Volume 4, Issue 1

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. Starting 2012: Sod2, DGAT1, p53, SPARC, QTL and reprogramming in aging. . 4:1-1. https://doi.org/10.18632/aging.100429

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Provider: TY - JOUR TI - Starting 2012: Sod2, DGAT1, p53, SPARC, QTL and reprogramming in aging JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100429 DO - 10.18632/aging.100429 SP - 1 EP - 1 PY - ER -

Provider: TY - JOUR TI - Starting 2012: Sod2, DGAT1, p53, SPARC, QTL and reprogramming in aging JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100429 DO - 10.18632/aging.100429 SP - 1 EP - 1 PY - AB - ER -

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. Interview with Michael Ristow. . 4:2-2. https://doi.org/10.18632/aging.100430

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Provider: TY - JOUR TI - Interview with Michael Ristow JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100430 DO - 10.18632/aging.100430 SP - 2 EP - 2 PY - ER -

Provider: TY - JOUR TI - Interview with Michael Ristow JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100430 DO - 10.18632/aging.100430 SP - 2 EP - 2 PY - AB - ER -

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Velarde MC, Flynn JM, Day NU, Melov S, Campisi J, . Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin. . 4:3-12. https://doi.org/10.18632/aging.100423

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Provider: TY - JOUR AU - Velarde, Michael C. AU - Flynn, James M. AU - Day, Nicholas U. AU - Melov, Simon AU - Campisi, Judith TI - Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100423 DO - 10.18632/aging.100423 SP - 3 EP - 12 PY - ER -

Provider: TY - JOUR AU - Velarde, Michael C. AU - Flynn, James M. AU - Day, Nicholas U. AU - Melov, Simon AU - Campisi, Judith TI - Mitochondrial oxidative stress caused by Sod2 deficiency promotes cellular senescence and aging phenotypes in the skin JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100423 DO - 10.18632/aging.100423 SP - 3 EP - 12 PY - AB - Cellular senescence arrests the proliferation of mammalian cells at risk for neoplastic transformation, and is also associated with aging. However, the factors that cause cellular senescence during aging are unclear. Excessive reactive oxygen species (ROS) have been shown to cause cellular senescence in culture, and accumulated molecular damage due to mitochondrial ROS has long been thought to drive aging phenotypes in vivo. Here, we test the hypothesis that mitochondrial oxidative stress can promote cellular senescence in vivo and contribute to aging phenotypes in vivo, specifically in the skin. We show that the number of senescent cells, as well as impaired mitochondrial (complex II) activity increase in naturally aged mouse skin. Using a mouse model of genetic Sod2 deficiency, we show that failure to express this important mitochondrial anti-oxidant enzyme also impairs mitochondrial complex II activity, causes nuclear DNA damage, and induces cellular senescence but not apoptosis in the epidermis. Sod2 deficiency also reduced the number of cells and thickness of the epidermis, while increasing terminal differentiation. Our results support the idea that mitochondrial oxidative stress and cellular senescence contribute to aging skin phenotypes in vivo. ER -

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Streeper RS, Grueter CA, Salomonis N, Cases S, Levin MC, Koliwad SK, Zhou P, Hirschey MD, Verdin E, Farese RV, . Deficiency of the lipid synthesis enzyme, DGAT1, extends longevity in mice. . 4:13-27. https://doi.org/10.18632/aging.100424

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Provider: TY - JOUR AU - Streeper, Ryan S. AU - Grueter, Carrie A. AU - Salomonis, Nathan AU - Cases, Sylvaine AU - Levin, Malin C. AU - Koliwad, Suneil K. AU - Zhou, Ping AU - Hirschey, Matthew D. AU - Verdin, Eric AU - Farese, Robert V. TI - Deficiency of the lipid synthesis enzyme, DGAT1, extends longevity in mice JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100424 DO - 10.18632/aging.100424 SP - 13 EP - 27 PY - ER -

Provider: TY - JOUR AU - Streeper, Ryan S. AU - Grueter, Carrie A. AU - Salomonis, Nathan AU - Cases, Sylvaine AU - Levin, Malin C. AU - Koliwad, Suneil K. AU - Zhou, Ping AU - Hirschey, Matthew D. AU - Verdin, Eric AU - Farese, Robert V. TI - Deficiency of the lipid synthesis enzyme, DGAT1, extends longevity in mice JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100424 DO - 10.18632/aging.100424 SP - 13 EP - 27 PY - AB - Calorie restriction results in leanness, which is linked to metabolic conditions that favor longevity. We show here that deficiency of the triglyceride synthesis enzyme acyl CoA:diacylglycerol acyltransferase 1 (DGAT1), which promotes leanness, also extends longevity without limiting food intake. Female DGAT1-deficient mice were protected from age-related increases in body fat, tissue triglycerides, and inflammation in white adipose tissue. This protection was accompanied by increased mean and maximal life spans of ~25% and ~10%, respectively. Middle-aged Dgat1−/− mice exhibited several features associated with longevity, including decreased levels of circulating insulin growth factor 1 (IGF1) and reduced fecundity. Thus, deletion of DGAT1 in mice provides a model of leanness and extended lifespan that is independent of calorie restriction. ER -

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Altilia S, Santoro A, Malagoli D, Lanzarini C, Álvarez JAB, Galazzo G, Porter DC, Crocco P, Rose G, Passarino G, Roninson IB, Franceschi C, Salvioli S, . TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells. . 4:28-39. https://doi.org/10.18632/aging.100425

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Provider: TY - JOUR AU - Altilia, Serena AU - Santoro, Aurelia AU - Malagoli, Davide AU - Lanzarini, Catia AU - Álvarez, Josué Adolfo Ballesteros AU - Galazzo, Gianluca AU - Porter, Donald Carl AU - Crocco, Paolina AU - Rose, Giuseppina AU - Passarino, Giuseppe AU - Roninson, Igor Boris AU - Franceschi, Claudio AU - Salvioli, Stefano TI - TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100425 DO - 10.18632/aging.100425 SP - 28 EP - 39 PY - ER -

Provider: TY - JOUR AU - Altilia, Serena AU - Santoro, Aurelia AU - Malagoli, Davide AU - Lanzarini, Catia AU - Álvarez, Josué Adolfo Ballesteros AU - Galazzo, Gianluca AU - Porter, Donald Carl AU - Crocco, Paolina AU - Rose, Giuseppina AU - Passarino, Giuseppe AU - Roninson, Igor Boris AU - Franceschi, Claudio AU - Salvioli, Stefano TI - TP53 codon 72 polymorphism affects accumulation of mtDNA damage in human cells JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100425 DO - 10.18632/aging.100425 SP - 28 EP - 39 PY - AB - Human TP53 gene is characterised by a polymorphism at codon 72 leading to an Arginine-to-Proline (R/P) substitution. The two resulting p53 isoforms have a different subcellular localisation after stress (more nuclear or more mitochondrial for the P or R isoform, respectively). p53P72 variant is more efficient than p53R72 in inducing the expression of genes involved in nuclear DNA repair. Since p53 is involved also in mitochondrial DNA (mtDNA) maintenance, we wondered whether these p53 isoforms are associated with different accumulation of mtDNA damage. We observed that cells bearing p53R72 accumulate lower amount of mtDNA damage upon rotenone stress with respect to cells bearing p53P72, and that p53R72 co-localises with polymerase gamma more than p53P72. We also analysed the in vivo accumulation of heteroplasmy in a 300 bp fragment of mtDNA D-loop of 425 aged subjects. We observed that subjects with heteroplasmy higher than 5% are significantly less than expected in the p53R72/R72 group. On the whole, these data suggest that the polymorphism of TP53 at codon 72 affects the accumulation of mtDNA mutations, likely through the different ability of the two p53 isoforms to bind to polymerase gamma, and may contribute to in vivo accumulation of mtDNA mutations. ER -

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Nakamura SK, Nakano S, Miyoshi T, Yamanouchi K, Matsuwaki T, Nishihara M, . Age-related resistance of skeletal muscle-derived progenitor cells to SPARC may explain a shift from myogenesis to adipogenesis. . 4:40-48. https://doi.org/10.18632/aging.100426

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Provider: TY - JOUR AU - Nakamura, Serena Katsuyuki AU - Nakano, Shin-ichi AU - Miyoshi, Takahiro AU - Yamanouchi, Keitaro AU - Matsuwaki, Takashi AU - Nishihara, Masugi TI - Age-related resistance of skeletal muscle-derived progenitor cells to SPARC may explain a shift from myogenesis to adipogenesis JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100426 DO - 10.18632/aging.100426 SP - 40 EP - 48 PY - ER -

Provider: TY - JOUR AU - Nakamura, Serena Katsuyuki AU - Nakano, Shin-ichi AU - Miyoshi, Takahiro AU - Yamanouchi, Keitaro AU - Matsuwaki, Takashi AU - Nishihara, Masugi TI - Age-related resistance of skeletal muscle-derived progenitor cells to SPARC may explain a shift from myogenesis to adipogenesis JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100426 DO - 10.18632/aging.100426 SP - 40 EP - 48 PY - AB - Aging causes phenotypic changes in skeletal muscle progenitor cells (SMPCs) that lead to the loss of myogenicity and adipogenesis. Secreted protein acidic and rich in cysteine (SPARC), which is secreted from SMPCs, stimulates myogenesis and inhibits adipogenesis. The present study aimed to examine whether changes in SPARC expression, its signaling pathway, or both are involved in age-related phenotypic changes in SMPCs. SPARC expression levels were comparable in SMPCs derived from young and old rats. However, when SPARC expression was reduced by a SPARC-specific siRNA, SMPCs from young rats showed reduced myogenesis and increased adipogenesis. In striking contrast, old rats showed little changes in these functions. Recombinant SPARC was effective in inhibiting adipogenesis and promoting myogenesis of SMPCs from young rats but had no effect on SMPCs from old rats when endogenous SPARC levels were reduced by the SPARC-siRNA. Further, the level of integrin α5, a subunit of the putative SPARC receptor, was decreased in SMPCs from old rats, and its inhibition in SMPCs from young rats by siRNA reduced adipogenesis in response to SPARC. These results suggest that, although SPARC plays a role in regulating SMPC function, SMPCs become refractory to the action of SPARC with age. Our data may explain an age-related shift from myogenesis to adipogenesis, associated with sarcopenia. ER -

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Korbolina EE, Kozhevnikova OS, Stefanova NA, Kolosova NG, . Quantitative trait loci on chromosome 1 for cataract and AMD-like retinopathy in senescence-accelerated OXYS rats. . 4:49-59. https://doi.org/10.18632/aging.100427

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Provider: TY - JOUR AU - Korbolina, Elena E. AU - Kozhevnikova, Ouyna S. AU - Stefanova, Nataliya A. AU - Kolosova, Natalia G. TI - Quantitative trait loci on chromosome 1 for cataract and AMD-like retinopathy in senescence-accelerated OXYS rats JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100427 DO - 10.18632/aging.100427 SP - 49 EP - 59 PY - ER -

Provider: TY - JOUR AU - Korbolina, Elena E. AU - Kozhevnikova, Ouyna S. AU - Stefanova, Nataliya A. AU - Kolosova, Natalia G. TI - Quantitative trait loci on chromosome 1 for cataract and AMD-like retinopathy in senescence-accelerated OXYS rats JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100427 DO - 10.18632/aging.100427 SP - 49 EP - 59 PY - AB - Age-related macular degeneration (AMD) and cataract are common age-related diseases in humans. Previously we showed that senescence-accelerated OXYS rats develop retinopathy and cataract, which are comparable to human AMD and senile cataract. Here we focused on the identification of quantitative trait loci (QTLs), which affect early-onset cataract and retinopathy in OXYS rats, using F2 hybrids bred by a reciprocal cross (OXYS×WAG and WAG×OXYS). Chromosome 1 showed significant associations between retinopathy and loci in the regions of markers D1Rat30 and D1Rat219 (QTL1) as well as D1Rat219 and D1Rat81 (QTL2); and between early cataract development with the locus in the region of the markers D1Rat219 and D1Rat81 (QTL2). To determine the effects of these QTLs, we generated two congenic strains by transferring chromosome 1 regions from OXYS into WAG background. Both congenic strains (named WAG/OXYS-1.1 and WAG/OXYS-1.2, respectively) display early cataract and retinopathy development. Thus, we confirmed that genes located in the analyzed regions of chromosome 1 are associated with the development of these diseases in OXYS rats. ER -

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Ohmine S, Squillace KA, Hartjes KA, Deeds MC, Armstrong AS, Thatava T, Sakuma T, Terzic A, Kudva Y, Ikeda Y, . Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency. . 4:60-73. https://doi.org/10.18632/aging.100428

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Provider: TY - JOUR AU - Ohmine, Seiga AU - Squillace, Karen A. AU - Hartjes, Katherine A. AU - Deeds, Michael C. AU - Armstrong, Adam S. AU - Thatava, Tayaramma AU - Sakuma, Toshie AU - Terzic, Andre AU - Kudva, Yogish AU - Ikeda, Yasuhiro TI - Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100428 DO - 10.18632/aging.100428 SP - 60 EP - 73 PY - ER -

Provider: TY - JOUR AU - Ohmine, Seiga AU - Squillace, Karen A. AU - Hartjes, Katherine A. AU - Deeds, Michael C. AU - Armstrong, Adam S. AU - Thatava, Tayaramma AU - Sakuma, Toshie AU - Terzic, Andre AU - Kudva, Yogish AU - Ikeda, Yasuhiro TI - Reprogrammed keratinocytes from elderly type 2 diabetes patients suppress senescence genes to acquire induced pluripotency JO - JA - VL - 4 IS - 1 PB - SN - UR - https://doi.org/10.18632/aging.100428 DO - 10.18632/aging.100428 SP - 60 EP - 73 PY - AB - Nuclear reprogramming enables patient-specific derivation of induced pluripotent stem (iPS) cells from adult tissue. Yet, iPS generation from patients with type 2 diabetes (T2D) has not been demonstrated. Here, we report reproducible iPS derivation of epidermal keratinocytes (HK) from elderly T2D patients. Transduced with human OCT4, SOX2, KLF4 and c-MYC stemness factors under serum-free and feeder-free conditions, reprogrammed cells underwent dedifferentiation with mitochondrial restructuring, induction of endogenous pluripotency genes - including NANOG, LIN28, and TERT, and down-regulation of cytoskeletal, MHC class I- and apoptosis-related genes. Notably, derived iPS clones acquired a rejuvenated state, characterized by elongated telomeres and suppressed senescence-related p15INK4b/p16INK4a gene expression and oxidative stress signaling. Stepwise guidance with lineage-specifying factors, including Indolactam V and GLP-1, redifferentiated HK-derived iPS clones into insulin-producing islet-like progeny. Thus, in elderly T2D patients, reprogramming of keratinocytes ensures a senescence-privileged status yielding iPS cells proficient for regenerative applications. ER -

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