Volume 4, Issue 10

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Donehower LA, . Rapamycin as longevity enhancer and cancer preventative agent in the context of p53 deficiency. . 4:660-661. https://doi.org/10.18632/aging.100494

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Provider: TY - JOUR AU - Donehower, Lawrence A. TI - Rapamycin as longevity enhancer and cancer preventative agent in the context of p53 deficiency JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100494 DO - 10.18632/aging.100494 SP - 660 EP - 661 PY - ER -

Provider: TY - JOUR AU - Donehower, Lawrence A. TI - Rapamycin as longevity enhancer and cancer preventative agent in the context of p53 deficiency JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100494 DO - 10.18632/aging.100494 SP - 660 EP - 661 PY - AB - ER -

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Vatner SF, Vatner DE, Yan L, . Models of longevity (Calorie Restriction and AC5 KO): Result of three bad hypotheses. . 4:662-663. https://doi.org/10.18632/aging.100495

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Provider: TY - JOUR AU - Vatner, Stephen F. AU - Vatner, Dorothy E. AU - Yan, Lin TI - Models of longevity (Calorie Restriction and AC5 KO): Result of three bad hypotheses JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100495 DO - 10.18632/aging.100495 SP - 662 EP - 663 PY - ER -

Provider: TY - JOUR AU - Vatner, Stephen F. AU - Vatner, Dorothy E. AU - Yan, Lin TI - Models of longevity (Calorie Restriction and AC5 KO): Result of three bad hypotheses JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100495 DO - 10.18632/aging.100495 SP - 662 EP - 663 PY - AB - ER -

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Albertini E, Kozieł R, Dürr A, Neuhaus M, Jansen-Dürr P, . Cystathionine beta synthase modulates senescence of human endothelial cells. . 4:664-673. https://doi.org/10.18632/aging.100491

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Provider: TY - JOUR AU - Albertini, Eva AU - Kozieł, Rafał AU - Dürr, Angela AU - Neuhaus, Michael AU - Jansen-Dürr, Pidder TI - Cystathionine beta synthase modulates senescence of human endothelial cells JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100491 DO - 10.18632/aging.100491 SP - 664 EP - 673 PY - ER -

Provider: TY - JOUR AU - Albertini, Eva AU - Kozieł, Rafał AU - Dürr, Angela AU - Neuhaus, Michael AU - Jansen-Dürr, Pidder TI - Cystathionine beta synthase modulates senescence of human endothelial cells JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100491 DO - 10.18632/aging.100491 SP - 664 EP - 673 PY - AB - Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescence in vitro, involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease. ER -

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Noren Hooten N, Fitzpatrick M, Kompaniez K, Jacob KD, Moore BR, Nagle J, Barnes J, Lohani A, Evans MK, . Coordination of DNA repair by NEIL1 and PARP-1: a possible link to aging. . 4:674-685. https://doi.org/10.18632/aging.100492

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Provider: TY - JOUR AU - Noren Hooten, Nicole AU - Fitzpatrick, Megan AU - Kompaniez, Kari AU - Jacob, Kimberly D. AU - Moore, Brittany R. AU - Nagle, Julia AU - Barnes, Janice AU - Lohani, Althaf AU - Evans, Michele K. TI - Coordination of DNA repair by NEIL1 and PARP-1: a possible link to aging JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100492 DO - 10.18632/aging.100492 SP - 674 EP - 685 PY - ER -

Provider: TY - JOUR AU - Noren Hooten, Nicole AU - Fitzpatrick, Megan AU - Kompaniez, Kari AU - Jacob, Kimberly D. AU - Moore, Brittany R. AU - Nagle, Julia AU - Barnes, Janice AU - Lohani, Althaf AU - Evans, Michele K. TI - Coordination of DNA repair by NEIL1 and PARP-1: a possible link to aging JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100492 DO - 10.18632/aging.100492 SP - 674 EP - 685 PY - AB - Oxidative DNA damage accumulates with age and is repaired primarily via the base excision repair (BER) pathway. This process is initiated by DNA glycosylases, which remove damaged bases in a substrate-specific manner. The DNA glycosylases human 8-oxoguanine-DNA glycosylase (OGG1) and NEIL1, a mammalian homolog of Escherichia coli endonuclease VIII, have overlapping yet distinct substrate specificity. Recently, we reported that OGG1 binds to the Poly(ADP-ribose) polymerase 1 (PARP-1), a DNA damage sensor protein that poly(ADP-ribosyl)ates nuclear proteins in response to DNA damage and other cellular signals. Here, we show that NEIL1 and PARP-1 bind both in vitro and in vivo. PARP-1 binds to the C-terminal-100 amino acids of NEIL1 and NEIL1 binds to the BRCT domain of PARP-1. NEIL1 stimulates the poly(ADP-ribosyl)ation activity of PARP-1. Furthermore, NEIL-deficient fibroblasts have impaired poly(ADP-ribosyl)ation of cellular proteins after DNA damage, which can be rescued by NEIL1 expression. Additionally, PARP-1 inhibits NEIL1 incision activity in a concentration-dependent manner. Consistent with the idea of impaired DNA repair during aging, we observed differential binding of PARP-1 to recombinant NEIL1 in older mice compared to younger mice. These data further support the idea that dynamic interplay between different base excision repair proteins is important for efficient BER. ER -

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Kolosova NG, Stefanova NA, Muraleva NA, Skulachev VP, . The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats. . 4:686-694. https://doi.org/10.18632/aging.100493

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Provider: TY - JOUR AU - Kolosova, Nataliya G. AU - Stefanova, Natalia A. AU - Muraleva, Natalia A. AU - Skulachev, Vladimir P. TI - The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100493 DO - 10.18632/aging.100493 SP - 686 EP - 694 PY - ER -

Provider: TY - JOUR AU - Kolosova, Nataliya G. AU - Stefanova, Natalia A. AU - Muraleva, Natalia A. AU - Skulachev, Vladimir P. TI - The mitochondria-targeted antioxidant SkQ1 but not N-acetylcysteine reverses aging-related biomarkers in rats JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100493 DO - 10.18632/aging.100493 SP - 686 EP - 694 PY - AB - Although antioxidants have been repeatedly tested in animal models and clinical studies, there is no evidence that antioxidants reduce already developed age-related decline. Recently we demonstrated that mitochondria-targeted antioxidant 10-(6'-plastoquinonyl) decyltriphenylphosphonium (SkQ1) delayed some manifestations of aging. Here we compared effects of SkQ1 and N-acetyl-L-cysteine (NAC) on age-dependent decline in blood levels of leukocytes, growth hormone (GH), insulin-like growth factor-1 (IGF-1), testosterone, dehydroepiandrosterone (DHEA) in Wistar and senescence-accelerated OXYS rats. When started late in life, supplementation with SkQ1 not only prevented age-related decline but also significantly reversed it. With NAC, all the observed effects were of the lower magnitude compared with SkQ1 (in spite of that dose of NAC was 16000 times higher). We suggest that supplementation with low doses of SkQ1 is a promising intervention to achieve a healthy ageing. ER -

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Tominaga-Yamanaka K, Abdelmohsen K, Martindale JL, Yang X, Taub DD, Gorospe M, . NF90 coordinately represses the senescence-associated secretory phenotype. . 4:695-708. https://doi.org/10.18632/aging.100497

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Provider: TY - JOUR AU - Tominaga-Yamanaka, Kumiko AU - Abdelmohsen, Kotb AU - Martindale, Jennifer L. AU - Yang, Xiaoling AU - Taub, Dennis D. AU - Gorospe, Myriam TI - NF90 coordinately represses the senescence-associated secretory phenotype JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100497 DO - 10.18632/aging.100497 SP - 695 EP - 708 PY - ER -

Provider: TY - JOUR AU - Tominaga-Yamanaka, Kumiko AU - Abdelmohsen, Kotb AU - Martindale, Jennifer L. AU - Yang, Xiaoling AU - Taub, Dennis D. AU - Gorospe, Myriam TI - NF90 coordinately represses the senescence-associated secretory phenotype JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100497 DO - 10.18632/aging.100497 SP - 695 EP - 708 PY - AB - A hallmark trait of cellular senescence is the acquisition of a senescence-associated secretory phenotype (SASP). SASP factors include cytokines and their receptors (IL-6, IL-8, osteoprotegerin, GM-CSF), chemokines and their ligands (MCP-1, HCC4), and oncogenes (Gro1 and Gro2), many of them encoded by mRNAs whose stability and translation are tightly regulated. Using two models of human fibroblast senescence (WI-38 and IDH4 cells), we report the identification of RNA-binding protein NF90 as a post-transcriptional repressor of several SASP factors. In ‘young’, proliferating fibroblasts, NF90 was highly abundant, associated with numerous SASP mRNAs, and inhibited their expression. By contrast, senescent cells expressed low levels of NF90, thus allowing SASP factor expression to increase. NF90 elicited these effects mainly by repressing the translation of target SASP mRNAs, since silencing NF90 did not increase the steady-state levels of SASP mRNAs but elevated key SASP factors including MCP-1, GROa, IL-6, and IL-8. Our findings indicate that NF90 contributes to maintaining low levels of SASP factors in non-senescent cells, while NF90 reduction in senescent cells allows SASP factor expression to rise. ER -

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Komarova EA, Antoch MP, Novototskaya LR, Chernova OB, Paszkiewicz G, Leontieva OV, Blagosklonny MV, Gudkov AV, . Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice. . 4:709-714. https://doi.org/10.18632/aging.100498

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Provider: TY - JOUR AU - Komarova, Elena A. AU - Antoch, Marina P. AU - Novototskaya, Liliya R. AU - Chernova, Olga B. AU - Paszkiewicz, Geraldine AU - Leontieva, Olga V. AU - Blagosklonny, Mikhail V. AU - Gudkov, Andrei V. TI - Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100498 DO - 10.18632/aging.100498 SP - 709 EP - 714 PY - ER -

Provider: TY - JOUR AU - Komarova, Elena A. AU - Antoch, Marina P. AU - Novototskaya, Liliya R. AU - Chernova, Olga B. AU - Paszkiewicz, Geraldine AU - Leontieva, Olga V. AU - Blagosklonny, Mikhail V. AU - Gudkov, Andrei V. TI - Rapamycin extends lifespan and delays tumorigenesis in heterozygous p53+/− mice JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100498 DO - 10.18632/aging.100498 SP - 709 EP - 714 PY - AB - The TOR (Target of Rapamycin) pathway accelerates cellular and organismal aging. Similar to rapamycin, p53 can inhibit the mTOR pathway in some mammalian cells. Mice lacking one copy of p53 (p53+/− mice) have an increased cancer incidence and a shorter lifespan. We hypothesize that rapamycin can delay cancer in heterozygous p53+/− mice. Here we show that rapamycin (given in a drinking water) extended the mean lifespan of p53+/− mice by 10% and when treatment started early in life (at the age less than 5 months) by 28%. In addition, rapamycin decreased the incidence of spontaneous tumors. This observation may have applications in management of Li-Fraumeni syndrome patients characterized by heterozygous mutations in the p53 gene. ER -

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Comas M, Toshkov I, Kuropatwinski KK, Chernova OB, Polinsky A, Blagosklonny MV, Gudkov AV, Antoch MP, . New nanoformulation of rapamycin Rapatar extends lifespan in homozygous p53^−/− mice by delaying carcinogenesis. . 4:715-722. https://doi.org/10.18632/aging.100496

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Provider: TY - JOUR AU - Comas, Maria AU - Toshkov, Ilia AU - Kuropatwinski, Karen K. AU - Chernova, Olga B. AU - Polinsky, Alexander AU - Blagosklonny, Mikhail V. AU - Gudkov, Andrei V. AU - Antoch, Marina P. TI - New nanoformulation of rapamycin Rapatar extends lifespan in homozygous <i>p53^−/−</i> mice by delaying carcinogenesis JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100496 DO - 10.18632/aging.100496 SP - 715 EP - 722 PY - ER -

Provider: TY - JOUR AU - Comas, Maria AU - Toshkov, Ilia AU - Kuropatwinski, Karen K. AU - Chernova, Olga B. AU - Polinsky, Alexander AU - Blagosklonny, Mikhail V. AU - Gudkov, Andrei V. AU - Antoch, Marina P. TI - New nanoformulation of rapamycin Rapatar extends lifespan in homozygous <i>p53^−/−</i> mice by delaying carcinogenesis JO - JA - VL - 4 IS - 10 PB - SN - UR - https://doi.org/10.18632/aging.100496 DO - 10.18632/aging.100496 SP - 715 EP - 722 PY - AB - The nutrient-sensing mTOR (mammalian Target of Rapamycin) pathway regulates cellular metabolism, growth functions, and proliferation and is involved in age-related diseases including cancer, type 2 diabetes, neurodegeneration and cardiovascular disease. The inhibition of mTOR by rapamycin, or calorie restriction, has been shown to extend lifespan and delays tumorigenesis in several experimental models suggesting that rapamycin may be used for cancer prevention. This requires continuous long-term treatment making oral formulations the preferred choice of administration route. However, rapamycin by itself has very poor water solubility and low absorption rate. Here we describe pharmacokinetic and biological properties of novel nanoformulated micelles of rapamycin, Rapatar. Micelles of Rapatar were rationally designed to increase water solubility of rapamycin to facilitate oral administration and to enhance its absorption. As a result, bioavailability of Rapatar was significantly increased (up to 12%) compared to unformulated rapamycin, which concentration in the blood following oral administration remained below level of detection. We also demonstrated that the new formulation does not induce toxicity during lifetime administration. Most importantly, Rapatar extended the mean lifespan by 30% and delayed tumor development in highly tumor-prone p53−/− mice. Our data demonstrate that water soluble Rapatar micelles represent safe, convenient and efficient form of rapamycin suitable for a long-term treatment and that Rapatar may be considered for tumor prevention. ER -

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