Volume 4, Issue 4

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Ratajczak MZ, Shin D, Liu R, Mierzejewska K, Ratajczak J, Kucia M, Zuba-Surma EK, . Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation – an update and comparison to other primitive small stem cells isolated from adult tissues. . 4:235-246. https://doi.org/10.18632/aging.100449

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Provider: TY - JOUR AU - Ratajczak, Mariusz Z. AU - Shin, Dong-Myung AU - Liu, Rui AU - Mierzejewska, Kasia AU - Ratajczak, Janina AU - Kucia, Magda AU - Zuba-Surma, Ewa K. TI - Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation – an update and comparison to other primitive small stem cells isolated from adult tissues JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100449 DO - 10.18632/aging.100449 SP - 235 EP - 246 PY - ER -

Provider: TY - JOUR AU - Ratajczak, Mariusz Z. AU - Shin, Dong-Myung AU - Liu, Rui AU - Mierzejewska, Kasia AU - Ratajczak, Janina AU - Kucia, Magda AU - Zuba-Surma, Ewa K. TI - Very small embryonic/epiblast-like stem cells (VSELs) and their potential role in aging and organ rejuvenation – an update and comparison to other primitive small stem cells isolated from adult tissues JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100449 DO - 10.18632/aging.100449 SP - 235 EP - 246 PY - AB - Very small embryonic-like stem cells (VSELs) are a population of developmentally early stem cells residing in adult tissues. These rare cells, which are slightly smaller than red blood cells, i) become mobilized during stress situations into peripheral blood, ii) are enriched in the Sca1+Lin−CD45− cell fraction in mice and the CD133+ Lin−CD45− cell fraction in humans, iii) express markers of pluripotent stem cells (e.g., Oct4, Nanog, and SSEA), and iv) display a distinct morphology characterized by a high nuclear/cytoplasmic ratio and undifferentiated chromatin. Recent evidence indicates that murine VSELs are kept quiescent in adult tissues and protected from teratoma formation by epigenetic modification of imprinted genes that regulate insulin/insulin like growth factor signaling (IIS). The successful reversal of these epigenetic changes in VSELs that render them quiescent will be crucial for efficient expansion of these cells. The most recent data in vivo from our and other laboratories demonstrated that both murine and human VSELs exhibit some characteristics of long-term repopulating hematopoietic stem cells (LT-HSCs), are at the top of the hierarchy in the mesenchymal lineage, and may differentiate into organ-specific cells (e.g., cardiomyocytes). Moreover, as recently demonstrated the number of these cells positively correlates in several murine models with longevity. Finally, while murine BM-derived VSELs have been extensively characterized more work is needed to better characterize these small cells at the molecular level in humans. ER -

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Bedford DC, Brindle PK, . Is histone acetylation the most important physiological function for CBP and p300?. . 4:247-255. https://doi.org/10.18632/aging.100453

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Provider: TY - JOUR AU - Bedford, David C. AU - Brindle, Paul K. TI - Is histone acetylation the most important physiological function for CBP and p300? JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100453 DO - 10.18632/aging.100453 SP - 247 EP - 255 PY - ER -

Provider: TY - JOUR AU - Bedford, David C. AU - Brindle, Paul K. TI - Is histone acetylation the most important physiological function for CBP and p300? JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100453 DO - 10.18632/aging.100453 SP - 247 EP - 255 PY - AB - Protein lysine acetyltransferases (HATs or PATs) acetylate histones and other proteins, and are principally modeled as transcriptional coactivators. CREB binding protein (CBP, CREBBP) and its paralog p300 (EP300) constitute the KAT3 family of HATs in mammals, which has mostly unique sequence identity compared to other HAT families. Although studies in yeast show that many histone mutations cause modest or specific phenotypes, similar studies are impractical in mammals and it remains uncertain if histone acetylation is the primary physiological function for CBP/p300. Nonetheless, CBP and p300 mutations in humans and mice show that these coactivators have important roles in development, physiology, and disease, possibly because CBP and p300 act as network “hubs” with more than 400 described protein interaction partners. Analysis of CBP and p300 mutant mouse fibroblasts reveals CBP/p300 are together chiefly responsible for the global acetylation of histone H3 residues K18 and K27, and contribute to other locus-specific histone acetylation events. CBP/p300 can also be important for transcription, but the recruitment of CBP/p300 and their associated histone acetylation marks do not absolutely correlate with a requirement for gene activation. Rather, it appears that target gene context (e.g. DNA sequence) influences the extent to which CBP and p300 are necessary for transcription. ER -

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McGee MD, Day N, Graham J, Melov S, . cep-1/p53-dependent dysplastic pathology of the aging C. elegans gonad. . 4:256-269. https://doi.org/10.18632/aging.100448

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Provider: TY - JOUR AU - McGee, Mathew D. AU - Day, Nicholas AU - Graham, Jill AU - Melov, Simon TI - <i>cep-1/p53</i>-dependent dysplastic pathology of the aging <i>C. elegans</i> gonad JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100448 DO - 10.18632/aging.100448 SP - 256 EP - 269 PY - ER -

Provider: TY - JOUR AU - McGee, Mathew D. AU - Day, Nicholas AU - Graham, Jill AU - Melov, Simon TI - <i>cep-1/p53</i>-dependent dysplastic pathology of the aging <i>C. elegans</i> gonad JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100448 DO - 10.18632/aging.100448 SP - 256 EP - 269 PY - AB - The C. elegans germline and somatic gonad are actively developing until the animal reaches adulthood, and then continue to undergo striking changes as the animal ages. Reported changes include a depletion of available sperm, a decrease in oocyte quality up till mid-life, a reduction in germline nuclei, a decrease in fertility, and an accumulation of DNA in the midbody of aging C. elegans. Here, we have focused on the aging gonad in old animals, and show in detail that the aging gonad undergoes a massive uterine growth composed of endoreduplicating oocytes, yolk, and expanses of chromatin. We use a novel series of imaging techniques in combination with histological methodology for reconstructing aged worms in 3-dimensions, and show in old animals growing masses swelling inside the uterus to occupy most of the diameter of the worm. We link this accelerated growth to the cep-1/p53 tumor suppressor. Because cep-1 is required for DNA damage induced apoptosis, and daf-2 limits longevity, these results suggest a role for age-related DNA damage in dysplastic uterine growths, which in some respects resemble premalignant changes that can occur in aging mammals. ER -

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Halicka HD, Zhao H, Li J, Traganos F, Studzinski GP, Darzynkiewicz Z, . Attenuation of constitutive DNA damage signaling by 1,25-dihydroxyvitamin D3. . 4:270-278. https://doi.org/10.18632/aging.100450

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Provider: TY - JOUR AU - Halicka, H. Dorota AU - Zhao, Hong AU - Li, Jiangwei AU - Traganos, Frank AU - Studzinski, George P. AU - Darzynkiewicz, Zbigniew TI - Attenuation of constitutive DNA damage signaling by 1,25-dihydroxyvitamin D3 JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100450 DO - 10.18632/aging.100450 SP - 270 EP - 278 PY - ER -

Provider: TY - JOUR AU - Halicka, H. Dorota AU - Zhao, Hong AU - Li, Jiangwei AU - Traganos, Frank AU - Studzinski, George P. AU - Darzynkiewicz, Zbigniew TI - Attenuation of constitutive DNA damage signaling by 1,25-dihydroxyvitamin D3 JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100450 DO - 10.18632/aging.100450 SP - 270 EP - 278 PY - AB - In addition to its traditional role in the regulation of calcium homeostasis and bone metabolism, vitamin D also exhibits immunomodulatory, anti-proliferative and cancer preventive activities. Molecular mechanisms that confer the chemo-preventive properties to vitamin D are poorly understood. We previously reported that constitutive phosphorylation of histone H2AX on Ser139 (γH2AX) and activation of ATM (Ser1981 phosphorylation), seen in untreated normal or tumor cells predominantly in S phase of the cell cycle, is to a large extent indicative of DNA replication stress occurring as a result of persistent DNA damage caused by endogenous oxidants, by-products of oxidative metabolism. In the present study we observed that exposure of mitogenically stimulated human lymphocytes, pulmonary carcinoma A549 and lymphoblastoid TK6 cells to 1,25-dihydroxyvitamin D3 (1,25-VD) reduced the level of constitutive expression of γH2AX and ATM-S1981P. We also observed that the H2O2-induced rise in the level of γH2AX in lymphocytes was attenuated by 1,25-VD. Whereas in lymphocytes 1,25-VD reduced by 50-70% the level of endogenous oxidants as determined by their ability to oxidize 2,7-dichlorodihydrofluorescein (DCFH) in A549 and TK6 cells the attenuation of DNA damage signaling by 1,25-VD was seen in the absence of detectable reduction in DCFH oxidation. These findings suggest that while the anti-oxidant activity of 1,25-VD may contribute to a reduction in the intensity of DNA replication stress in lymphocytes, other factors play a role in the 1,25-VD effects seen in A549 and TK6 cells. The data are consistent with the recent report on the interaction between DNA damage signaling (ATM activation) and 1,25D receptor (VDR) phosphorylation that lead to enhancement of DNA repair efficiency, and provide further support for the chemo-preventive and anti-aging properties of this vitamin/hormone. ER -

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Kofman AE, McGraw MR, Payne CJ, . Rapamycin increases oxidative stress response gene expression in adult stem cells. . 4:279-289. https://doi.org/10.18632/aging.100451

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Provider: TY - JOUR AU - Kofman, Amber E. AU - McGraw, Margeaux R. AU - Payne, Christopher J. TI - Rapamycin increases oxidative stress response gene expression in adult stem cells JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100451 DO - 10.18632/aging.100451 SP - 279 EP - 289 PY - ER -

Provider: TY - JOUR AU - Kofman, Amber E. AU - McGraw, Margeaux R. AU - Payne, Christopher J. TI - Rapamycin increases oxidative stress response gene expression in adult stem cells JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100451 DO - 10.18632/aging.100451 SP - 279 EP - 289 PY - AB - Balancing quiescence with proliferation is of paramount importance for adult stem cells in order to avoid hyperproliferation and cell depletion. In some models, stem cell exhaustion may be reversed with the drug rapamycin, which was shown can suppress cellular senescence in vitro and extend lifespan in animals. We hypothesized that rapamycin increases the expression of oxidative stress response genes in adult stem cells, and that these gene activities diminish with age. To test our hypothesis, we exposed mice to rapamycin and then examined the transcriptome of their spermatogonial stem cells (SSCs). Gene expression microarray analysis revealed that numerous oxidative stress response genes were upregulated upon rapamycin treatment, including superoxide dismutase 1, glutathione reductase, and delta-aminolevulinate dehydratase. When we examined the expression of these genes in 55-week-old wild type SSCs, their levels were significantly reduced compared to 3-week-old SSCs, suggesting that their downregulation is coincident with the aging process in adult stem cells. We conclude that rapamycin-induced stimulation of oxidative stress response genes may promote cellular longevity in SSCs, while a decline in gene expression in aged stem cells could reflect the SSCs' diminished potential to alleviate oxidative stress, a hallmark of aging. ER -

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Dellago H, Khan A, Nussbacher M, Gstraunthaler A, Lämmermann I, Schosserer M, Mück C, Anrather D, Scheffold A, Ammerer G, Jansen-Dürr P, Rudolph KL, Voglauer-Grillari R, et al, . ATM-dependent phosphorylation of SNEV^hPrp19/hPso4 is involved in extending cellular life span and suppression of apoptosis. . 4:290-304. https://doi.org/10.18632/aging.100452

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Provider: TY - JOUR AU - Dellago, Hanna AU - Khan, Abdulhameed AU - Nussbacher, Monika AU - Gstraunthaler, Anna AU - Lämmermann, Ingo AU - Schosserer, Markus AU - Mück, Christoph AU - Anrather, Dorothea AU - Scheffold, Annika AU - Ammerer, Gustav AU - Jansen-Dürr, Pidder AU - Rudolph, Karl Lenhard AU - Voglauer-Grillari, Regina AU - Grillari, Johannes TI - ATM-dependent phosphorylation of SNEV^hPrp19/hPso4 is involved in extending cellular life span and suppression of apoptosis JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100452 DO - 10.18632/aging.100452 SP - 290 EP - 304 PY - ER -

Provider: TY - JOUR AU - Dellago, Hanna AU - Khan, Abdulhameed AU - Nussbacher, Monika AU - Gstraunthaler, Anna AU - Lämmermann, Ingo AU - Schosserer, Markus AU - Mück, Christoph AU - Anrather, Dorothea AU - Scheffold, Annika AU - Ammerer, Gustav AU - Jansen-Dürr, Pidder AU - Rudolph, Karl Lenhard AU - Voglauer-Grillari, Regina AU - Grillari, Johannes TI - ATM-dependent phosphorylation of SNEV^hPrp19/hPso4 is involved in extending cellular life span and suppression of apoptosis JO - JA - VL - 4 IS - 4 PB - SN - UR - https://doi.org/10.18632/aging.100452 DO - 10.18632/aging.100452 SP - 290 EP - 304 PY - AB - Defective DNA repair is widely acknowledged to negatively impact on healthy aging, since mutations in DNA repair factors lead to accelerated and premature aging. However, the opposite, namely if improved DNA repair will also increase the life or health span is less clear, and only few studies have tested if overexpression of DNA repair factors modulates life and health span in cells or organisms. Recently, we identified and characterized SNEVhPrp19/hPso4, a protein that plays a role in DNA repair and pre-mRNA splicing, and observed a doubling of the replicative life span upon ectopic overexpression, accompanied by lower basal DNA damage and apoptosis levels as well as an increased resistance to oxidative stress. Here we find that SNEVhPrp19/hPso4 is phosphorylated at S149 in an ataxia telangiectasia mutated protein (ATM)-dependent manner in response to oxidative stress and DNA double strand break inducing agents. By overexpressing wild-type SNEVhPrp19/hPso4 and a phosphorylation-deficient point-mutant, we found that S149 phosphorylation is necessary for mediating the resistance to apoptosis upon oxidative stress and is partially necessary for elongating the cellular life span. Therefore, ATM dependent phosphorylation of SNEVhPrp19/hPso4 upon DNA damage or oxidative stress might represent a novel axis capable of modulating cellular life span. ER -

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