Volume 7, Issue 12

Antidepressants synergize with chemotherapy against cancer stem cells

Gerry Melino,

https://doi.org/10.18632/aging.100848 pp 1024—1025

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Melino G, . Antidepressants synergize with chemotherapy against cancer stem cells. Aging (Albany NY). 7:1024-1025. https://doi.org/10.18632/aging.100848

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Fasting plus tyrosine kinase inhibitors in cancer

Irene Caffa, Valter D. Longo, Alessio Nencioni,

https://doi.org/10.18632/aging.100857 pp 1026—1027

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c-Fos importance for brain development

Fabiola N. Velazquez, Beatriz L. Caputto, François D. Boussin,

https://doi.org/10.18632/aging.100862 pp 1028—1029

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TOR-inhibitors as gero-suppressors

Mikhail Nikiforov,

https://doi.org/10.18632/aging.100869 pp 1030—1031

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The PTEN tumor suppressor gene and its role in lymphoma pathogenesis

Xiaoxiao Wang, Huiqiang Huang, Ken H. Young,

https://doi.org/10.18632/aging.100855 pp 1032—1049

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Wang X, Huang H, Young KH, . The PTEN tumor suppressor gene and its role in lymphoma pathogenesis. Aging (Albany NY). 7:1032-1049. https://doi.org/10.18632/aging.100855

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Provider: 
                TY  - JOUR
                AU  - Wang, Xiaoxiao 
                AU  - Huang, Huiqiang 
                AU  - Young, Ken H. 
                TI  - The PTEN tumor suppressor gene and its role in lymphoma pathogenesis
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100855
                DO  - 10.18632/aging.100855
                SP  - 1032
                EP  - 1049
                PY  - 
                AB  - 
                        The phosphatase and tensin homolog gene PTEN is one of the most frequently mutated tumor suppressor genes in human cancer. Loss of PTEN function occurs in a variety of human cancers via its mutation, deletion, transcriptional silencing, or protein instability. PTEN deficiency in cancer has been associated with advanced disease, chemotherapy resistance, and poor survival. Impaired PTEN function, which antagonizes phosphoinositide 3-kinase (PI3K) signaling, causes the accumulation of phosphatidylinositol (3,4,5)-triphosphate and thereby the suppression of downstream components of the PI3K pathway, including the protein kinase B and mammalian target of rapamycin kinases. In addition to having lipid phosphorylation activity, PTEN has critical roles in the regulation of genomic instability, DNA repair, stem cell self-renewal, cellular senescence, and cell migration. Although PTEN deficiency in solid tumors has been studied extensively, rare studies have investigated PTEN alteration in lymphoid malignancies. However, genomic or epigenomic aberrations of PTEN and dysregulated signaling are likely critical in lymphoma pathogenesis and progression. This review provides updated summary on the role of PTEN deficiency in human cancers, specifically in lymphoid malignancies; the molecular mechanisms of PTEN regulation; and the distinct functions of nuclear PTEN. Therapeutic strategies for rescuing PTEN deficiency in human cancers are proposed.
                      
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DNA repair and aging: the impact of the p53 family

Sara Nicolai, Antonello Rossi, Nicola Di Daniele, Gerry Melino, Margherita Annicchiarico-Petruzzelli, Giuseppe Raschellà,

https://doi.org/10.18632/aging.100858 pp 1050—1065

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Nicolai S, Rossi A, Di Daniele N, Melino G, Annicchiarico-Petruzzelli M, Raschellà G, . DNA repair and aging: the impact of the p53 family. Aging (Albany NY). 7:1050-1065. https://doi.org/10.18632/aging.100858

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                TY  - JOUR
                AU  - Nicolai, Sara 
                AU  - Rossi, Antonello 
                AU  - Di Daniele, Nicola 
                AU  - Melino, Gerry 
                AU  - Annicchiarico-Petruzzelli, Margherita 
                AU  - Raschellà, Giuseppe 
                TI  - DNA repair and aging: the impact of the p53 family
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100858
                DO  - 10.18632/aging.100858
                SP  - 1050
                EP  - 1065
                PY  - 
                AB  - Cells are constantly exposed to endogenous and exogenous factors that threaten the integrity of their DNA. The maintenance of genome stability is of paramount importance in the prevention of both cancer and aging processes. To deal with DNA damage, cells put into operation a sophisticated and coordinated mechanism, collectively known as DNA damage response (DDR). The DDR orchestrates different cellular processes, such as DNA repair, senescence and apoptosis. Among the key factors of the DDR, the related proteins p53, p63 and p73, all belonging to the same family of transcription factors, play multiple relevant roles. Indeed, the members of this family are directly involved in the induction of cell cycle arrest that is necessary to allow the cells to repair. Alternatively, they can promote cell death in case of prolonged or irreparable DNA damage. They also take part in a more direct task by modulating the expression of core factors involved in the process of DNA repair or by directly interacting with them. In this review we will analyze the fundamental roles of the p53 family in the aging process through their multifaceted function in DDR.
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Telomere length is a prognostic biomarker in elderly advanced ovarian cancer patients: a multicenter GINECO study

Claire Falandry, Béatrice Horard, Amandine Bruyas, Eric Legouffe, Jacques Cretin, Jérôme Meunier, Jérôme Alexandre, Valérie Delecroix, Michel Fabbro, Marie-Noëlle Certain, Raymonde Maraval-Gaget, Eric Pujade-Lauraine, Eric Gilson, Gilles Freyer,

https://doi.org/10.18632/aging.100840 pp 1066—1074

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Falandry C, Horard B, Bruyas A, Legouffe E, Cretin J, Meunier J, Alexandre J, Delecroix V, Fabbro M, Certain M, Maraval-Gaget R, Pujade-Lauraine E, Gilson E, et al, . Telomere length is a prognostic biomarker in elderly advanced ovarian cancer patients: a multicenter GINECO study. Aging (Albany NY). 7:1066-1074. https://doi.org/10.18632/aging.100840

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                TY  - JOUR
                AU  - Falandry, Claire 
                AU  - Horard, Béatrice 
                AU  - Bruyas, Amandine 
                AU  - Legouffe, Eric 
                AU  - Cretin, Jacques 
                AU  - Meunier, Jérôme 
                AU  - Alexandre, Jérôme 
                AU  - Delecroix, Valérie 
                AU  - Fabbro, Michel 
                AU  - Certain, Marie-Noëlle 
                AU  - Maraval-Gaget, Raymonde 
                AU  - Pujade-Lauraine, Eric 
                AU  - Gilson, Eric 
                AU  - Freyer, Gilles 
                TI  - Telomere length is a prognostic biomarker in elderly advanced ovarian cancer patients: a multicenter GINECO study
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100840
                DO  - 10.18632/aging.100840
                SP  - 1066
                EP  - 1074
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Falandry, Claire 
                AU  - Horard, Béatrice 
                AU  - Bruyas, Amandine 
                AU  - Legouffe, Eric 
                AU  - Cretin, Jacques 
                AU  - Meunier, Jérôme 
                AU  - Alexandre, Jérôme 
                AU  - Delecroix, Valérie 
                AU  - Fabbro, Michel 
                AU  - Certain, Marie-Noëlle 
                AU  - Maraval-Gaget, Raymonde 
                AU  - Pujade-Lauraine, Eric 
                AU  - Gilson, Eric 
                AU  - Freyer, Gilles 
                TI  - Telomere length is a prognostic biomarker in elderly advanced ovarian cancer patients: a multicenter GINECO study
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100840
                DO  - 10.18632/aging.100840
                SP  - 1066
                EP  - 1074
                PY  - 
                AB  -           Purpose          Age induces a progressive decline in functional reserve and impacts cancer treatments. Telomere attrition leads to tissue senescence. We tested the hypothesis that telomere length (TL) could predict patient vulnerability and outcome with cancer treatment.                          Patients and methods          An ancillary study in the Elderly Women GINECO Trial 3 was performed to evaluate the impact of geriatric covariates on survival in elderly advanced ovarian cancer patients receiving six cycles of carboplatin. TL was estimated from peripheral blood at inclusion using standard procedures.                          Results          TL (in base pairs) was estimated for 109/111 patients (median 6.1 kb; range [4.5-8.3 kb]). With a cut-off of 5.77 kb, TL discriminated two patient groups, long telomere (LT) and short telomeres (ST), with significantly different treatment completion rates of 0.80 (95%CI [0.71-0.89]) and 0.59 (95%CI [0.41-0.76]), respectively (odds ratio [OR]=2.8, p=0.02). ST patients were at higher risk of serious adverse events (SAE, OR=2.7; p=0.02) and had more unplanned hospital admissions (OR=2.1; p=0.08). After adjustment on FIGO stage, TL shorter than 6 kb was a risk factor of premature death (HR=1.57; p=0.06).                          Conclusion          This exploratory study identifies TL as predictive factor of decreased treatment completion, SAE risk, unplanned hospital admissions and OS after adjustment on FIGO stage.        
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A shortened interval between vaccinations with the trivalent inactivated influenza vaccine increases responsiveness in the aged

Senthil Kannan, Andrew Kossenkov, Raj K. Kurupati, Jason ZQ Xiang, Susan A. Doyle, Kenneth E. Schmader, Louise Schowe, Hildegund C. Ertl,

https://doi.org/10.18632/aging.100852 pp 1077—1085

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Kannan S, Kossenkov A, Kurupati RK, Xiang JZ, Doyle SA, Schmader KE, Schowe L, Ertl HC, . A shortened interval between vaccinations with the trivalent inactivated influenza vaccine increases responsiveness in the aged. Aging (Albany NY). 7:1077-1085. https://doi.org/10.18632/aging.100852

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                TY  - JOUR
                AU  - Kannan, Senthil 
                AU  - Kossenkov, Andrew 
                AU  - Kurupati, Raj K. 
                AU  - Xiang, Jason ZQ 
                AU  - Doyle, Susan A. 
                AU  - Schmader, Kenneth E. 
                AU  - Schowe, Louise 
                AU  - Ertl, Hildegund C. 
                TI  - A shortened interval between vaccinations with the trivalent inactivated influenza vaccine increases responsiveness in the aged
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100852
                DO  - 10.18632/aging.100852
                SP  - 1077
                EP  - 1085
                PY  - 
                AB  - We tested antibody responses to the trivalent inactivated influenza vaccine (TIV) in 34 aged individuals (&gt;65yrs) during the 2012/13 vaccination seasons. Nearly all had been vaccinated the previous year although the time interval between the two vaccine doses differed. One subgroup was re-vaccinated in 2012/13 within 6-9 months of their 2011/12 vaccination, the other received the two doses of vaccine in the typical ~12 month interval. Unexpectedly the sub-cohort with early revaccination exhibited significantly increased response rates and antibody titers to TIV compared to their normally re-vaccinated aged counter parts. Microarray analyses of gene expression in whole blood RNA taken at the day of the 2012/13 re-vaccination revealed statistically significant differences in expression of 754 genes between the individuals with early re-vaccination compared to subjects vaccinated in a normal 12 month interval. These observations suggest that TIV has long-lasting effects on the immune system affecting B cell responses as well as the transcriptome of peripheral blood mononuclear cells and this residual effect may augment vaccination response in patients where the effect of the previous vaccination has not yet diminished.
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Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5)

Dominik H. Pesta, Rachel J. Perry, Fitsum Guebre-Egziabher, Dongyan Zhang, Michael Jurczak, Antje Fischer-Rosinsky, Martin A. Daniels, Diana M. Willmes, Sanjay Bhanot, Stefan R. Bornstein, Felix Knauf, Varman T. Samuel, Gerald I. Shulman, Andreas L. Birkenfeld,

https://doi.org/10.18632/aging.100854 pp 1086—1093

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Pesta DH, Perry RJ, Guebre-Egziabher F, Zhang D, Jurczak M, Fischer-Rosinsky A, Daniels MA, Willmes DM, Bhanot S, Bornstein SR, Knauf F, Samuel VT, Shulman GI, et al, . Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5). Aging (Albany NY). 7:1086-1093. https://doi.org/10.18632/aging.100854

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Provider: 
 TY - JOUR
 AU - Pesta, Dominik H. 
 AU - Perry, Rachel J. 
 AU - Guebre-Egziabher, Fitsum 
 AU - Zhang, Dongyan 
 AU - Jurczak, Michael 
 AU - Fischer-Rosinsky, Antje 
 AU - Daniels, Martin A. 
 AU - Willmes, Diana M. 
 AU - Bhanot, Sanjay 
 AU - Bornstein, Stefan R. 
 AU - Knauf, Felix 
 AU - Samuel, Varman T. 
 AU - Shulman, Gerald I. 
 AU - Birkenfeld, Andreas L. 
 TI - Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5)
 JO - 
 JA - Aging (Albany NY)
 VL - 7
 IS - 12
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.100854
 DO - 10.18632/aging.100854
 SP - 1086
 EP - 1093
 PY - 
 ER -

Provider: 
 TY - JOUR
 AU - Pesta, Dominik H. 
 AU - Perry, Rachel J. 
 AU - Guebre-Egziabher, Fitsum 
 AU - Zhang, Dongyan 
 AU - Jurczak, Michael 
 AU - Fischer-Rosinsky, Antje 
 AU - Daniels, Martin A. 
 AU - Willmes, Diana M. 
 AU - Bhanot, Sanjay 
 AU - Bornstein, Stefan R. 
 AU - Knauf, Felix 
 AU - Samuel, Varman T. 
 AU - Shulman, Gerald I. 
 AU - Birkenfeld, Andreas L. 
 TI - Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5)
 JO - 
 JA - Aging (Albany NY)
 VL - 7
 IS - 12
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.100854
 DO - 10.18632/aging.100854
 SP - 1086
 EP - 1093
 PY - 
 AB - 
 Reducing the expression of the Indy (I&apos;m Not Dead Yet) gene in lower organisms extends life span by mechanisms resembling caloric restriction. Similarly, deletion of the mammalian homolog, mIndy (Slc13a5), encoding for a plasma membrane tricarboxylate transporter, protects from aging- and diet-induced adiposity and insulin resistance in mice. The organ specific contribution to this phenotype is unknown. We examined the impact of selective inducible hepatic knockdown of mIndy on whole body lipid and glucose metabolism using 2&#x2032;-O-methoxyethyl chimeric anti-sense oligonucleotides (ASOs) in high-fat fed rats. 4-week treatment with 2&#x2032;-O-methoxyethyl chimeric ASO reduced mIndy mRNA expression by 91% (P&lt;0.001) compared to control ASO. Besides similar body weights between both groups, mIndy-ASO treatment lead to a 74% reduction in fasting plasma insulin concentrations as well as a 35% reduction in plasma triglycerides. Moreover, hepatic triglyceride content was significantly reduced by the knockdown of mIndy, likely mediating a trend to decreased basal rates of endogenous glucose production as well as an increased suppression of hepatic glucose production by 25% during a hyperinsulinemic-euglycemic clamp. Together, these data suggest that inducible liver-selective reduction of mIndy in rats is able to ameliorate hepatic steatosis and insulin resistance, conditions occurring with high calorie diets and during aging.
 
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Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus

Ana Maria Marques Orellana, Andrea Rodrigues Vasconcelos, Jacqueline Alves Leite, Larissa de Sá Lima, Diana Zukas Andreotti, Carolina Demarchi Munhoz, Elisa Mitiko Kawamoto, Cristoforo Scavone,

https://doi.org/10.18632/aging.100853 pp 1094—1108

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Orellana AMM, Vasconcelos AR, Leite JA, de Sá Lima L, Andreotti DZ, Munhoz CD, Kawamoto EM, Scavone C, . Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus. Aging (Albany NY). 7:1094-1108. https://doi.org/10.18632/aging.100853

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                TY  - JOUR
                AU  - Orellana, Ana Maria Marques 
                AU  - Vasconcelos, Andrea Rodrigues 
                AU  - Leite, Jacqueline Alves 
                AU  - de Sá Lima, Larissa 
                AU  - Andreotti, Diana Zukas 
                AU  - Munhoz, Carolina Demarchi 
                AU  - Kawamoto, Elisa Mitiko 
                AU  - Scavone, Cristoforo 
                TI  - Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100853
                DO  - 10.18632/aging.100853
                SP  - 1094
                EP  - 1108
                PY  - 
                AB  - Aging is a multifactorial process associated with an increased susceptibility to neurodegenerative disorders which can be related to chronic inflammation. Chronic inflammation, however, can be characterized by the persistent elevated glucocorticoid (GCs) levels, activation of the proinflammatory transcription factor NF-кB, as well as an increase in cytokines. Interestingly, both NF-кB and cytokines can be even modulated by Glycogen Synthase Kinase 3 beta (GSK-3β) activity, which is a key protein that can intermediate inflammation and metabolism, once it has a critical role in AKT signaling pathway, and can also intermediate WNT/β-CATENIN signaling pathway. The aim of this study was to verify age-related changes in inflammatory status, as well as in the AKT and WNT signaling pathways. Results showed an age-related increase in neuroinflammation as indicated by NF-кB activation, TNF-α and GCs increased levels, a decrease in AKT activation and an increase in GSK-3β activity in both 12- and 24- month old animals. Aging also seems to induce a progressive decrease in canonical WNT/β-CATENIN signaling pathway once there is a decrease in DVL-2 levels and in the transcription of Axin2 gene. Little is known about the DVL-2 regulation as well as its roles in WNT signaling pathway, but for the first time it was suggested that DVL-2 expression can be changed along aging.
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RPD3 histone deacetylase and nutrition have distinct but interacting effects on Drosophila longevity

Stewart Frankel, Jared Woods, Tahereh Ziafazeli, Blanka Rogina,

https://doi.org/10.18632/aging.100856 pp 1112—1128

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Frankel S, Woods J, Ziafazeli T, Rogina B, . RPD3 histone deacetylase and nutrition have distinct but interacting effects on Drosophila longevity. Aging (Albany NY). 7:1112-1128. https://doi.org/10.18632/aging.100856

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 TY - JOUR
 AU - Frankel, Stewart 
 AU - Woods, Jared 
 AU - Ziafazeli, Tahereh 
 AU - Rogina, Blanka 
 TI - RPD3 histone deacetylase and nutrition have distinct but interacting effects on Drosophila longevity
 JO - 
 JA - Aging (Albany NY)
 VL - 7
 IS - 12
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.100856
 DO - 10.18632/aging.100856
 SP - 1112
 EP - 1128
 PY - 
 AB - 
 Single-gene mutations that extend longevity have revealed regulatory pathways related to aging and longevity. RPD3 is a conserved histone deacetylase (Class I HDAC). Previously we showed that Drosophila rpd3 mutations increase longevity. Here we tested the longevity effects of RPD3 on multiple nutrient levels. Dietary restriction (DR) has additive effects on RPD3-mediated longevity extension, but the effect may be modestly attenuated relative to controls. RPD3 and DR therefore appear to operate by distinct but interacting mechanisms. Since RPD3 regulates transcription, the mRNA levels for two proteins involved in nutrient signaling, 4E-BP and Tor, were examined in rpd3 mutant flies. 4E-BP mRNA was reduced under longevity-increasing conditions. Epistasis between RPD3 and 4E-BP with regard to longevity was then tested. Flies only heterozygous for a mutation in Thor, the 4E-BP gene, have modestly decreased life spans. Flies mutant for both rpd3 and Thor show a superposition of a large RPD3-mediated increase and a small Thor-mediated decrease in longevity at all food levels, consistent with each gene product having distinct effects on life span. However, DR-mediated extension was absent in males carrying both mutations and lessened in females. Our results support the view that multiple discrete but interacting mechanisms regulate longevity.
 
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Increased epigenetic age and granulocyte counts in the blood of Parkinson's disease patients

Steve Horvath, Beate R Ritz,

https://doi.org/10.18632/aging.100859 pp 1130—1142

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Horvath S, Ritz BR, . Increased epigenetic age and granulocyte counts in the blood of Parkinson's disease patients. Aging (Albany NY). 7:1130-1142. https://doi.org/10.18632/aging.100859

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                TY  - JOUR
                AU  - Horvath, Steve 
                AU  - Ritz, Beate R 
                TI  - Increased epigenetic age and granulocyte counts in the blood of Parkinson's disease patients
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100859
                DO  - 10.18632/aging.100859
                SP  - 1130
                EP  - 1142
                PY  - 
                AB  - It has been a long standing hypothesis that blood tissue of PD Parkinson's disease (PD) patients may exhibit signs of accelerated aging. Here we use DNA methylation based biomarkers of aging (“epigenetic clock”) to assess the aging rate of blood in two ethnically distinct case-control data sets. Using n=508 Caucasian and n=84 Hispanic blood samples, we assess a) the intrinsic epigenetic age acceleration of blood (IEAA), which is independent of blood cell counts, and b) the extrinsic epigenetic age acceleration rate of blood (EEAA) which is associated with age dependent changes in blood cell counts. Blood of PD subjects exhibits increased age acceleration according to both IEAA (p=0.019) and EEAA (p=6.1×10−3). We find striking differences in imputed blood cell counts between PD cases and controls. Compared to control subjects, PD subjects contains more granulocytes (p=1.0×10−9 in Caucasians, p=0.00066 in Hispanics) but fewer T helper cells (p=1.4×10−6 in Caucasians, p=0.0024 in Hispanics) and fewer B cells (p=1.6×10−5 in Caucasians, p=4.5×10−5 in Hispanics). Overall, this study shows that the epigenetic age of the immune system is significantly increased in PD patients and that granulocytes play a significant role
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NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation

Hao Tang, Xiuqin Fan, Junyue Xing, Zhenyun Liu, Bin Jiang, Yali Dou, Myriam Gorospe, Wengong Wang,

https://doi.org/10.18632/aging.100860 pp 1143—1155

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Tang H, Fan X, Xing J, Liu Z, Jiang B, Dou Y, Gorospe M, Wang W, . NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation. Aging (Albany NY). 7:1143-1155. https://doi.org/10.18632/aging.100860

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                TY  - JOUR
                AU  - Tang, Hao 
                AU  - Fan, Xiuqin 
                AU  - Xing, Junyue 
                AU  - Liu, Zhenyun 
                AU  - Jiang, Bin 
                AU  - Dou, Yali 
                AU  - Gorospe, Myriam 
                AU  - Wang, Wengong 
                TI  - NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100860
                DO  - 10.18632/aging.100860
                SP  - 1143
                EP  - 1155
                PY  - 
                AB  - A rise in the levels of the cyclin-dependent kinase (CDK) inhibitor p27KIP1 is important for the growth arrest of senescent cells, but the mechanisms responsible for this increase are poorly understood. Here, we show that the tRNA methyltransferase NSun2 represses the expression of p27 in replicative senescence. NSun2 methylated the 5′-untranslated region (UTR) of p27 mRNA at cytosine C64 in vitro and in cells, thereby repressing the translation of p27. During replicative senescence, increased p27 protein levels were accompanied by decreased NSun2 protein levels. Knockdown of NSun2 in human diploid fibroblasts (HDFs) elevated p27 levels and reduced the expression of CDK1 (encoded by CDK1 mRNA, a previously reported target of NSun2), which in turn further repressed cell proliferation and accelerated replicative senescence, while overexpression of NSun2 exerted the opposite effect. Ectopic overexpression of the p27 5′UTR fragment rescued the effect of NSun2 overexpression in lowering p27, increasing CDK1, promoting cell proliferation, and delaying replicative senescence. Our findings indicate that NSun2-mediated mRNA methylation regulates p27 and CDK1 levels during replicative senescence.
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Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring

Steve Horvath, Chiara Pirazzini, Maria Giulia Bacalini, Davide Gentilini, Anna Maria Di Blasio, Massimo Delledonne, Daniela Mari, Beatrice Arosio, Daniela Monti, Giuseppe Passarino, Francesco De Rango, Patrizia D'Aquila, Cristina Giuliani, Elena Marasco, Sebastiano Collino, Patrick Descombes, Paolo Garagnani, Claudio Franceschi,

https://doi.org/10.18632/aging.100861 pp 1159—1170

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Horvath S, Pirazzini C, Bacalini MG, Gentilini D, Di Blasio AM, Delledonne M, Mari D, Arosio B, Monti D, Passarino G, De Rango F, D'Aquila P, Giuliani C, et al, . Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring. Aging (Albany NY). 7:1159-1170. https://doi.org/10.18632/aging.100861

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Provider: 
                TY  - JOUR
                AU  - Horvath, Steve 
                AU  - Pirazzini, Chiara 
                AU  - Bacalini, Maria Giulia 
                AU  - Gentilini, Davide 
                AU  - Di Blasio, Anna Maria 
                AU  - Delledonne, Massimo 
                AU  - Mari, Daniela 
                AU  - Arosio, Beatrice 
                AU  - Monti, Daniela 
                AU  - Passarino, Giuseppe 
                AU  - De Rango, Francesco 
                AU  - D'Aquila, Patrizia 
                AU  - Giuliani, Cristina 
                AU  - Marasco, Elena 
                AU  - Collino, Sebastiano 
                AU  - Descombes, Patrick 
                AU  - Garagnani, Paolo 
                AU  - Franceschi, Claudio 
                TI  - Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100861
                DO  - 10.18632/aging.100861
                SP  - 1159
                EP  - 1170
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Horvath, Steve 
                AU  - Pirazzini, Chiara 
                AU  - Bacalini, Maria Giulia 
                AU  - Gentilini, Davide 
                AU  - Di Blasio, Anna Maria 
                AU  - Delledonne, Massimo 
                AU  - Mari, Daniela 
                AU  - Arosio, Beatrice 
                AU  - Monti, Daniela 
                AU  - Passarino, Giuseppe 
                AU  - De Rango, Francesco 
                AU  - D'Aquila, Patrizia 
                AU  - Giuliani, Cristina 
                AU  - Marasco, Elena 
                AU  - Collino, Sebastiano 
                AU  - Descombes, Patrick 
                AU  - Garagnani, Paolo 
                AU  - Franceschi, Claudio 
                TI  - Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100861
                DO  - 10.18632/aging.100861
                SP  - 1159
                EP  - 1170
                PY  - 
                AB  - Given the dramatic increase in ageing populations, it is of great importance to understand the genetic and molecular determinants of healthy ageing and longevity. Semi-supercentenarians (subjects who reached an age of 105-109 years) arguably represent the gold standard of successful human ageing because they managed to avoid or postpone the onset of major age-related diseases. Relatively few studies have looked at epigenetic determinants of extreme longevity in humans. Here we test whether families with extreme longevity are epigenetically distinct from controls according to an epigenetic biomarker of ageing which is known as “epigenetic clock”. We analyze the DNA methylation levels of peripheral blood mononuclear cells (PBMCs) from Italian families constituted of 82 semi-supercentenarians (mean age: 105.6 ± 1.6 years), 63 semi-supercentenarians' offspring (mean age: 71.8 ± 7.8 years), and 47 age-matched controls (mean age: 69.8 ± 7.2 years). We demonstrate that the offspring of semi-supercentenarians have a lower epigenetic age than age-matched controls (age difference=5.1 years, p=0.00043) and that centenarians are younger (8.6 years) than expected based on their chronological age. By contrast, no significant difference could be observed for estimated blood cell counts (such as naïve or exhausted cytotoxic T cells or helper T cells). Future studies will be needed to replicate these findings in different populations and to extend them to other tissues. Overall, our results suggest that epigenetic processes might play a role in extreme longevity and healthy human ageing
                ER  -

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DNA repair in species with extreme lifespan differences

Sheila L MacRae, Matthew McKnight Croken, R.B Calder, Alexander Aliper, Brandon Milholland, Ryan R White, Alexander Zhavoronkov, Vadim N Gladyshev, Andrei Seluanov, Vera Gorbunova, Zhengdong D Zhang, Jan Vijg,

https://doi.org/10.18632/aging.100866 pp 1171—1182

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MacRae SL, Croken MM, Calder R, Aliper A, Milholland B, White RR, Zhavoronkov A, Gladyshev VN, Seluanov A, Gorbunova V, Zhang ZD, Vijg J, . DNA repair in species with extreme lifespan differences. Aging (Albany NY). 7:1171-1182. https://doi.org/10.18632/aging.100866

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Provider: 
                TY  - JOUR
                AU  - MacRae, Sheila L 
                AU  - Croken, Matthew McKnight 
                AU  - Calder, R.B 
                AU  - Aliper, Alexander 
                AU  - Milholland, Brandon 
                AU  - White, Ryan R 
                AU  - Zhavoronkov, Alexander 
                AU  - Gladyshev, Vadim N 
                AU  - Seluanov, Andrei 
                AU  - Gorbunova, Vera 
                AU  - Zhang, Zhengdong D 
                AU  - Vijg, Jan 
                TI  - DNA repair in species with extreme lifespan differences
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100866
                DO  - 10.18632/aging.100866
                SP  - 1171
                EP  - 1182
                PY  - 
                AB  - Differences in DNA repair capacity have been hypothesized to underlie the great range of maximum lifespans among mammals. However, measurements of individual DNA repair activities in cells and animals have not substantiated such a relationship because utilization of repair pathways among animals—depending on habitats, anatomical characteristics, and life styles—varies greatly between mammalian species. Recent advances in high-throughput genomics, in combination with increased knowledge of the genetic pathways involved in genome maintenance, now enable a comprehensive comparison of DNA repair transcriptomes in animal species with extreme lifespan differences. Here we compare transcriptomes of liver, an organ with high oxidative metabolism and abundant spontaneous DNA damage, from humans, naked mole rats, and mice, with maximum lifespans of ∼120, 30, and 3 years, respectively, with a focus on genes involved in DNA repair. The results show that the longer-lived species, human and naked mole rat, share higher expression of DNA repair genes, including core genes in several DNA repair pathways. A more systematic approach of signaling pathway analysis indicates statistically significant upregulation of several DNA repair signaling pathways in human and naked mole rat compared with mouse. The results of this present work indicate, for the first time, that DNA repair is upregulated in a major metabolic organ in long-lived humans and naked mole rats compared with short-lived mice. These results strongly suggest that DNA repair can be considered a genuine longevity assurance system
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Knockout of Angiotensin AT₂ receptors accelerates healing but impairs quality

Mahya Faghih, Sayed M Hosseini, Barbara Smith, Amir Mehdi Ansari, Frank Lay, Ali Karim Ahmed, Tedashi Inagami, Guy P Marti, John W Harmon, Jeremy D Walston, Peter M Abadir,

https://doi.org/10.18632/aging.100868 pp 1185—1197

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Faghih M, Hosseini SM, Smith B, Ansari AM, Lay F, Ahmed AK, Inagami T, Marti GP, Harmon JW, Walston JD, Abadir PM, . Knockout of Angiotensin AT₂ receptors accelerates healing but impairs quality. Aging (Albany NY). 7:1185-1197. https://doi.org/10.18632/aging.100868

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Provider: 
 TY - JOUR
 AU - Faghih, Mahya 
 AU - Hosseini, Sayed M 
 AU - Smith, Barbara 
 AU - Ansari, Amir Mehdi 
 AU - Lay, Frank 
 AU - Ahmed, Ali Karim 
 AU - Inagami, Tedashi 
 AU - Marti, Guy P 
 AU - Harmon, John W 
 AU - Walston, Jeremy D 
 AU - Abadir, Peter M 
 TI - Knockout of Angiotensin AT2 receptors accelerates healing but impairs quality
 JO - 
 JA - Aging (Albany NY)
 VL - 7
 IS - 12
 PB - 
 SN - 
 UR - https://doi.org/10.18632/aging.100868
 DO - 10.18632/aging.100868
 SP - 1185
 EP - 1197
 PY - 
 AB - Wounds are among the most common, painful, debilitating and costly conditions in older adults. Disruption of the angiotensin type 1 receptors (AT1R), has been associated with impaired wound healing, suggesting a critical role for AT1R in this repair process. Biological functions of angiotensin type 2 receptors (AT2R) are less studied. We investigated effects of genetically disrupting AT2R on rate and quality of wound healing. Our results suggest that AT2R effects on rate of wound closure depends on the phase of wound healing. We observed delayed healing during early phase of wound healing (inflammation). An accelerated healing rate was seen during later stages (proliferation and remodeling). By day 12, fifty percent of AT2R−/− mice had complete wound closure as compared to none in either C57/BL6 or AT1R−/− mice. There was a significant increase in AT1R, TGFβ1 and TGFβ2 expression during the proliferative and remodeling phases in AT2R−/− mice. Despite the accelerated closure rate, AT2R−/− mice had more fragile healed skin. Our results suggest that in the absence of AT2R, wound healing rate is accelerated, but yielded worse skin quality. Elucidating the contribution of both of the angiotensin receptors may help fine tune future intervention aimed at wound repair in older individuals
 ER -

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Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning

Morgan E Levine, Ake T Lu, David A Bennett, Steve Horvath,

https://doi.org/10.18632/aging.100864 pp 1198—1211

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Levine ME, Lu AT, Bennett DA, Horvath S, . Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning. Aging (Albany NY). 7:1198-1211. https://doi.org/10.18632/aging.100864

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Provider: 
                TY  - JOUR
                AU  - Levine, Morgan E 
                AU  - Lu, Ake T 
                AU  - Bennett, David A 
                AU  - Horvath, Steve 
                TI  - Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100864
                DO  - 10.18632/aging.100864
                SP  - 1198
                EP  - 1211
                PY  - 
                AB  - There is an urgent need to develop molecular biomarkers of brain age in order to advance our understanding of age related neurodegeneration. Recently, we developed a highly accurate epigenetic biomarker of tissue age (known as epigenetic clock) which is based on DNA methylation levels. Here we use n=700 dorsolateral prefrontal cortex (DLPFC) samples from Caucasian subjects of the Religious Order Study and the Rush Memory and Aging Project to examine the association between epigenetic age and Alzheimer’s disease (AD) related cognitive decline, and AD related neuropathological markers.        Epigenetic age acceleration of DLPFC is correlated with several neuropathological measurements including diffuse plaques (r=0.12, p=0.0015), neuritic plaques (r=0.11, p=0.0036), and amyloid load (r=0.091, p=0.016). Further, it is associated with a decline in global cognitive functioning (β=−0.500, p=0.009), episodic memory (β=−0.411, p=0.009) and working memory (β=−0.405, p=0.011) among individuals with AD. The neuropathological markers may mediate the association between epigenetic age and cognitive decline. Genetic complex trait analysis (GCTA) revealed that epigenetic age acceleration is heritable (h2=0.41) and has significant genetic correlations with diffuse plaques (r=0.24, p=0.010) and possibly working memory (r=−0.35, p=0.065). Overall, these results suggest that the epigenetic clock may lend itself as a molecular biomarker of brain age
                ER  -

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Survival of irradiated recipient mice after transplantation of bone marrow from young, old and “early aging” mice

Ian Guest, Zoran Ilic, Heidi Scrable, Stewart Sell,

https://doi.org/10.18632/aging.100867 pp 1212—1222

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Guest I, Ilic Z, Scrable H, Sell S, . Survival of irradiated recipient mice after transplantation of bone marrow from young, old and “early aging” mice. Aging (Albany NY). 7:1212-1222. https://doi.org/10.18632/aging.100867

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                TY  - JOUR
                AU  - Guest, Ian 
                AU  - Ilic, Zoran 
                AU  - Scrable, Heidi 
                AU  - Sell, Stewart 
                TI  - Survival of irradiated recipient mice after transplantation of bone marrow from young, old and “early aging” mice
                JO  - 
                JA  - Aging (Albany NY)
                VL  - 7
                IS  - 12
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100867
                DO  - 10.18632/aging.100867
                SP  - 1212
                EP  - 1222
                PY  - 
                AB  - Bone marrow transplantation is used to examine survival, hematopoietic stem cell function and pathology in recipients of young and old wild type bone marrow derived stem cells (BMDSCs) as well as cells from p53-based models of premature aging. There is no difference in the long term survival of recipients of 8 week-old p53+/m donor cells compared to recipients of 8 week-old wild-type (WT) donor cells (70 weeks) or of recipients of 16–18 weeks-old donor cells from either p53+/m or WT mice. There is shorter survival in recipients of older versus younger WT donor bone marrow, but the difference is only significant when comparing 8 and 18 week-old donors. In the p44-based model, short term survival/engraftment is significantly reduced in recipients of 11 month-old p44 donor cells compared to 4 week-old p44 or wild type donor cells of either age; mid-life survival at 40 weeks is also significantly less in recipients of p44 cells. BMDSCs are readily detectable within recipient bone marrow, lymph node, intestinal villi and liver sinusoids, but not in epithelial derived cells. These results indicate that recipients of young BMDSCs may survive longer than recipients of old bone marrow, but the difference is marginal at best.
                ER  -

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Volume 7, Issue 12

Editorials

Antidepressants synergize with chemotherapy against cancer stem cells

Gerry Melino,

Fasting plus tyrosine kinase inhibitors in cancer

Irene Caffa, Valter D. Longo, Alessio Nencioni,

c-Fos importance for brain development

Fabiola N. Velazquez, Beatriz L. Caputto, François D. Boussin,

TOR-inhibitors as gero-suppressors

Mikhail Nikiforov,

Reviews

The PTEN tumor suppressor gene and its role in lymphoma pathogenesis

Xiaoxiao Wang, Huiqiang Huang, Ken H. Young,

DNA repair and aging: the impact of the p53 family

Sara Nicolai, Antonello Rossi, Nicola Di Daniele, Gerry Melino, Margherita Annicchiarico-Petruzzelli, Giuseppe Raschellà,

Research Papers

Telomere length is a prognostic biomarker in elderly advanced ovarian cancer patients: a multicenter GINECO study

Claire Falandry, Béatrice Horard, Amandine Bruyas, Eric Legouffe, Jacques Cretin, Jérôme Meunier, Jérôme Alexandre, Valérie Delecroix, Michel Fabbro, Marie-Noëlle Certain, Raymonde Maraval-Gaget, Eric Pujade-Lauraine, Eric Gilson, Gilles Freyer,

A shortened interval between vaccinations with the trivalent inactivated influenza vaccine increases responsiveness in the aged

Senthil Kannan, Andrew Kossenkov, Raj K. Kurupati, Jason ZQ Xiang, Susan A. Doyle, Kenneth E. Schmader, Louise Schowe, Hildegund C. Ertl,

Prevention of diet-induced hepatic steatosis and hepatic insulin resistance by second generation antisense oligonucleotides targeted to the longevity gene mIndy (Slc13a5)

Dominik H. Pesta, Rachel J. Perry, Fitsum Guebre-Egziabher, Dongyan Zhang, Michael Jurczak, Antje Fischer-Rosinsky, Martin A. Daniels, Diana M. Willmes, Sanjay Bhanot, Stefan R. Bornstein, Felix Knauf, Varman T. Samuel, Gerald I. Shulman, Andreas L. Birkenfeld,

Age-related neuroinflammation and changes in AKT-GSK-3β and WNT/ β-CATENIN signaling in rat hippocampus

Ana Maria Marques Orellana, Andrea Rodrigues Vasconcelos, Jacqueline Alves Leite, Larissa de Sá Lima, Diana Zukas Andreotti, Carolina Demarchi Munhoz, Elisa Mitiko Kawamoto, Cristoforo Scavone,

RPD3 histone deacetylase and nutrition have distinct but interacting effects on Drosophila longevity

Stewart Frankel, Jared Woods, Tahereh Ziafazeli, Blanka Rogina,

Increased epigenetic age and granulocyte counts in the blood of Parkinson's disease patients

Steve Horvath, Beate R Ritz,

NSun2 delays replicative senescence by repressing p27 (KIP1) translation and elevating CDK1 translation

Hao Tang, Xiuqin Fan, Junyue Xing, Zhenyun Liu, Bin Jiang, Yali Dou, Myriam Gorospe, Wengong Wang,

Decreased epigenetic age of PBMCs from Italian semi-supercentenarians and their offspring

DNA repair in species with extreme lifespan differences

Sheila L MacRae, Matthew McKnight Croken, R.B Calder, Alexander Aliper, Brandon Milholland, Ryan R White, Alexander Zhavoronkov, Vadim N Gladyshev, Andrei Seluanov, Vera Gorbunova, Zhengdong D Zhang, Jan Vijg,

Knockout of Angiotensin AT₂ receptors accelerates healing but impairs quality

Mahya Faghih, Sayed M Hosseini, Barbara Smith, Amir Mehdi Ansari, Frank Lay, Ali Karim Ahmed, Tedashi Inagami, Guy P Marti, John W Harmon, Jeremy D Walston, Peter M Abadir,

Epigenetic age of the pre-frontal cortex is associated with neuritic plaques, amyloid load, and Alzheimer’s disease related cognitive functioning

Morgan E Levine, Ake T Lu, David A Bennett, Steve Horvath,

Survival of irradiated recipient mice after transplantation of bone marrow from young, old and “early aging” mice

Ian Guest, Zoran Ilic, Heidi Scrable, Stewart Sell,

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