Volume 3, Issue 5

RasGrf1 and Aging

Kelvin J. A. Davies, Henry Jay Forman,

https://doi.org/10.18632/aging.100331 pp 455

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Davies KJA, Forman HJ, . RasGrf1 and Aging. . 3:455-455. https://doi.org/10.18632/aging.100331

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Cdc14b: A New Player in Aging

Zhubo Wei, Pumin Zhang,

https://doi.org/10.18632/aging.100332 pp 456

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The isoenzyme pattern of LDH does not play a physiological role; except perhaps during fast transitions in energy metabolism

Bjørn Quistorff, Niels Grunnet,

https://doi.org/10.18632/aging.100329 pp 457—460

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Quistorff B, Grunnet N, . The isoenzyme pattern of LDH does not play a physiological role; except perhaps during fast transitions in energy metabolism. . 3:457-460. https://doi.org/10.18632/aging.100329

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BRCA1 A-Complex fine tunes repair functions of BRCA1

Janelle L Harris, Kum Kum Khanna,

https://doi.org/10.18632/aging.100334 pp 461—463

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Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective

Alessandra Valerio, Giuseppe D'Antona, Enzo Nisoli,

https://doi.org/10.18632/aging.100322 pp 464—478

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Valerio A, D'Antona G, Nisoli E, . Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective. . 3:464-478. https://doi.org/10.18632/aging.100322

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                TY  - JOUR
                AU  - Valerio, Alessandra 
                AU  - D'Antona, Giuseppe 
                AU  - Nisoli, Enzo 
                TI  - Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective
                JO  - 
                JA  - 
                VL  - 3
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100322
                DO  - 10.18632/aging.100322
                SP  - 464
                EP  - 478
                PY  - 
                AB  - Malnutrition is common among older persons, with important consequences increasing frailty and morbidity and reducing health expectancy. On the contrary, calorie restriction (CR, a low-calorie dietary regimen with adequate nutrition) slows the progression of age-related diseases and extends the lifespan of many species. Identification of strategies mimicking key CR mechanisms – increased mitochondrial respiration and reduced production of oxygen radicals – is a hot topic in gerontology. Dietary supplementation with essential and/or branched chain amino acids (BCAAs) exerts a variety of beneficial effects in experimental animals and humans and has been recently demonstrated to support cardiac and skeletal muscle mitochondrial biogenesis, prevent oxidative damage, and enhance physical endurance in middle-aged mice, resulting in prolonged survival. Here we review recent studies addressing the possible role of BCAAs in energy metabolism and in the longevity of species ranging from unicellular organisms to mammals. We also summarize observations from human studies supporting the exciting hypothesis that dietary BCAA enriched mixture supplementation might be a health-promoting strategy in aged patients at risk.
                ER  -

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Disrupting the circadian clock: Gene-specific effects on aging, cancer, and other phenotypes

Elizabeth A. Yu, David R. Weaver,

https://doi.org/10.18632/aging.100323 pp 479—493

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Yu EA, Weaver DR, . Disrupting the circadian clock: Gene-specific effects on aging, cancer, and other phenotypes. . 3:479-493. https://doi.org/10.18632/aging.100323

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                TY  - JOUR
                AU  - Yu, Elizabeth A. 
                AU  - Weaver, David R. 
                TI  - Disrupting the circadian clock: Gene-specific effects on aging, cancer, and other phenotypes
                JO  - 
                JA  - 
                VL  - 3
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100323
                DO  - 10.18632/aging.100323
                SP  - 479
                EP  - 493
                PY  - 
                AB  - The circadian clock imparts 24-hour rhythmicity on gene expression and cellular physiology in virtually all cells. Disruption of the genes necessary for the circadian clock to function has diverse effects, including aging-related phenotypes. Some circadian clock genes have been described as tumor suppressors, while other genes have less clear functions in aging and cancer. In this Review, we highlight a recent study [Dubrovsky et al., Aging 2: 936-944, 2010] and discuss the much larger field examining the relationship between circadian clock genes, circadian rhythmicity, aging-related phenotypes, and cancer.
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The promise of human embryonic stem cells in aging-associated diseases

Odessa Yabut, Harold S. Bernstein,

https://doi.org/10.18632/aging.100328 pp 494—508

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Yabut O, Bernstein HS, . The promise of human embryonic stem cells in aging-associated diseases. . 3:494-508. https://doi.org/10.18632/aging.100328

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                TY  - JOUR
                AU  - Yabut, Odessa 
                AU  - Bernstein, Harold S. 
                TI  - The promise of human embryonic stem cells in aging-associated diseases
                JO  - 
                JA  - 
                VL  - 3
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100328
                DO  - 10.18632/aging.100328
                SP  - 494
                EP  - 508
                PY  - 
                AB  - Aging-associated diseases are often caused by progressive loss or dysfunction of cells that ultimately affect the overall function of tissues and organs. Successful treatment of these diseases could benefit from cell-based therapy that would regenerate lost cells or otherwise restore tissue function. Human embryonic stem cells (hESCs) promise to be an important therapeutic candidate in treating aging-associated diseases due to their unique capacity for self-renewal and pluripotency. To date, there are numerous hESC lines that have been developed and characterized. We will discuss how hESC lines are derived, their molecular and cellular properties, and how their ability to differentiate into all three embryonic germ layers is determined. We will also outline the methods currently employed to direct their differentiation into populations of tissue-specific, functional cells. Finally, we will highlight the general challenges that must be overcome and the strategies being developed to generate highly-purified hESC-derived cell populations that can safely be used for clinical applications.
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Cockayne Syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo

Irina V. Kovtun, Kurt O. Johnson, Cynthia T. McMurray,

https://doi.org/10.18632/aging.100324 pp 509—514

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Kovtun IV, Johnson KO, McMurray CT, . Cockayne Syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo. . 3:509-514. https://doi.org/10.18632/aging.100324

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                TY  - JOUR
                AU  - Kovtun, Irina V. 
                AU  - Johnson, Kurt O. 
                AU  - McMurray, Cynthia T. 
                TI  - Cockayne Syndrome B protein antagonizes OGG1 in modulating CAG repeat length <i>in vivo</i>
                JO  - 
                JA  - 
                VL  - 3
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100324
                DO  - 10.18632/aging.100324
                SP  - 509
                EP  - 514
                PY  - 
                AB  - OGG1 and MSH2/MSH3 promote CAG repeat expansion at Huntington's disease (HD) locus in vivo during removal of oxidized bases from DNA. CSB, a transcription-coupled repair (TCR) protein, facilitates repair of some of the same oxidative lesions. In vitro, a knock down CSB results in a reduction of transcription-induced deletions at CAG repeat tract. To test the role of CSB in vivo, we measured intergenerational and somatic expansion of CAG tracts in HD mice lacking CSB, OGG1, or both. We provide evidence that CSB protects CAG repeats from expansion by either active reduction of the tract length during parent-child transmission, or by antagonizing the action of OGG1, which tends to promote expansion in somatic cells. These results raise a possibility that actions of transcription-coupled and base excision repair pathways lead to different outcomes at CAG tracts in vivo.
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Mutations in the BRCT binding site of BRCA1 result in hyper-recombination

Seth M. Dever, Sarah E. Golding, Elizabeth Rosenberg, Bret R. Adams, Michael O. Idowu, John M. Quillin, Nicholas Valerie, Bo Xu, Lawrence F. Povirk, Kristoffer Valerie,

https://doi.org/10.18632/aging.100325 pp 515—532

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Dever SM, Golding SE, Rosenberg E, Adams BR, Idowu MO, Quillin JM, Valerie N, Xu B, Povirk LF, Valerie K, . Mutations in the BRCT binding site of BRCA1 result in hyper-recombination. . 3:515-532. https://doi.org/10.18632/aging.100325

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                TY  - JOUR
                AU  - Dever, Seth M. 
                AU  - Golding, Sarah E. 
                AU  - Rosenberg, Elizabeth 
                AU  - Adams, Bret R. 
                AU  - Idowu, Michael O. 
                AU  - Quillin, John M. 
                AU  - Valerie, Nicholas 
                AU  - Xu, Bo 
                AU  - Povirk, Lawrence F. 
                AU  - Valerie, Kristoffer 
                TI  - Mutations in the BRCT binding site of BRCA1 result in hyper-recombination
                JO  - 
                JA  - 
                VL  - 3
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100325
                DO  - 10.18632/aging.100325
                SP  - 515
                EP  - 532
                PY  - 
                AB  - We introduced a K1702M mutation in the BRCA1 BRCT domain known to prevent the binding of proteins harboring pS-X-X-F motifs such as Abraxas-RAP80, BRIP1, and CtIP. Surprisingly, rather than impairing homologous recombination repair (HRR), expression of K1702M resulted in hyper-recombination coinciding with an accumulation of cells in S-G2 and no effect on nonhomologous end-joining. These cells also showed increased RAD51 and RPA nuclear staining. More pronounced effects were seen with a naturally occurring BRCT mutant (M1775R) that also produced elevated levels of ssDNA, in part co-localizing with RPA, in line with excessive DNA resection. M1775R induced unusual, thread-like promyelocytic leukemia (PML) nuclear bodies and clustered RPA foci rather than the typical juxtaposed RPA-PML foci seen with wild-type BRCA1. Interestingly, K1702M hyper-recombination diminished with a second mutation in the BRCA1 RING domain (I26A) known to reduce BRCA1 ubiquitin-ligase activity. These in vitro findings correlated with elevated nuclear RAD51 and RPA staining of breast cancer tissue from a patient with the M1775R mutation. Altogether, the disruption of BRCA1 (BRCT)-pS-X-X-F protein binding results in ubiquitination-dependent hyper-recombination via excessive DNA resection and the appearance of atypical PML-NBs. Thus, certain BRCA1 mutations that cause hyper-recombination instead of reduced DSB repair might lead to breast cancer.
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Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans

Edward P. Weiss, Dennis T. Villareal, Luigi Fontana, Dong-Ho Han, John O. Holloszy,

https://doi.org/10.18632/aging.100327 pp 533—542

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Weiss EP, Villareal DT, Fontana L, Han D, Holloszy JO, . Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans. . 3:533-542. https://doi.org/10.18632/aging.100327

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                TY  - JOUR
                AU  - Weiss, Edward P. 
                AU  - Villareal, Dennis T. 
                AU  - Fontana, Luigi 
                AU  - Han, Dong-Ho 
                AU  - Holloszy, John O. 
                TI  - Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans
                JO  - 
                JA  - 
                VL  - 3
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100327
                DO  - 10.18632/aging.100327
                SP  - 533
                EP  - 542
                PY  - 
                AB  - Plasma dehydroepiandrosterone (DHEA) decreases ~80% between ages 25 and 75 yr. In a preliminary study, we found that 6 mo of DHEA replacement improved insulin action in elderly individuals. The purpose of the present larger, randomized double-blind study was to determine whether a longer period of DHEA replacement improves glucose tolerance. Fifty-seven men and 68 women aged 65 to 75 yr were randomly assigned to 50 mg DHEA or placebo once daily. Year one was a randomized, double blind trial. Year 2 was an open label continuation. DHEA replacement improved glucose tolerance in participants who had abnormal GT initially, reduced plasma triglycerides, and the inflammatory cytokines IL6 and TNFα. This trial was registered at clinicaltrials.gov as NCT00182975.
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Interference between PARPs and SIRT1: a novel approach to healthy ageing?

Carles Cantó, Johan Auwerx,

https://doi.org/10.18632/aging.100326 pp 543—547

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Cantó C, Auwerx J, . Interference between PARPs and SIRT1: a novel approach to healthy ageing?. . 3:543-547. https://doi.org/10.18632/aging.100326

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Maternal diet, aging and diabetes meet at a chromatin loop

Susan E. Ozanne, Ionel Sandovici, Miguel Constância,

https://doi.org/10.18632/aging.100330 pp 548—554

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Ozanne SE, Sandovici I, Constância M, . Maternal diet, aging and diabetes meet at a chromatin loop. . 3:548-554. https://doi.org/10.18632/aging.100330

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                TY  - JOUR
                AU  - Ozanne, Susan E. 
                AU  - Sandovici, Ionel 
                AU  - Constância, Miguel 
                TI  - Maternal diet, aging and diabetes meet at a chromatin loop
                JO  - 
                JA  - 
                VL  - 3
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100330
                DO  - 10.18632/aging.100330
                SP  - 548
                EP  - 554
                PY  - 
                AB  - We have recently demonstrated that exposure to a suboptimal diet during early development leads to abnormal epigenetic regulation of a promoter-enhancer interaction at the gene encoding HNF-4α, a key transcription factor required for pancreatic β-cell differentiation and glucose homeostasis. In addition, our studies revealed that the suboptimal maternal diet amplifies the age-associated epigenetic silencing of this locus. In this research perspective we discuss these novel findings in the context of the growing list of epigenetic mechanisms by which the environment can affect gene activity and emphasize their implications for the understanding of the mechanistic basis of the development of type 2 diabetes with age.
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Embryonic anti-aging niche

Irina M. Conboy, Hanadie Yousef, Michael J. Conboy,

https://doi.org/10.18632/aging.100333 pp 555—563

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Conboy IM, Yousef H, Conboy MJ, . Embryonic anti-aging niche. . 3:555-563. https://doi.org/10.18632/aging.100333

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                TY  - JOUR
                AU  - Conboy, Irina M. 
                AU  - Yousef, Hanadie 
                AU  - Conboy, Michael J. 
                TI  - Embryonic anti-aging niche
                JO  - 
                JA  - 
                VL  - 3
                IS  - 5
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100333
                DO  - 10.18632/aging.100333
                SP  - 555
                EP  - 563
                PY  - 
                AB  - Although functional organ stem cells persist in the old, tissue damage invariably overwhelms tissue repair, ultimately causing the demise of an organism. The poor performance of stem cells in an aged organ, such as skeletal muscle, is caused by the changes in regulatory pathways such as Notch, MAPK and TGF-β, where old differentiated tissue actually inhibits its own regeneration. This perspective analyzes the current literature on regulation of organ stem cells by their young versus old niches and suggests that determinants of healthy and prolonged life might be under a combinatorial control of cell cycle check point proteins and mitogens, which need to be tightly balanced in order to promote tissue regeneration without tumor formation. While responses of adult stem cells are regulated extrinsically and age-specifically, we put forward experimental evidence suggesting that embryonic cells have an intrinsic youthful barrier to aging and produce soluble pro-regenerative proteins that signal the MAPK pathway for rejuvenating myogenesis. Future identification of this activity will improve our understanding of embryonic versus adult regulation of tissue regeneration suggesting novel strategies for organ rejuvenation. Comprehensively, the current intersection of aging and stem cell science indicates that if the age-imposed decline in the regenerative capacity of stem cells was understood, the debilitating lack of organ maintenance in the old could be ameliorated and perhaps, even reversed.
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Volume 3, Issue 5

Editorials

RasGrf1 and Aging

Kelvin J. A. Davies, Henry Jay Forman,

Cdc14b: A New Player in Aging

Zhubo Wei, Pumin Zhang,

Discussions

The isoenzyme pattern of LDH does not play a physiological role; except perhaps during fast transitions in energy metabolism

Bjørn Quistorff, Niels Grunnet,

BRCA1 A-Complex fine tunes repair functions of BRCA1

Janelle L Harris, Kum Kum Khanna,

Reviews

Branched-chain amino acids, mitochondrial biogenesis, and healthspan: an evolutionary perspective

Alessandra Valerio, Giuseppe D'Antona, Enzo Nisoli,

Disrupting the circadian clock: Gene-specific effects on aging, cancer, and other phenotypes

Elizabeth A. Yu, David R. Weaver,

The promise of human embryonic stem cells in aging-associated diseases

Odessa Yabut, Harold S. Bernstein,

Research Papers

Cockayne Syndrome B protein antagonizes OGG1 in modulating CAG repeat length in vivo

Irina V. Kovtun, Kurt O. Johnson, Cynthia T. McMurray,

Mutations in the BRCT binding site of BRCA1 result in hyper-recombination

Seth M. Dever, Sarah E. Golding, Elizabeth Rosenberg, Bret R. Adams, Michael O. Idowu, John M. Quillin, Nicholas Valerie, Bo Xu, Lawrence F. Povirk, Kristoffer Valerie,

Dehydroepiandrosterone (DHEA) replacement decreases insulin resistance and lowers inflammatory cytokines in aging humans

Edward P. Weiss, Dennis T. Villareal, Luigi Fontana, Dong-Ho Han, John O. Holloszy,

Research Perspectives

Interference between PARPs and SIRT1: a novel approach to healthy ageing?

Carles Cantó, Johan Auwerx,

Maternal diet, aging and diabetes meet at a chromatin loop

Susan E. Ozanne, Ionel Sandovici, Miguel Constância,

Embryonic anti-aging niche

Irina M. Conboy, Hanadie Yousef, Michael J. Conboy,

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