Volume 6, Issue 1

Montoliu I, Scherer M, Beguelin F, DaSilva L, Mari D, Salvioli S, Martin FJ, Capri M, Bucci L, Ostan R, Garagnani P, Monti D, Biagi E, et al, . Serum profiling of healthy aging identifies phospho- and sphingolipid species as markers of human longevity. . 6:9-25. https://doi.org/10.18632/aging.100630

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                TY  - JOUR
                AU  - Montoliu, Ivan 
                AU  - Scherer, Max 
                AU  - Beguelin, Fiona 
                AU  - DaSilva, Laeticia 
                AU  - Mari, Daniela 
                AU  - Salvioli, Stefano 
                AU  - Martin, François-Pierre J. 
                AU  - Capri, Miriam 
                AU  - Bucci, Laura 
                AU  - Ostan, Rita 
                AU  - Garagnani, Paolo 
                AU  - Monti, Daniela 
                AU  - Biagi, Elena 
                AU  - Brigidi, Patrizia 
                AU  - Kussmann, Martin 
                AU  - Rezzi, Serge 
                AU  - Franceschi, Claudio 
                AU  - Collino, Sebastiano 
                TI  - Serum profiling of healthy aging identifies phospho- and sphingolipid species as markers of human longevity
                JO  - 
                JA  - 
                VL  - 6
                IS  - 1
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100630
                DO  - 10.18632/aging.100630
                SP  - 9
                EP  - 25
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Montoliu, Ivan 
                AU  - Scherer, Max 
                AU  - Beguelin, Fiona 
                AU  - DaSilva, Laeticia 
                AU  - Mari, Daniela 
                AU  - Salvioli, Stefano 
                AU  - Martin, François-Pierre J. 
                AU  - Capri, Miriam 
                AU  - Bucci, Laura 
                AU  - Ostan, Rita 
                AU  - Garagnani, Paolo 
                AU  - Monti, Daniela 
                AU  - Biagi, Elena 
                AU  - Brigidi, Patrizia 
                AU  - Kussmann, Martin 
                AU  - Rezzi, Serge 
                AU  - Franceschi, Claudio 
                AU  - Collino, Sebastiano 
                TI  - Serum profiling of healthy aging identifies phospho- and sphingolipid species as markers of human longevity
                JO  - 
                JA  - 
                VL  - 6
                IS  - 1
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100630
                DO  - 10.18632/aging.100630
                SP  - 9
                EP  - 25
                PY  - 
                AB  - As centenarians well represent the model of healthy aging, there are many important implications in revealing the underlying molecular mechanisms behind such successful aging. By combining NMR metabonomics and shot-gun lipidomics in serum we analyzed metabolome and lipidome composition of a group of centenarians with respect to elderly individuals. Specifically, NMR metabonomics profiling of serum revealed that centenarians are characterized by a metabolic phenotype distinct from that of elderly subjects, in particular regarding amino acids and lipid species. Shot- gun lipidomics approach displays unique changes in lipids biosynthesis in centenarians, with 41 differently abundant lipid species with respect to elderly subjects. These findings reveal phospho/sphingolipids as putative markers and biological modulators of healthy aging, in humans. Considering the particular actions of these metabolites, these data are suggestive of a better counteractive antioxidant capacity and a well-developed membrane lipid remodelling process in the healthy aging phenotype.
                ER  -

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Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma

Fabio Marongiu, Maria Paola Serra, Marcella Sini, Fabrizio Angius, Ezio Laconi,

https://doi.org/10.18632/aging.100631 pp 26—34

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Marongiu F, Serra MP, Sini M, Angius F, Laconi E, . Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma. . 6:26-34. https://doi.org/10.18632/aging.100631

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                TY  - JOUR
                AU  - Marongiu, Fabio 
                AU  - Serra, Maria Paola 
                AU  - Sini, Marcella 
                AU  - Angius, Fabrizio 
                AU  - Laconi, Ezio 
                TI  - Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma
                JO  - 
                JA  - 
                VL  - 6
                IS  - 1
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100631
                DO  - 10.18632/aging.100631
                SP  - 26
                EP  - 34
                PY  - 
                AB  - Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re-normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease. Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre-neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease.
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SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation

Valerio Pazienza, Michela Borghesan, Tommaso Mazza, Fareeba Sheedfar, Concetta Panebianco, Roger Williams, Gianluigi Mazzoccoli, Angelo Andriulli, Tomoko Nakanishi, Manlio Vinciguerra,

https://doi.org/10.18632/aging.100632 pp 35—47

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Pazienza V, Borghesan M, Mazza T, Sheedfar F, Panebianco C, Williams R, Mazzoccoli G, Andriulli A, Nakanishi T, Vinciguerra M, . SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation. . 6:35-47. https://doi.org/10.18632/aging.100632

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                TY  - JOUR
                AU  - Pazienza, Valerio 
                AU  - Borghesan, Michela 
                AU  - Mazza, Tommaso 
                AU  - Sheedfar, Fareeba 
                AU  - Panebianco, Concetta 
                AU  - Williams, Roger 
                AU  - Mazzoccoli, Gianluigi 
                AU  - Andriulli, Angelo 
                AU  - Nakanishi, Tomoko 
                AU  - Vinciguerra, Manlio 
                TI  - SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation
                JO  - 
                JA  - 
                VL  - 6
                IS  - 1
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100632
                DO  - 10.18632/aging.100632
                SP  - 35
                EP  - 47
                PY  - 
                AB  - Non-alcoholic-fatty-liver-disease (NAFLD) encompasses conditions associated to fat deposition in the liver, which are generally deteriorated during the aging process. MacroH2A1, a variant of histone H2A, is a key transcriptional regulator involved in tumorigenic processes and cell senescence, and featuring two alternatively splicing isoforms, macroH2A1.1 and macroH2A1.2. MacroH2A1.1 binds with high affinity O-acetyl ADP ribose, a small metabolite produced by the reaction catalysed by NAD+-dependent deacetylase SIRT1, whereas macroH2A1.2 is unable to do so. The functional significance of this binding is unknown. We previously reported that the hepatic levels of macroH2A1.1 and macroH2A1.2 are differentially expressed in mice models of NAFLD. Here we show that over-expression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatocytes against lipid accumulation. MacroH2A1.1 over-expressing cells display ameliorated glucose metabolism, reduced expression of lipidogenic genes and fatty acids content. SIRT1/macroH2A1.1-dependent epigenetic regulation of lipid metabolism may be relevant to NAFLD development.
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BMAL1-dependent regulation of the mTOR signaling pathway delays aging

Rohini V. Khapre, Anna A. Kondratova, Sonal Patel, Yuliya Dubrovsky, Michelle Wrobel, Marina P. Antoch, Roman V. Kondratov,

https://doi.org/10.18632/aging.100633 pp 48—57

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Khapre RV, Kondratova AA, Patel S, Dubrovsky Y, Wrobel M, Antoch MP, Kondratov RV, . BMAL1-dependent regulation of the mTOR signaling pathway delays aging. . 6:48-57. https://doi.org/10.18632/aging.100633

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                TY  - JOUR
                AU  - Khapre, Rohini V. 
                AU  - Kondratova, Anna A. 
                AU  - Patel, Sonal 
                AU  - Dubrovsky, Yuliya 
                AU  - Wrobel, Michelle 
                AU  - Antoch, Marina P. 
                AU  - Kondratov, Roman V. 
                TI  - BMAL1-dependent regulation of the mTOR signaling pathway delays aging
                JO  - 
                JA  - 
                VL  - 6
                IS  - 1
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100633
                DO  - 10.18632/aging.100633
                SP  - 48
                EP  - 57
                PY  - 
                AB  - The circadian clock, an internal time-keeping system, has been linked with control of aging, but molecular mechanisms of regulation are not known. BMAL1 is a transcriptional factor and core component of the circadian clock; BMAL1 deficiency is associated with premature aging and reduced lifespan. Here we report that activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is increased upon BMAL1 deficiency both in vivo and in cell culture. Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1−/− mice by 50%. Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling. We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism.
                ER  -

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Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion

Chen-Tseh Zhu, Chengyi Chang, Robert A. Reenan, Stephen L. Helfand,

https://doi.org/10.18632/aging.100634 pp 58—69

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Zhu C, Chang C, Reenan RA, Helfand SL, . Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion. . 6:58-69. https://doi.org/10.18632/aging.100634

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                TY  - JOUR
                AU  - Zhu, Chen-Tseh 
                AU  - Chang, Chengyi 
                AU  - Reenan, Robert A. 
                AU  - Helfand, Stephen L. 
                TI  - <i>Indy</i> gene variation in natural populations confers fitness advantage and life span extension through transposon insertion
                JO  - 
                JA  - 
                VL  - 6
                IS  - 1
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100634
                DO  - 10.18632/aging.100634
                SP  - 58
                EP  - 69
                PY  - 
                AB  - Natural selection acts to maximize reproductive fitness. However, antagonism between life span and reproductive success frequently poses a dilemma pitting the cost of fecundity against longevity. Here, we show that natural populations of Drosophila melanogaster harbor a Hoppel transposon insertion variant in the longevity gene Indy (I'm not dead yet), which confers both increased reproduction and longevity through metabolic changes. Heterozygosity for this natural long-lived variant has been maintained in isolates despite long-term inbreeding under laboratory conditions and advantageously confers increased fecundity. DNA sequences of variant chromosome isolates show evidence of selective sweep acting on the advantageous allele, suggesting that natural selection acts to maintain this variant. The transposon insertion also regulates Indy expression level, which has experimentally been shown to affect life span and fecundity. Thus, in the wild, evolution reaffirms that the mechanism of heterozygote advantage has acted upon the Indy gene to assure increased reproductive fitness and, coincidentally, longer life span through regulatory transposon mutagenesis.
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Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks

Rika Kusumoto-Matsuo, Deblina Ghosh, Parimal Karmakar, Alfred May, Dale Ramsden, Vilhelm A. Bohr,

https://doi.org/10.18632/aging.100629 pp 70—81

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Kusumoto-Matsuo R, Ghosh D, Karmakar P, May A, Ramsden D, Bohr VA, . Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks. . 6:70-81. https://doi.org/10.18632/aging.100629

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                TY  - JOUR
                AU  - Kusumoto-Matsuo, Rika 
                AU  - Ghosh, Deblina 
                AU  - Karmakar, Parimal 
                AU  - May, Alfred 
                AU  - Ramsden, Dale 
                AU  - Bohr, Vilhelm A. 
                TI  - Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks
                JO  - 
                JA  - 
                VL  - 6
                IS  - 1
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100629
                DO  - 10.18632/aging.100629
                SP  - 70
                EP  - 81
                PY  - 
                AB  - WRN protein, defective in Werner syndrome (WS), a human segmental progeria, is a target of serine/threonine kinases involved in sensing DNA damage. DNA-PK phosphorylates WRN in response to DNA double strand breaks (DSBs). However, the main phosphorylation sites and functional importance of the phosphorylation of WRN has remained unclear. Here, we identify Ser-440 and −467 in WRN as major phosphorylation sites mediated by DNA-PK. In vitro, DNA-PK fails to phosphorylate a GST-WRN fragment with S440A and/or S467A substitution. In addition, full length WRN with the mutation expressed in 293T cells was not phosphorylated in response to DSBs produced by bleomycin. Accumulation of the mutant WRN at the site of laser-induced DSBs occurred with the same kinetics as wild type WRN in live HeLa cells. While the wild type WRN relocalized to the nucleoli after 24 hours recovery from etoposide-induced DSBs, the mutant WRN remained mostly in the nucleoplasm. Consistent with this, WS cells expressing the mutants exhibited less DNA repair efficiency and more sensitivity to etoposide, compared to those expressing wild type. Our findings indicate that phosphorylation of Ser-440 and −467 in WRN are important for relocalization of WRN to nucleoli, and that it is required for efficient DSB repair.
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Volume 6, Issue 1

Editorials

Hypothalamic Sirt1 in aging

Akiko Satoh, Shin-ichiro Imai,

Metabolic and immune integration in aging and age-related disease

Rebecca I. Clark, David W. Walker, Marc S. Dionne,

DAF-16 and PQM-1: Partners in longevity

Ronald G. Tepper, Coleen T. Murphy, Harmen J. Bussemaker,

Tissue-specific aging: a tale of functional asymmetry

Ismene Karakasilioti, George A. Garinis,

Research Papers

Serum profiling of healthy aging identifies phospho- and sphingolipid species as markers of human longevity

Ivan Montoliu, Max Scherer, Fiona Beguelin, Laeticia DaSilva, Daniela Mari, Stefano Salvioli, François-Pierre J. Martin, Miriam Capri, Laura Bucci, Rita Ostan, Paolo Garagnani, Daniela Monti, Elena Biagi, Patrizia Brigidi, Martin Kussmann, Serge Rezzi, Claudio Franceschi, Sebastiano Collino,

Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma

Fabio Marongiu, Maria Paola Serra, Marcella Sini, Fabrizio Angius, Ezio Laconi,

SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation

Valerio Pazienza, Michela Borghesan, Tommaso Mazza, Fareeba Sheedfar, Concetta Panebianco, Roger Williams, Gianluigi Mazzoccoli, Angelo Andriulli, Tomoko Nakanishi, Manlio Vinciguerra,

BMAL1-dependent regulation of the mTOR signaling pathway delays aging

Rohini V. Khapre, Anna A. Kondratova, Sonal Patel, Yuliya Dubrovsky, Michelle Wrobel, Marina P. Antoch, Roman V. Kondratov,

Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion

Chen-Tseh Zhu, Chengyi Chang, Robert A. Reenan, Stephen L. Helfand,

Serines 440 and 467 in the Werner syndrome protein are phosphorylated by DNA-PK and affects its dynamics in response to DNA double strand breaks

Rika Kusumoto-Matsuo, Deblina Ghosh, Parimal Karmakar, Alfred May, Dale Ramsden, Vilhelm A. Bohr,

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