Volume 3, Issue 2

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                TY  - JOUR
                AU  - Blagosklonny, Mikhail V. 
                TI  - Cell cycle arrest is not senescence
                JO  - 
                JA  - 
                VL  - 3
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100281
                DO  - 10.18632/aging.100281
                SP  - 94
                EP  - 101
                PY  - 
                AB  - DNA damaging agents and radiation, cytotoxins and anti-cancer drugs, telomere erosion and cytokines, culture shock and mitogenic stimuli, oncogenes and tumor suppressors can induce both cell cycle arrest and cellular senescence. Due to this semi-coincidence, senescence is confused with cell cycle arrest, or even more misleadingly, with growth inhibition. With such misconceptions, cellular senescence cannot be linked to organismal aging. Also, the relation between cancer and senescence is distorted. Here I discuss why the link between arrest and senescence is semi-coincidental and how senescence is related to aging and cancer.
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Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress

Ozkan Ozden, Seong-Hoon Park, Hyun-Seok Kim, Haiyan Jiang, Mitchell C. Coleman, Douglas R. Spitz, David Gius,

https://doi.org/10.18632/aging.100291 pp 102—107

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Ozden O, Park S, Kim H, Jiang H, Coleman MC, Spitz DR, Gius D, . Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress. . 3:102-107. https://doi.org/10.18632/aging.100291

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                TY  - JOUR
                AU  - Ozden, Ozkan 
                AU  - Park, Seong-Hoon 
                AU  - Kim, Hyun-Seok 
                AU  - Jiang, Haiyan 
                AU  - Coleman, Mitchell C. 
                AU  - Spitz, Douglas R. 
                AU  - Gius, David 
                TI  - Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress
                JO  - 
                JA  - 
                VL  - 3
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100291
                DO  - 10.18632/aging.100291
                SP  - 102
                EP  - 107
                PY  - 
                AB  - A fundamental observation in biology is that mitochondrial function, as measured by increased reactive oxygen species (ROS), changes significantly with age, suggesting a potential mechanistic link between the cellular processes governing longevity and mitochondrial metabolism homeostasis. In addition, it is well established that altered ROS levels are observed in multiple age-related illnesses including carcinogenesis, neurodegenerative, fatty liver, insulin resistance, and cardiac disease, to name just a few. Manganese superoxide dismutase (MnSOD) is the primary mitochondrial ROS scavenging enzyme that converts superoxide to hydrogen peroxide, which is subsequently converted to water by catalase and other peroxidases. It has recently been shown that MnSOD enzymatic activity is regulated by the reversible acetylation of specific, evolutionarily conserved lysine(s) in the protein. These results, suggest for the first time, that the mitochondria contain bidirectional post-translational signaling networks, similar to that observed in the cytoplasm and nucleus, and that changes in lysine acetylation alter MnSOD enzymatic activity. In addition, these new results demonstrate that the mitochondrial anti-aging or fidelity / sensing protein, SIRT3, responds to changes in mitochondrial nutrient and/or redox status to alter the enzymatic activity of specific downstream targets, including MnSOD that adjusts and/or maintains ROS levels as well as metabolic homeostatic poise.
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The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation

Jamie O. Brett, Valérie M. Renault, Victoria A. Rafalski, Ashley E. Webb, Anne Brunet,

https://doi.org/10.18632/aging.100285 pp 108—124

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Brett JO, Renault VM, Rafalski VA, Webb AE, Brunet A, . The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation. . 3:108-124. https://doi.org/10.18632/aging.100285

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                TY  - JOUR
                AU  - Brett, Jamie O. 
                AU  - Renault, Valérie M. 
                AU  - Rafalski, Victoria A. 
                AU  - Webb, Ashley E. 
                AU  - Brunet, Anne 
                TI  - The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation
                JO  - 
                JA  - 
                VL  - 3
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100285
                DO  - 10.18632/aging.100285
                SP  - 108
                EP  - 124
                PY  - 
                AB  - In adult mammals, neural stem cells (NSCs) generate new neurons that are important for specific types of learning and memory. Controlling adult NSC number and function is fundamental for preserving the stem cell pool and ensuring proper levels of neurogenesis throughout life. Here we study the importance of the microRNA gene cluster miR-106b~25 (miR-106b, miR-93, and miR-25) in primary cultures of neural stem/progenitor cells (NSPCs) isolated from adult mice. We find that knocking down miR-25 decreases NSPC proliferation, whereas ectopically expressing miR-25 promotes NSPC proliferation. Expressing the entire miR-106b~25 cluster in NSPCs also increases their ability to generate new neurons. Interestingly, miR-25 has a number of potential target mRNAs involved in insulin/insulin-like growth factor-1 (IGF) signaling, a pathway implicated in aging. Furthermore, the regulatory region of miR-106b~25 is bound by FoxO3, a member of the FoxO family of transcription factors that maintains adult stem cells and extends lifespan downstream of insulin/IGF signaling. These results suggest that miR-106b~25 regulates NSPC function and is part of a network involving the insulin/IGF-FoxO pathway, which may have important implications for the homeostasis of the NSC pool during aging.
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Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants

Robert J. Shmookler Reis, Lulu Xu, Hoonyong Lee, Minho Chae, John J. Thaden, Puneet Bharill, Cagdas Tazearslan, Eric Siegel, Ramani Alla, Piotr Zimniak, Srinivas Ayyadevara,

https://doi.org/10.18632/aging.100275 pp 125—147

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Shmookler Reis RJ, Xu L, Lee H, Chae M, Thaden JJ, Bharill P, Tazearslan C, Siegel E, Alla R, Zimniak P, Ayyadevara S, . Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants. . 3:125-147. https://doi.org/10.18632/aging.100275

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                TY  - JOUR
                AU  - Shmookler Reis, Robert J. 
                AU  - Xu, Lulu 
                AU  - Lee, Hoonyong 
                AU  - Chae, Minho 
                AU  - Thaden, John J. 
                AU  - Bharill, Puneet 
                AU  - Tazearslan, Cagdas 
                AU  - Siegel, Eric 
                AU  - Alla, Ramani 
                AU  - Zimniak, Piotr 
                AU  - Ayyadevara, Srinivas 
                TI  - Modulation of lipid biosynthesis contributes to stress resistance and longevity of <i>C. elegans</i> mutants
                JO  - 
                JA  - 
                VL  - 3
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100275
                DO  - 10.18632/aging.100275
                SP  - 125
                EP  - 147
                PY  - 
                AB  - Many lifespan-modulating genes are involved in either generation of oxidative substrates and end-products, or their detoxification and removal. Among such metabolites, only lipoperoxides have the ability to produce free-radical chain reactions. For this study, fatty-acid profiles were compared across a panel of C. elegans mutants that span a tenfold range of longevities in a uniform genetic background. Two lipid structural properties correlated extremely well with lifespan in these worms: fatty-acid chain length and susceptibility to oxidation both decreased sharply in the longest-lived mutants (affecting the insulinlike-signaling pathway). This suggested a functional model in which longevity benefits from a reduction in lipid peroxidation substrates, offset by a coordinate decline in fatty-acid chain length to maintain membrane fluidity. This model was tested by disrupting the underlying steps in lipid biosynthesis, using RNAi knockdown to deplete transcripts of genes involved in fatty-acid metabolism. These interventions produced effects on longevity that were fully consistent with the functions and abundances of their products. Most knockdowns also produced concordant effects on survival of hydrogen peroxide stress, which can trigger lipoperoxide chain reactions.
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If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice

Vladimir N. Anisimov, Lev M. Berstein, Irina G. Popovich, Mark A. Zabezhinski, Peter A. Egormin, Tatiana S. Piskunova, Anna V. Semenchenko, Margarita L. Tyndyk, Maria N. Yurova, Irina G. Kovalenko, Tatiana E. Poroshina,

https://doi.org/10.18632/aging.100273 pp 148—157

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Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Kovalenko IG, Poroshina TE, . If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. . 3:148-157. https://doi.org/10.18632/aging.100273

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                TY  - JOUR
                AU  - Anisimov, Vladimir N. 
                AU  - Berstein, Lev M. 
                AU  - Popovich, Irina G. 
                AU  - Zabezhinski, Mark A. 
                AU  - Egormin, Peter A. 
                AU  - Piskunova, Tatiana S. 
                AU  - Semenchenko, Anna V. 
                AU  - Tyndyk, Margarita L. 
                AU  - Yurova, Maria N. 
                AU  - Kovalenko, Irina G. 
                AU  - Poroshina, Tatiana E. 
                TI  - If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice
                JO  - 
                JA  - 
                VL  - 3
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100273
                DO  - 10.18632/aging.100273
                SP  - 148
                EP  - 157
                PY  - 
                AB  - Hyperglycemia and hyperinsulinemia accelerate both aging and cancer. Antidiabetic biguanides such as metformin decrease glucose, insulin and IGF-1 level. Metformin increases lifespan and prevents cancer in mice, although its effects vary, depending on mice strain and gender. Here we showed that chronic treatment of female outbred SHR mice with metformin started at the age of 3, 9 or 15 months decreased body temperature and postponed age-related switch-off of estrous function. Surprisingly, metformin did not affect levels of serum cholesterol, triglycerides, glucose and insulin. Treatment with metformin started at the age of 3 months increased mean life span by 14% and maximum life span by 1 month. The treatment started at the age of 9 months insignificantly increased mean life span by only 6%, whereas the treatment started at the age of 15 months failed to increase life span. The mean life span of tumor-free mice was increased by 21% in ‘the youngest group’, by 7% in ‘middle-aged group’ and in contrast was reduced by 13% in ‘the oldest group’. When started at the age of 3 and 9 months, metformin delayed the first tumor detection by 22% and 25%, correspondingly. Thus, in female SHR mice, metformin increased life span and postponed tumors when started at the young and middle but not at the old age. In contrast, metformin improves reproductive function when started at any age.
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SIRT-ain relief from age-inducing stress

Dan Zhang, Yufei Liu, Danica Chen,

https://doi.org/10.18632/aging.100283 pp 158—161

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Zhang D, Liu Y, Chen D, . SIRT-ain relief from age-inducing stress. . 3:158-161. https://doi.org/10.18632/aging.100283

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                TY  - JOUR
                AU  - Zhang, Dan 
                AU  - Liu, Yufei 
                AU  - Chen, Danica 
                TI  - SIRT-ain relief from age-inducing stress
                JO  - 
                JA  - 
                VL  - 3
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100283
                DO  - 10.18632/aging.100283
                SP  - 158
                EP  - 161
                PY  - 
                AB  - Aging is one of the most fundamental biological processes. It results in a decline in physiological function and an increased risk for pernicious diseases such as cancer. Oxidative stress has been proposed as a major cause of aging, but experimental tests of this hypothesis have been discouraging. Calorie restriction (CR) prevents age-related decline, but there are still gaps in our knowledge of the exact mechanisms underlying this feat. Finally, a tenuous balance exists between aging and cancer, calling for a search for interventions that prevent both aging and cancer. Recent work on the mammalian sirtuin SIRT3 has shed light on these long-standing issues and suggested new approaches to ameliorate the ravages of aging.
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SirT1 brings stemness closer to cancer and aging

Vincenzo Calvanese, Mario F. Fraga,

https://doi.org/10.18632/aging.100272 pp 162—167

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Calvanese V, Fraga MF, . SirT1 brings stemness closer to cancer and aging. . 3:162-167. https://doi.org/10.18632/aging.100272

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Recent developments in the use of γ -H2AX as a quantitative DNA double-strand break biomarker

Christophe E. Redon, Asako J. Nakamura, Olga A. Martin, Palak R. Parekh, Urbain S. Weyemi, William M. Bonner,

https://doi.org/10.18632/aging.100284 pp 168—174

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Redon CE, Nakamura AJ, Martin OA, Parekh PR, Weyemi US, Bonner WM, . Recent developments in the use of γ -H2AX as a quantitative DNA double-strand break biomarker. . 3:168-174. https://doi.org/10.18632/aging.100284

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                TY  - JOUR
                AU  - Redon, Christophe E. 
                AU  - Nakamura, Asako J. 
                AU  - Martin, Olga A. 
                AU  - Parekh, Palak R. 
                AU  - Weyemi, Urbain S. 
                AU  - Bonner, William M. 
                TI  - Recent developments in the use of γ -H2AX as a quantitative DNA double-strand break biomarker
                JO  - 
                JA  - 
                VL  - 3
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100284
                DO  - 10.18632/aging.100284
                SP  - 168
                EP  - 174
                PY  - 
                AB  - The past year has seen considerable developments in the use of the DNA double-strand breaks (DSBs) to evaluate genome alterations in cells undergoing a variety of genotoxic stresses in vitro and in vivo. When the γ -H2AX foci which mark the DSBs are stained, individual breaks are detectible, making the assay suitable for situations requiring great sensitivity. While the methods for the detection of γ -H2AX foci are still evolving, particularly for in vivo detection, the basic assay has proven to be useful in several diverse areas of research. We will highlight recent developments of the assay in four areas: radiation biodosimetry, the evaluation or validation of new cancer drugs in clinical studies, chronic inflammation, and environmental genotoxicity.
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Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat

Mahua Choudhury, Karen R. Jonscher, Jacob E. Friedman,

https://doi.org/10.18632/aging.100289 pp 175—178

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Choudhury M, Jonscher KR, Friedman JE, . Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat. . 3:175-178. https://doi.org/10.18632/aging.100289

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                TY  - JOUR
                AU  - Choudhury, Mahua 
                AU  - Jonscher, Karen R. 
                AU  - Friedman, Jacob E. 
                TI  - Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat
                JO  - 
                JA  - 
                VL  - 3
                IS  - 2
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100289
                DO  - 10.18632/aging.100289
                SP  - 175
                EP  - 178
                PY  - 
                AB  - Aging is associated with various metabolic disorders that may have their origin in the liver, including non-alcoholic fatty liver disease, obesity, type 2 diabetes mellitus, and atherosclerosis. Although well-characterized in models of caloric restriction, relatively little is known about the role of sirtuins and acetylation under conditions of caloric excess. Sirtuins are NAD (+)-dependent protein deacetylases that mediate adaptive responses to a variety of stresses, including calorie restriction and metabolic stress. Sirtuin 3 (SIRT3) is localized within the mitochondrial matrix, where it regulates acetylation levels of a diverse set of metabolic enzymes. When normal mice are fed a high fat diet they demonstrate reduced SIRT3 activity, impaired mitochondrial function, and hyperacetylation of a diverse set of proteins in their livers. Furthermore, SIRT3 knockout mice have signs of accelerated aging and cancer. Understanding SIRT3's biochemical function and regulation in the liver under conditions of caloric excess may potentially increase our understanding of the normal aging process and diseases associated with aging, such as diabetes, fatty liver disease, or cancer.
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Volume 3, Issue 2

Commentaries

MicroRNAs and senescence

Ivan Martinez, Laura L. Almstead, Daniel DiMaio,

Leukemogenesis and ageing: ‘fit for transformation’ ?

Mel Greaves,

Longevity, lipids and C. elegans

A.J. Hulbert,

Normalizing a hyperactive mTOR initiates muscle growth during obesity

David L. Williamson, Joshua C. Drake,

Essays and Commentaries

Linking Nutrition, Maturation and Aging: From Thrifty Genes to the Spendthrift Phenotype

David Stipp,

Reviews

Cell cycle arrest is not senescence

Mikhail V. Blagosklonny,

Acetylation of MnSOD directs enzymatic activity responding to cellular nutrient status or oxidative stress

Ozkan Ozden, Seong-Hoon Park, Hyun-Seok Kim, Haiyan Jiang, Mitchell C. Coleman, Douglas R. Spitz, David Gius,

Research Papers

The microRNA cluster miR-106b~25 regulates adult neural stem/progenitor cell proliferation and neuronal differentiation

Jamie O. Brett, Valérie M. Renault, Victoria A. Rafalski, Ashley E. Webb, Anne Brunet,

Modulation of lipid biosynthesis contributes to stress resistance and longevity of C. elegans mutants

Robert J. Shmookler Reis, Lulu Xu, Hoonyong Lee, Minho Chae, John J. Thaden, Puneet Bharill, Cagdas Tazearslan, Eric Siegel, Ramani Alla, Piotr Zimniak, Srinivas Ayyadevara,

If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice

Vladimir N. Anisimov, Lev M. Berstein, Irina G. Popovich, Mark A. Zabezhinski, Peter A. Egormin, Tatiana S. Piskunova, Anna V. Semenchenko, Margarita L. Tyndyk, Maria N. Yurova, Irina G. Kovalenko, Tatiana E. Poroshina,

Research Perspectives

SIRT-ain relief from age-inducing stress

Dan Zhang, Yufei Liu, Danica Chen,

SirT1 brings stemness closer to cancer and aging

Vincenzo Calvanese, Mario F. Fraga,

Recent developments in the use of γ -H2AX as a quantitative DNA double-strand break biomarker

Christophe E. Redon, Asako J. Nakamura, Olga A. Martin, Palak R. Parekh, Urbain S. Weyemi, William M. Bonner,

Reduced mitochondrial function in obesity-associated fatty liver: SIRT3 takes on the fat

Mahua Choudhury, Karen R. Jonscher, Jacob E. Friedman,

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