein response increases neurodegeneration in aged rat hippocampus following proteasome inhibitionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
We examined in young and aged rat hippocampus the activation of the unfolded protein response (UPR) under cellular stress induced by proteasome inhibition. Lactacystin injection blocked proteasome activity in young and aged animals in a similar extent and increased the amount of ubiquitinated proteins. Young animals activated the three UPR arms, IRE1[alpha], ATF6[alpha] and PERK, whereas aged rats failed to induce the IRE1[alpha] and ATF6[alpha] pathways. In consequence, aged animals did not induce the expression of pro-survival factors (chaperones, Bcl-XL and Bcl-2), displayed a more sustained expression of pro-apoptotic ...
Source: Aging Cell - September 10, 2009 Category: Cytology Authors: María Paz Gavilán, Cristina Pintado, Elena Gavilán, Sebastián Jiménez, Rosa M. Ríos, Javier Vitorica, Angélica Castaño, Diego Ruano Source Type: journals

Mortality shifts in Caenorhabditis elegans: remembrance of conditions pastEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The analysis of age-specific mortality can yield insights into how anti-aging interventions operate that cannot be matched by simple assessment of longevity. Mortality, as opposed to longevity, can be used to assess the effects of an anti-aging intervention on a daily basis, rather than only after most animals have died. Various gerontogene mutations in Caenorhabditis elegans have been shown to increase longevity as much as tenfold and to decrease mortality at some ages even more. Environmental alterations, such as reduced food intake (dietary restriction) and lower temperature also result in reduced mortality soon after t...
Source: Aging Cell - September 10, 2009 Category: Cytology Authors: Deqing Wu, Shane L. Rea, James R. Cypser, Thomas E. Johnson Source Type: journals

The efficiency of mitochondrial electron transport chain is increased in the long-lived mrg19 Saccharomyces cerevisiaeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we provide evidence for the existence of an alternative pathway to explain the observed higher mitochondrial efficiency in the long-lived mrg19 mutant of Saccharomyces cerevisiae. Although we observe similar amounts of mitochondria in mrg19 and wild-type (wt) yeast, we find that mrg19 mitochondria have higher expression of ETC components per mitochondria in comparison with the wt. These findings demonstrate that more efficient mitochondria because of increased ETC per mitochondria can also produce less mtROS. Taken together, our findings provide evidence for an alternative explanation for the involvement of ...
Source: Aging Cell - September 1, 2009 Category: Cytology Authors: Nitish Mittal, M. Madan Babu, Nilanjan Roy Source Type: journals

Calorie restriction reduces rDNA recombination independently of rDNA silencingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Calorie restriction (CR) extends lifespan in yeast, worms, flies and mammals, suggesting that it acts via a conserved mechanism. In yeast, activation of the NAD-dependent histone deacetylase, Sir2, by CR is thought to increase silencing at the ribosomal DNA, thereby reducing the recombination-induced generation of extrachromosomal rDNA circles, hence increasing replicative lifespan. Although accumulation of extrachromosomal rDNA circles is specific to yeast aging, it is thought that Sirtuin activation represents a conserved longevity mechanism through which the beneficial effects of CR are mediated in various species. We s...
Source: Aging Cell - September 1, 2009 Category: Cytology Authors: Michèle Riesen, Alan Morgan Source Type: journals

Effects of myostatin deletion in aging miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Inhibitors of myostatin, a negative regulator of skeletal muscle mass, are being developed to mitigate aging-related muscle loss. Knock-out (KO) mouse studies suggest myostatin also affects adiposity, glucose handling and cardiac growth. However, the cardiac consequences of inhibiting myostatin remain unclear. Myostatin inhibition can potentiate cardiac growth in specific settings (Morissette et al., 2006), a concern because of cardiac hypertrophy is associated with adverse clinical outcomes. Therefore, we examined the systemic and cardiac effects of myostatin deletion in aged mice (27[ndash]30 months old). Heart mass incr...
Source: Aging Cell - August 30, 2009 Category: Cytology Authors: Michael R. Morissette, Janelle C. Stricker, Michael A. Rosenberg, Cattleya Buranasombati, Emily B. Levitan, Murray A. Mittleman, Anthony Rosenzweig Source Type: journals

Quantification of mitochondrial DNA mutation loadEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Mitochondrial DNA (mtDNA) mutations are an important cause of genetic disease and have been proposed to play a role in the ageing process. Quantification of total mtDNA mutation load in ageing tissues is difficult as mutational events are rare in a background of wild-type molecules, and detection of individual mutated molecules is beyond the sensitivity of most sequencing based techniques. The methods currently most commonly used to document the incidence of mtDNA point mutations in ageing include post-PCR cloning, single-molecule PCR and the random mutation capture assay. The mtDNA mutation load obtained by these differen...
Source: Aging Cell - August 12, 2009 Category: Cytology Authors: Laura C. Greaves, Nina E. Beadle, Geoffrey A. Taylor, Daniel Commane, John C. Mathers, Konstantin Khrapko, Doug M. Turnbull Source Type: journals

d4eBP acts downstream of both dTOR and dFoxo to modulate cardiac functional aging in DrosophilaEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
dTOR (target of rapamycin) and dFoxo respond to changes in the nutritional environment to induce a broad range of responses in multiple tissue types. Both dTOR and dFoxo have been demonstrated to control the rate of age-related decline in cardiac function. Here, we show that the Eif4e-binding protein (d4eBP) is sufficient to protect long-term cardiac function against age-related decline and that up-regulation of dEif4e is sufficient to recapitulate the effects of high dTOR or insulin signaling. We also provide evidence that d4eBP acts tissue-autonomously and downstream of dTOR and dFoxo in the myocardium, where it enhances...
Source: Aging Cell - August 6, 2009 Category: Cytology Authors: Robert Wessells, Erin Fitzgerald, Nicole Piazza, Karen Ocorr, Samantha Morley, Claire Davies, Hui-Ying Lim, Lisa Elmén, Michael Hayes, Sean Oldham, Rolf Bodmer Source Type: journals

Increased CaVβ1a expression with aging contributes to skeletal muscle weaknessEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Ca2+ release from the sarcoplasmic reticulum (SR) into the cytosol is a crucial part of excitation[ndash]contraction (E-C) coupling. Excitation[ndash]contraction uncoupling, a deficit in Ca2+ release from the SR, is thought to be responsible for at least some of the loss in specific force observed in aging skeletal muscle. Excitation[ndash]contraction uncoupling may be caused by alterations in expression of the voltage-dependent calcium channel [alpha]1s (CaV1.1) and [beta]1a (CaV[beta]1a) subunits, both of which are necessary for E-C coupling to occur. While previous studies have found CaV1.1 expression declines in old ro...
Source: Aging Cell - August 4, 2009 Category: Cytology Authors: Jackson R. Taylor, Zhenlin Zheng, Zhong-Min Wang, Anthony M. Payne, María L. Messi, Osvaldo Delbono Source Type: journals

Aging-dependent upregulation of IL-23p19 gene expression in dendritic cells is associated with differential transcription factor binding and histone modificationsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Age-associated changes in immune response increase the risk of infection and promote inflammation and autoimmunity in older adults. The newly discovered cytokine IL-23 contributes to the maintenance and expansion of Th-17 cells, which promote proinflammatory responses. Our preliminary findings suggested that Th-17 responses are increased in aged mice. IL-23 consists of p40 and p19 subunits. Expression of the p19 subunit is regulated at the transcriptional level by NF-[kappa]B p65 and c-Rel transcription factors. Using bone-marrow-derived dendritic cells (DCs) from C57BL/6 mice, we show that IL-23 protein production and p19...
Source: Aging Cell - August 2, 2009 Category: Cytology Authors: Rabab El Mezayen, Mohamed El Gazzar, Rebecca Myer, Kevin P. High Source Type: journals

Calorie restriction alters mitochondrial protein acetylationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Calorie restriction (CR) increases lifespan in organisms ranging from budding yeast through mammals. Mitochondrial adaptation represents a key component of the response to CR. Molecular mechanisms underlying this adaptation are largely unknown. Here we show that lysine acetylation of mitochondrial proteins is altered during CR in a tissue-specific fashion. Via large-scale mass spectrometry screening, we identify 72 candidate proteins involved in a variety of metabolic pathways with altered acetylation during CR. Mitochondrial acetylation changes may play an important role in the pro-longevity CR response. (Source: Aging Cell)
Source: Aging Cell - July 29, 2009 Category: Cytology Authors: Bjoern Schwer, Mark Eckersdorff, Yu Li, Jeffrey C. Silva, Damian Fermin, Martin V. Kurtev, Cosmas Giallourakis, Michael J. Comb, Frederick W. Alt, David B. Lombard Source Type: journals

Some highlights of research on aging with invertebrates, 2009Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This annual review focuses on invertebrate model organisms, which shed light on new mechanisms in aging and provide excellent systems for both genome-wide and in-depth analysis. This year, protein interaction networks have been used in a new bioinformatic approach to identify novel genes that extend replicative lifespan in yeast. In an extended approach, using a new, human protein interaction network, information from the invertebrates was used to identify new, candidate genes for lifespan extension and their orthologues were validated in the nematode Caenorhabditis elegans. Chemosensation of diffusible substances from bac...
Source: Aging Cell - July 23, 2009 Category: Cytology Authors: Linda Partridge Source Type: journals

Nutrients, not caloric restriction, extend lifespan in Queensland fruit flies (Bactrocera tryoni)Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Caloric restriction (CR) has been widely accepted as a mechanism explaining increased lifespan (LS) in organisms subjected to dietary restriction (DR), but recent studies investigating the role of nutrients have challenged the role of CR in extending longevity. Fuelling this debate is the difficulty in experimentally disentangling CR and nutrient effects due to compensatory feeding (CF) behaviour. We quantified CF by measuring the volume of solution imbibed and determined how calories and nutrients influenced LS and fecundity in unmated females of the Queensland fruit fly, Bactocera tryoni (Diptera: Tephritidae). We restri...
Source: Aging Cell - July 14, 2009 Category: Cytology Authors: Benjamin G. Fanson, Christopher W. Weldon, Diana Pérez-Staples, Stephen J. Simpson, Phillip W. Taylor Source Type: journals

Condition-adapted stress and longevity gene regulation by Caenorhabditis elegans SKN-1/NrfEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Studies in model organisms have identified regulatory processes that profoundly influence aging, many of which modulate resistance against environmental or metabolic stresses. In Caenorhabditis elegans, the transcription regulator SKN-1 is important for oxidative stress resistance and acts in multiple longevity pathways. SKN-1 is the ortholog of mammalian Nrf proteins, which induce Phase 2 detoxification genes in response to stress. Phase 2 enzymes defend against oxygen radicals and conjugate electrophiles that are produced by Phase 1 detoxification enzymes, which metabolize lipophilic compounds. Here, we have used express...
Source: Aging Cell - July 2, 2009 Category: Cytology Authors: Riva P. Oliveira, Jess Porter Abate, Kieran Dilks, Jessica Landis, Jasmine Ashraf, Coleen T. Murphy, T. Keith Blackwell Source Type: journals

Endogenous cGMP regulates adult longevity via the insulin signaling pathway in Caenorhabditis elegansEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
G-proteins, including GPA-3, play an important role in regulating physiological responses in Caenorhabditis elegans. When confronted with an environmental stimulus such as dauer pheromone, or poor nutrients, C. elegans receives and integrates external signals through its nervous system (i.e. amphid neurons), which interprets and translates them into biological action. Here it is shown that a suppressed neuronal cGMP level caused by GPA-3 activation leads to a significant increase (47.3%) in the mean lifespan of adult C. elegans through forkhead transcription factor family O (FOXO)-mediated signal. A reduced neuronal cGMP l...
Source: Aging Cell - June 24, 2009 Category: Cytology Authors: Jeong-Hoon Hahm, Sunhee Kim, Young-Ki Paik Source Type: journals

Nicotinamide enhances mitochondria quality through autophagy activation in human cellsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Nicotinamide (NAM) treatment causes a decrease in mitochondrial respiration and reactive oxygen species production in primary human fibroblasts and extends their replicative lifespan. In the current study, it is reported that NAM treatment induces a decrease in mitochondrial mass and an increase in membrane potential ([Delta][Psi]m) by accelerating autophagic degradation of mitochondria. In the NAM-treated cells, the level of LC3-II as well as the number of LC3 puncta and lysosomes co-localizing with mitochondria substantially increased. Furthermore, in the NAM-treated cells, the levels of Fis1, Drp1, and Mfn1, proteins th...
Source: Aging Cell - June 5, 2009 Category: Cytology Authors: Hyun Tae Kang, Eun Seong Hwang Source Type: journals

The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancerEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This study found no statistically significant association between leukocyte telomere length and advanced prostate cancer risk. However, correlations of telomere length with healthy lifestyles were noted, suggesting the role of these factors in telomere biology maintenance and potentially impacting overall health status. (Source: Aging Cell)
Source: Aging Cell - June 1, 2009 Category: Cytology Authors: Lisa Mirabello, Wen-Yi Huang, Jason Y.Y. Wong, Nilanjan Chatterjee, Douglas Reding, E. David Crawford, Immaculata De Vivo, Richard B. Hayes, Sharon A. Savage Source Type: journals

p53/CEP-1 increases or decreases lifespan, depending on level of mitochondrial bioenergetic stressEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
In this study, we show that the C. elegans p53 ortholog cep-1 mediates these opposite effects. We found that cep-1 is required to extend longevity in response to mild suppression of several bioenergetically relevant mitochondrial proteins, including frataxin [ndash] the protein defective in patients with Friedreich's Ataxia. Importantly, we show that cep-1 also mediates both the developmental arrest and life shortening induced by severe mitochondrial stress. These findings support an evolutionarily conserved function for p53 in modulating organismal responses to mitochondrial dysfunction and suggest that metabolic checkpoi...
Source: Aging Cell - May 31, 2009 Category: Cytology Authors: Natascia Ventura, Shane L. Rea, Alfonso Schiavi, Alessandro Torgovnick, Roberto Testi, Thomas E. Johnson Source Type: journals

The low abundance of clonally expanded mitochondrial DNA point mutations in aged substantia nigra neuronsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Clonally expanded mitochondrial DNA (mtDNA) deletions accumulate with age in human substantia nigra (SN) and high levels cause respiratory chain deficiency. In other human tissues, mtDNA point mutations clonally expand with age. Here, the abundance of mtDNA point mutations within single SN neurons from aged controls was investigated. From 31 single cytochrome c oxidase normal SN neurons, only one clonally expanded mtDNA point mutation was identified, suggesting in these neurons mtDNA point mutations occur rarely, whereas mtDNA deletions are frequently observed. This contrasts observations in mitotic tissues and suggests th...
Source: Aging Cell - May 30, 2009 Category: Cytology Authors: Amy K. Reeve, Kim J. Krishnan, Geoffrey Taylor, Joanna L. Elson, Andreas Bender, Robert W. Taylor, Christopher M. Morris, Doug M. Turnbull Source Type: journals

Expression of p16INK4a in peripheral blood T-cells is a biomarker of human agingEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Expression of the p16INK4a tumor suppressor sharply increases with age in most mammalian tissues, and contributes to an age-induced functional decline of certain self-renewing compartments. These observations have suggested that p16INK4a expression could be a biomarker of mammalian aging. To translate this notion to human use, we determined p16INK4a expression in cellular fractions of human whole blood, and found highest expression in peripheral blood T-lymphocytes (PBTL). We then measured INK4/ARF transcript expression in PBTL from two independent cohorts of healthy humans (170 donors total), and analyzed their relationsh...
Source: Aging Cell - May 21, 2009 Category: Cytology Authors: Yan Liu, Hanna K. Sanoff, Hyunsoon Cho, Christin E. Burd, Chad Torrice, Joseph G. Ibrahim, Nancy E. Thomas, Norman E. Sharpless Source Type: journals

Aging alters PPARγ in rodent and human adipose tissue by modulating the balance in steroid receptor coactivator-1Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Age is an important risk factor for the development of metabolic diseases (e.g. obesity, diabetes and atherosclerosis). Yet, little is known about the molecular mechanisms occurring upon aging that affect energy metabolism. Although visceral white adipose tissue (vWAT) is known for its key impact on metabolism, recent studies have indicated it could also be a key regulator of lifespan, suggesting that it can serve as a node for age-associated fat accretion. Here we show that aging triggers changes in the transcriptional milieu of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR[gamma]) in vWAT, w...
Source: Aging Cell - May 21, 2009 Category: Cytology Authors: Stéphanie Miard, Luce Dombrowski, Sophie Carter, Louise Boivin, Frédéric Picard Source Type: journals

Lifespan extension in genetically modified miceEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Major advances in aging research have been made by studying the effect of genetic modifications on the lifespan of organisms, such as yeast, invertebrates (worms and flies) and mice. Data from yeast and invertebrates have been the most plentiful because of the ease in which genetic manipulations can be made and the rapidity by which lifespan experiments can be performed. With the ultimate focus on advancing human health, testing genetic interventions in mammals is crucial, and the mouse has proven to be the mammal most amenable to this task. Lifespan studies in mice are resource intensive, requiring up to 4 years to comple...
Source: Aging Cell - May 21, 2009 Category: Cytology Authors: Warren Ladiges, Holly Van Remmen, Randy Strong, Yuji Ikeno, Piper Treuting, Peter Rabinovitch, Arlan Richardson Source Type: journals

Reduced expression of alpha-1,2-mannosidase I extends lifespan in Drosophila melanogaster and Caenorhabditis elegansEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Exposure to sub-lethal levels of stress, or hormesis, was a means to induce longevity. By screening for mutations that enhance resistance to multiple stresses, we identified multiple alleles of alpha-1,2-mannosidase I (mas1) which, in addition to promoting stress resistance, also extended longevity. Longevity enhancement is also observed when mas1 expression is reduced via RNA interference in both Drosophila melanogaster and Caenorhabditis elegans. The screen also identified Edem1 (Edm1), a gene downstream of mas1, as a modulator of lifespan. As double mutants for both mas1 and Edm1 showed no additional longevity enhanceme...
Source: Aging Cell - May 11, 2009 Category: Cytology Authors: Ya-Lin Liu, Wan-Chih Lu, Theodore J. Brummel, Chiou-Hwa Yuh, Pei-Ting Lin, Tzu-Yu Kao, Fang-Yi Li, Pin-Chao Liao, Seymour Benzer, Horng-Dar Wang Source Type: journals

Autophagy and amino acid homeostasis are required for chronological longevity in Saccharomyces cerevisiaeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Following cessation of growth, yeast cells remain viable in a nondividing state for a period of time known as the chronological lifespan (CLS). Autophagy is a degradative process responsible for amino acid recycling in response to nitrogen starvation and amino acid limitation. We have investigated the role of autophagy during chronological aging of yeast grown in glucose minimal media containing different supplemental essential and nonessential amino acids. Deletion of ATG1 or ATG7, both of which are required for autophagy, reduced CLS, whereas deletion of ATG11, which is required for selective targeting of cellular compon...
Source: Aging Cell - April 30, 2009 Category: Cytology Authors: Ashley L. Alvers, Laura K. Fishwick, Michael S. Wood, Doreen Hu, Hye S. Chung, William A. Dunn Jr, John P. Aris Source Type: journals

Endothelial dysfunction in aged humans is related with oxidative stress and vascular inflammationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Vascular endothelial dysfunction occurs during the human aging process, and it is considered as a crucial event in the development of many vasculopathies. We investigated the underlying mechanisms of this process, particularly those related with oxidative stress and inflammation, in the vasculature of subjects aged 18[ndash]91 years without cardiovascular disease or risk factors. In isolated mesenteric microvessels from these subjects, an age-dependent impairment of the endothelium-dependent relaxations to bradykinin was observed. Similar results were observed by plethysmography in the forearm blood flow in response to ace...
Source: Aging Cell - April 29, 2009 Category: Cytology Authors: Leocadio Rodríguez-Mañas, Mariam El-Assar, Susana Vallejo, Pedro López-Dóriga, Joaquin Solís, Roberto Petidier, Manuel Montes, Julián Nevado, Marta Castro, Carmen Gómez-Guerrero, Concepción Peiró, Carlos F. Sánchez-Ferrer Source Type: journals

Diminished contraction-induced intracellular signaling towards mitochondrial biogenesis in aged skeletal muscleEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The intent of this study was to determine whether aging affects signaling pathways involved in mitochondrial biogenesis in response to a single bout of contractile activity. Acute stimulation (1 Hz, 5 min) of the tibialis anterior (TA) resulted in a greater rate of fatigue in old (36 month), compared to young (6 month) F344XBN rats, which was associated with reduced ATP synthesis and a lower mitochondrial volume. To investigate fiber type-specific signaling, the TA was sectioned into red (RTA) and white (WTA) portions, possessing two- to 2.5-fold differences in mitochondrial content. The expression and contraction-mediated...
Source: Aging Cell - April 21, 2009 Category: Cytology Authors: Vladimir Ljubicic, David A. Hood Source Type: journals

Do mtDNA deletions drive premature aging in mtDNA mutator mice?Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Deletions in mitochondrial DNA (mtDNA) have long been suspected to be involved in mammalian aging, but their role remains controversial. Recent research has demonstrated that relatively higher levels of mtDNA deletions correlate with premature aging in mtDNA mutator mice, which led to the conclusion that premature aging in these mice is driven by mtDNA deletions. However, it is reported here that the absolute level of deletions in mutator mice is quite low, especially when compared with the level of point mutations in these mice. It is thus argued that the available data are insufficient to conclude that mtDNA mutations dr...
Source: Aging Cell - April 21, 2009 Category: Cytology Authors: Yevgenya Kraytsberg, David K. Simon, Douglas M. Turnbull, Konstantin Khrapko Source Type: journals

IGF-1, nutrition and aging: the big pictureEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Aging Cell)
Source: Aging Cell - March 6, 2009 Category: Cytology Authors: Luigi Fontana, Edward P. Weiss, Dennis T. Villareal, Samuel Klein, John O. Holloszy Source Type: journals

Aging, IGF-1, and dietEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Aging Cell)
Source: Aging Cell - March 5, 2009 Category: Cytology Authors: Michael Pollak Source Type: journals

ING1a expression increases during replicative senescence and induces a senescent phenotypeEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The ING family of tumor suppressor proteins affects cell growth, apoptosis and response to DNA damage by modulating chromatin structure through association with different HAT and HDAC complexes. The major splicing isoforms of the ING1 locus are ING1a and INGlb. While INGlb plays a role in inducing apoptosis, the function of ING1a is currently unknown. Here we show that alternative splicing of the ING1 message alters the INGla:INGlb ratio by ~30-fold in senescent compared to low passage primary fibroblasts. INGla antagonizes INGlb function in apoptosis, induces the formation of structures resembling senescence-associated he...
Source: Aging Cell - October 7, 2008 Category: Cytology Authors: Mohamed A. Soliman, Philip Berardi, Svitlana Pastyryeva, Paul Bonnefin, Xiaolan Feng, Ana Colina, Dallan Young, Karl Riabowol Source Type: journals

Mitochondrial turnover in liver is fast in vivo and is accelerated by dietary restriction: application of a simple dynamic modelEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
'Mitochondrial dysfunction', which may result from an accumulation of damaged mitochondria in cells due to a slowed-down rate of mitochondrial turnover and inadequate removal of damaged mitochondria during aging, has been implicated as both cause and consequence of the aging process and a number of age-related pathologies. Despite growing interest in mitochondrial function during aging, published data on mitochondrial turnover are scarce, and differ from each other by up to one order of magnitude. Here we demonstrate that re-utilization of the radioactively labelled precursor in pulse-chase assays is the most likely cause ...
Source: Aging Cell - September 6, 2008 Category: Cytology Authors: Satomi Miwa, Conor Lawless, Thomas von Zglinicki Source Type: journals

p16INK4a-induced senescence is disabled by melanoma-associated mutationsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
The p16INK4a-Rb tumour suppressor pathway is required for the initiation and maintenance of cellular senescence, a state of permanent growth arrest that acts as a natural barrier against cancer progression. Senescence can be overcome if the pathway is not fully engaged, and this may occur when p16INK4a is inactivated. p16INK4a is frequently altered in human cancer and germline mutations affecting p16INK4a have been linked to melanoma susceptibility. To characterize the functions of melanoma-associated p16INK4a mutations, in terms of promoting proliferative arrest and initiating senescence, we utilized an inducible expressi...
Source: Aging Cell - September 5, 2008 Category: Cytology Authors: Sebastian Haferkamp, Therese M. Becker, Lyndee L. Scurr, Richard F. Kefford, Helen Rizos Source Type: journals

Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humansEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Reduced function mutations in the insulin/IGF-I signaling pathway increase maximal lifespan and health span in many species. Calorie restriction (CR) decreases serum IGF-1 concentration by ~40%, protects against cancer and slows aging in rodents. However, the long-term effects of CR with adequate nutrition on circulating IGF-1 levels in humans are unknown. Here we report data from two long-term CR studies (1 and 6 years) showing that severe CR without malnutrition did not change IGF-1 and IGF-1 : IGFBP-3 ratio levels in humans. In contrast, total and free IGF-1 concentrations were significantly lower in moderately protein-...
Source: Aging Cell - September 5, 2008 Category: Cytology Authors: Luigi Fontana, Edward P. Weiss, Dennis T. Villareal, Samuel Klein, John O. Holloszy Source Type: journals

Mitochondrial iron accumulation with age and functional consequencesEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
During the aging process, an accumulation of non-heme iron disrupts cellular homeostasis and contributes to the mitochondrial dysfunction typical of various neuromuscular degenerative diseases. Few studies have investigated the effects of iron accumulation on mitochondrial integrity and function in skeletal muscle and liver tissue. Thus, we isolated liver mitochondria (LM), as well as quadriceps-derived subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), from male Fischer 344× Brown Norway rats at 8, 18, 29 and 37 months of age. Non-heme iron content in SSM, IFM and LM was significantly higher with ag...
Source: Aging Cell - September 5, 2008 Category: Cytology Authors: Arnold Y. Seo, Jinze Xu, Stephane Servais, Tim Hofer, Emanuele Marzetti, Stephanie E. Wohlgemuth, Mitchell D. Knutson, Hae Young Chung, Christiaan Leeuwenburgh Source Type: journals

Mutation in aging mice occurs in diverse cell types that proliferate postmutationEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
To determine the relationship between aging, cell proliferation and mutation in different cell types, hearts, brains and kidneys from G11 PLAP mice between 1 week and 24 months of age were examined. Mutant cells were detected in tissue sections by staining for Placental Alkaline Phosphatase (PLAP) activity, an activity that marks cells that have sustained a frameshift mutation in a mononucleotide tract inserted into the coding region of the human gene encoding PLAP. The number of PLAP+ cells increased with age in all three tissues. The types of cells exhibiting a mutant phenotype included cells that are proliferative, such...
Source: Aging Cell - August 27, 2008 Category: Cytology Authors: Jared M. Fischer, James R. Stringer Source Type: journals

Some highlights of research on aging with invertebrates, 2008Email this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
This annual review focuses on invertebrate model organisms, which shed light on new mechanisms in aging and provide excellent systems for in-depth analysis. This year, the first quantitative estimate of evolutionary conservation of genetic effects on lifespan has pointed to the key importance of genes involved in protein synthesis, a finding confirmed and extended by experimental work. Work in Caenorhabditis elegans and Drosophila has highlighted the importance of phase 2 detoxification in extension of lifespan by reduced insulin/Igf-like signalling. Thorough characterization of systems for dietary restriction in C. elegan...
Source: Aging Cell - August 9, 2008 Category: Cytology Authors: Linda Partridge Source Type: journals

Aging Cell manuscripts on the road to PubMed Central: shifting from manual to automatic transmissionEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Aging Cell)
Source: Aging Cell - July 15, 2008 Category: Cytology Authors: Adam Antebi, Ana Maria Cuervo, Richard Miller, John Sedivy Tags: Announcement Source Type: journals

CorrigendumEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
(Source: Aging Cell)
Source: Aging Cell - July 13, 2008 Category: Cytology Source Type: journals

Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogasterEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aging Cell, Volume 0, Issue 0, Page ???, December 2004. Summary The inability to properly balance energy intake and expenditure with nutrient supply forms the basis for some of today's most pressing health issues, including diabetes and obesity. Mechanisms of nutrient homeostasis may also lie at the root of ... (Source: Aging Cell)
Source: Aging Cell - June 18, 2008 Category: Cytology Tags: article Source Type: journals

Aging-related changes in astrocytes in the rat retina: imbalance between cell proliferation and cell death reduces astrocyte availabilityEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aging Cell, Volume 0, Issue 0, Page ???, December 2004. Summary The aim of this study was to investigate changes in astrocyte density, morphology, proliferation and apoptosis occurring in the central nervous system during physiological aging. Astrocytes in retinal whole-mount preparations from Wistar rats ... (Source: Aging Cell)
Source: Aging Cell - June 18, 2008 Category: Cytology Tags: article Source Type: journals

Aging-related differences in basal heat shock protein 70 levels in lymphocytes are linked to altered frequencies of lymphocyte subsetsEmail this article to a colleague. Save this article to My Clippings. Discuss or comment on this article.
Aging Cell, Volume 0, Issue 0, Page ???, December 2004. Summary Cell stress responses are ubiquitous in all organisms and are characterized by the induced synthesis of heat shock proteins (Hsp). Previous studies as well as recent reports by our group have consistently suggested that aging leads to an increase ... (Source: Aging Cell)
Source: Aging Cell - June 18, 2008 Category: Cytology Tags: article Source Type: journals