Volume 4, Issue 6

Chemoprevention of age-related macular regeneration (AMD) with rapamycin

X. F. Steven Zheng,

https://doi.org/10.18632/aging.100469 pp 375—376

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Zheng XFS, . Chemoprevention of age-related macular regeneration (AMD) with rapamycin. . 4:375-376. https://doi.org/10.18632/aging.100469

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To the heart of the problem. mIGF-1: local effort for global impact

Antonio Musarò,

https://doi.org/10.18632/aging.100466 pp 377—378

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Beyond average: potential for measurement of short telomeres

Elsa Vera, Maria A. Blasco,

https://doi.org/10.18632/aging.100462 pp 379—392

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Vera E, Blasco MA, . Beyond average: potential for measurement of short telomeres. . 4:379-392. https://doi.org/10.18632/aging.100462

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                TY  - JOUR
                AU  - Vera, Elsa 
                AU  - Blasco, Maria A. 
                TI  - Beyond average: potential for measurement of short telomeres
                JO  - 
                JA  - 
                VL  - 4
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100462
                DO  - 10.18632/aging.100462
                SP  - 379
                EP  - 392
                PY  - 
                AB  - The length of telomeres, and in particular the abundance of short telomeres, has been proposed as a biomarker of aging and of general health status. A wide variety of studies show the association of short telomeres with age related pathologies and cancer, as well as with lifespan and mortality. These facts highlight the importance of measuring telomere length in human populations and by using reliable methods to uncover the association between telomere length and human disease. This review discusses the advantages and drawbacks of current telomere length measurement methods. Most of these methods provide mean telomere length values per cell or per sample and very few of them are able to measure the abundance of short telomeres, which are the ones indicative of telomere dysfunction. The information provided by each method and their suitability for different studies is discussed here.
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Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: New insight into the role of mitophagy in cell stemness

Alejandro Vazquez-Martin, Sílvia Cufí, Bruna Corominas-Faja, Cristina Oliveras-Ferraros, Luciano Vellon, Javier A. Menendez,

https://doi.org/10.18632/aging.100465 pp 393—401

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Vazquez-Martin A, Cufí S, Corominas-Faja B, Oliveras-Ferraros C, Vellon L, Menendez JA, . Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: New insight into the role of mitophagy in cell stemness. . 4:393-401. https://doi.org/10.18632/aging.100465

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                TY  - JOUR
                AU  - Vazquez-Martin, Alejandro 
                AU  - Cufí, Sílvia 
                AU  - Corominas-Faja, Bruna 
                AU  - Oliveras-Ferraros, Cristina 
                AU  - Vellon, Luciano 
                AU  - Menendez, Javier A. 
                TI  - Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: New insight into the role of mitophagy in cell stemness
                JO  - 
                JA  - 
                VL  - 4
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100465
                DO  - 10.18632/aging.100465
                SP  - 393
                EP  - 401
                PY  - 
                AB  - Recent studies have suggested a pivotal role for autophagy in stem cell maintenance and differentiation. Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) has been also suggested to bio-energetically take advantage of mitochondrial autophagy (mitophagy). We have preliminary addressed how mitophagy might play a role in the regulation of induced pluripotency using mdivi-1 (for mitochondrial division inhibitor), a highly efficacious small molecule that selectively inhibits the self-assembly of DRP1, a member of the dynamin family of large GTPases that mediates mitochondrial fission. At mdivi-1 concentrations that rapidly induced the formation of mitochondrial net-like or collapsed perinuclear mitochondrial structures, we observed that the reprogramming efficiency of mouse embryonic fibroblasts transduced with the Yamanaka three-factor cocktail (OCT4, KLF4, and SOX2) is drastically reduced by more than 95%. Treatment of MEFs with mdivi-1 at the early stages of reprogramming before the appearance of iPSC colonies was sufficient to completely inhibit somatic cell reprogramming. Therefore, the observed effects on reprogramming efficiencies were due likely to the inhibition of the process of reprogramming itself and not to an impairment of iPSC colony survival or growth. Moreover, the typical morphology of established iPSC colonies with positive alkaline phosphatase staining was negatively affected by mdivi-1 exposure. In the presence of mdivi-1, the colony morphology of the iPSCs was lost, and they somewhat resembled fibroblasts. The alkaline phosphatase staining was also significantly reduced, a finding that is indicative of differentiation. Our current findings provide new insight into how mitochondrial division is integrated into the reprogramming factors-driven transcriptional network that specifies the unique pluripotency of stem cells.
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Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice

Giulia Bolasco, Raffaele Calogero, Matteo Carrara, Mumna Al Banchaabouchi, Daniel Bilbao, Gianluigi Mazzoccoli, Manlio Vinciguerra,

https://doi.org/10.18632/aging.100464 pp 402—416

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Bolasco G, Calogero R, Carrara M, Al Banchaabouchi M, Bilbao D, Mazzoccoli G, Vinciguerra M, . Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice. . 4:402-416. https://doi.org/10.18632/aging.100464

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                TY  - JOUR
                AU  - Bolasco, Giulia 
                AU  - Calogero, Raffaele 
                AU  - Carrara, Matteo 
                AU  - Al Banchaabouchi, Mumna 
                AU  - Bilbao, Daniel 
                AU  - Mazzoccoli, Gianluigi 
                AU  - Vinciguerra, Manlio 
                TI  - Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice
                JO  - 
                JA  - 
                VL  - 4
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100464
                DO  - 10.18632/aging.100464
                SP  - 402
                EP  - 416
                PY  - 
                AB  - Locally acting insulin growth factor isoform (mIGF-1) and the NAD+-dependent protein deacetylase SIRT1 are implicated in life and health span. Heart failure is associated with aging and is a major cause of death. mIGF-1 protects the heart from oxidative stresses via SIRT1. SIRT1 subcellular localization and its genomic regulation by mIGF-1 are unknown. We show here that SIRT1 is located in the nuclei of a significant fraction of cardiomyocytes. Using high throughput sequencing approaches in mIGF-1 transgenic mice, we identified new targets of the mIGF-1/SIRT1 signaling. In addition to its potent cardioprotective properties, cardiac-restricted mIGF-1 transgene induced systemic changes such as high blood pressure, leukocytosis and an enhanced fear response, in a SIRT1-dependent manner. Cardiac mIGF-1/SIRT1 signaling may thus modulate disparate systemic functions.
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DNA binding residues in the RQC domain of Werner protein are critical for its catalytic activities

Takashi Tadokoro, Tomasz Kulikowicz, Lale Dawut, Deborah L. Croteau, Vilhelm A. Bohr,

https://doi.org/10.18632/aging.100463 pp 417—429

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Tadokoro T, Kulikowicz T, Dawut L, Croteau DL, Bohr VA, . DNA binding residues in the RQC domain of Werner protein are critical for its catalytic activities. . 4:417-429. https://doi.org/10.18632/aging.100463

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                TY  - JOUR
                AU  - Tadokoro, Takashi 
                AU  - Kulikowicz, Tomasz 
                AU  - Dawut, Lale 
                AU  - Croteau, Deborah L. 
                AU  - Bohr, Vilhelm A. 
                TI  - DNA binding residues in the RQC domain of Werner protein are critical for its catalytic activities
                JO  - 
                JA  - 
                VL  - 4
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100463
                DO  - 10.18632/aging.100463
                SP  - 417
                EP  - 429
                PY  - 
                AB  - Werner protein (WRN), member of the RecQ helicase family, is a helicase and exonuclease, and participates in multiple DNA metabolic processes including DNA replication, recombination and DNA repair. Mutations in the WRN gene cause Werner syndrome, associated with premature aging, genome instability and cancer predisposition. The RecQ C-terminal (RQC) domain of WRN, containing α2-α3 loop and β-wing motifs, is important for DNA binding and for many protein interactions. To better understand the critical functions of this domain, we generated recombinant WRN proteins (using a novel purification scheme) with mutations in Arg-993 within the α2-α3 loop of the RQC domain and in Phe-1037 of the μ-wing motif. We then studied the catalytic activities and DNA binding of these mutant proteins as well as some important functional protein interactions. The mutant proteins were defective in DNA binding and helicase activity, and interestingly, they had deficient exonuclease activity and strand annealing function. The RQC domain of WRN has not previously been implicated in exonuclease or annealing activities. The mutant proteins could not stimulate NEIL1 incision activity as did the wild type. Thus, the Arg-993 and Phe-1037 in the RQC domain play essential roles in catalytic activity, and in functional interactions mediated by WRN.
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Replicatively senescent cells are arrested in G1 and G2 phases

Zhiyong Mao, Zhonghe Ke, Vera Gorbunova, Andrei Seluanov,

https://doi.org/10.18632/aging.100467 pp 431—435

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Mao Z, Ke Z, Gorbunova V, Seluanov A, . Replicatively senescent cells are arrested in G1 and G2 phases. . 4:431-435. https://doi.org/10.18632/aging.100467

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                TY  - JOUR
                AU  - Mao, Zhiyong 
                AU  - Ke, Zhonghe 
                AU  - Gorbunova, Vera 
                AU  - Seluanov, Andrei 
                TI  - Replicatively senescent cells are arrested in G1 and G2 phases
                JO  - 
                JA  - 
                VL  - 4
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100467
                DO  - 10.18632/aging.100467
                SP  - 431
                EP  - 435
                PY  - 
                AB  - Most human somatic cells do not divide indefinitely but enter a terminal growth arrest termed replicative senescence. Replicatively senescent cells are generally believed to arrest in G1 or G0 stage of the cell cycle. While doing cell cycle analysis on three different lines of normal human fibroblasts we observed that 36-60% of the replicatively senescent cells had 4N DNA content. Only up to 5% of senescent cells had more than one nucleus ruling out the possibility that the 4N cell population were G1-arrested bi-nucleated cells. Furthermore, it is unlikely that the 4N cells are tetraploids, because actively dividing pre-senescent cultures lacked the 8N tetraploid G2 population. Collectively these results suggest that the 4N population consists of G2 arrested cells. The notion that a large fraction of senescent cell population is arrested in G2 is important for understanding the biology of replicative senescence.
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The Tellurium compound, AS101, increases SIRT1 level and activity and prevents type 2 diabetes

Meital Halperin-Sheinfeld, Asaf Gertler, Eitan Okun, Benjamin Sredni, Haim Y. Cohen,

https://doi.org/10.18632/aging.100468 pp 436—447

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Halperin-Sheinfeld M, Gertler A, Okun E, Sredni B, Cohen HY, . The Tellurium compound, AS101, increases SIRT1 level and activity and prevents type 2 diabetes. . 4:436-447. https://doi.org/10.18632/aging.100468

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                TY  - JOUR
                AU  - Halperin-Sheinfeld, Meital 
                AU  - Gertler, Asaf 
                AU  - Okun, Eitan 
                AU  - Sredni, Benjamin 
                AU  - Cohen, Haim Y. 
                TI  - The Tellurium compound, AS101, increases SIRT1 level and activity and prevents type 2 diabetes
                JO  - 
                JA  - 
                VL  - 4
                IS  - 6
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100468
                DO  - 10.18632/aging.100468
                SP  - 436
                EP  - 447
                PY  - 
                AB  - The histone deacetylase, SIRT1, plays a major role in glucose regulation and lipid metabolism. Ammonium Trichloro (dioxoethylene-o,o') Tellurate, AS101, is a potent in vitro and in vivo immunomodulator, with several potential therapeutic applications. AS101 administration resulted in upregulation of SIRT1 protein expression and activity. These effects were associated with decreased levels of serum insulin like growth factor-1 (IGF-1) and of insulin. The properties of AS101 prompted us to investigate its potential therapeutic role in rats with type 2 diabetes (T2D). T2D was induced by a high fat diet combined with a low dose of Streptozotocin (STZ). Treatment with AS101 before manifestation of hyperglycemia, resulted in increased insulin sensitivity, and decreased blood glucose levels, and prevented symptoms of diabetes including defective glucose clearance, fatty liver, and abnormal distribution of insulin-producing beta cells in the pancreas. Treatment after disease emergence resulted in partial restoration of normal glucose homeostasis. Diabetic rats showed a reduction in liver SIRT1 levels. In both treatment regimens the reduction in SIRT1 levels in the liver were blocked by AS101 consumption. Together, these findings demonstrate the therapeutic potential of AS101 for treating T2D, and for reversing impaired fat and glucose metabolism.
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Volume 4, Issue 6

Chemoprevention of age-related macular regeneration (AMD) with rapamycin

X. F. Steven Zheng,

To the heart of the problem. mIGF-1: local effort for global impact

Antonio Musarò,

Review

Beyond average: potential for measurement of short telomeres

Elsa Vera, Maria A. Blasco,

Research Perspective

Mitochondrial fusion by pharmacological manipulation impedes somatic cell reprogramming to pluripotency: New insight into the role of mitophagy in cell stemness

Alejandro Vazquez-Martin, Sílvia Cufí, Bruna Corominas-Faja, Cristina Oliveras-Ferraros, Luciano Vellon, Javier A. Menendez,

Research Papers

Cardioprotective mIGF-1/SIRT1 signaling induces hypertension, leukocytosis and fear response in mice

Giulia Bolasco, Raffaele Calogero, Matteo Carrara, Mumna Al Banchaabouchi, Daniel Bilbao, Gianluigi Mazzoccoli, Manlio Vinciguerra,

DNA binding residues in the RQC domain of Werner protein are critical for its catalytic activities

Takashi Tadokoro, Tomasz Kulikowicz, Lale Dawut, Deborah L. Croteau, Vilhelm A. Bohr,

Replicatively senescent cells are arrested in G1 and G2 phases

Zhiyong Mao, Zhonghe Ke, Vera Gorbunova, Andrei Seluanov,

The Tellurium compound, AS101, increases SIRT1 level and activity and prevents type 2 diabetes

Meital Halperin-Sheinfeld, Asaf Gertler, Eitan Okun, Benjamin Sredni, Haim Y. Cohen,

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