Volume 5, Issue 11

Repression of Alzheimer's beta-Secretase

Francesca-Fang Liao, Ruishan Wang, Edwards A. Park,

https://doi.org/10.18632/aging.100612 pp 789—790

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Liao F, Wang R, Park EA, . Repression of Alzheimer's beta-Secretase. . 5:789-790. https://doi.org/10.18632/aging.100612

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Treating fatty liver and insulin resistance

Rachel J. Perry, Gerald I. Shulman,

https://doi.org/10.18632/aging.100617 pp 791—792

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Immunostimulatory activity of lifespan-extending agents

José Manuel Bravo-San Pedro, Laura Senovilla,

https://doi.org/10.18632/aging.100619 pp 793—801

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Bravo-San Pedro JM, Senovilla L, . Immunostimulatory activity of lifespan-extending agents. . 5:793-801. https://doi.org/10.18632/aging.100619

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                TY  - JOUR
                AU  - Bravo-San Pedro, José Manuel 
                AU  - Senovilla, Laura 
                TI  - Immunostimulatory activity of lifespan-extending agents
                JO  - 
                JA  - 
                VL  - 5
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100619
                DO  - 10.18632/aging.100619
                SP  - 793
                EP  - 801
                PY  - 
                AB  - During the past two decades, several interventions have been shown to increase the healthy lifespan of model organisms as evolutionarily distant from each other as yeast, worms, flies and mammals. These anti-aging maneuvers include (but are not limited to) cycles of caloric restriction, physical exercise as well as the administration of multiple, chemically unrelated agents, such as resveratrol, spermidine and various rapamycin-like compounds collectively known as rapalogs. Most, if not all, lifespan-extending agents promote macroautophagy (hereafter referred to as autophagy), an evolutionarily old mechanism that contributes to the maintenance of intracellular homeostasis and plays a critical role in the adaptive response of cells to stress. In line with this notion, the activation of autophagy appears to mediate significant anti-ageing effects in several organisms, including mice. Here, we focus on rapalogs to discuss the possibility that part of the beneficial activity of lifespan-extending agents stems from their ability to exert immunostimulatory effects. Accumulating evidence indicates indeed that the immune system can recognize and eliminate not only cells that are prone to undergo malignant transformation, but also senescent cells, thus playing a significant role in the control of organismal aging. In addition, it has recently become clear that rapamycin and other rapalogs, which for a long time have been viewed (and used in the clinic) as pure immunosuppressants, can mediate robust immunostimulatory functions, at least in some circumstances.
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Enhancing protein disaggregation restores proteasome activity in aged cells

Veronica Andersson, Sarah Hanzén, Beidong Liu, Mikael Molin, Thomas Nyström,

https://doi.org/10.18632/aging.100613 pp 802—812

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Andersson V, Hanzén S, Liu B, Molin M, Nyström T, . Enhancing protein disaggregation restores proteasome activity in aged cells. . 5:802-812. https://doi.org/10.18632/aging.100613

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                TY  - JOUR
                AU  - Andersson, Veronica 
                AU  - Hanzén, Sarah 
                AU  - Liu, Beidong 
                AU  - Molin, Mikael 
                AU  - Nyström, Thomas 
                TI  - Enhancing protein disaggregation restores proteasome activity in aged cells
                JO  - 
                JA  - 
                VL  - 5
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100613
                DO  - 10.18632/aging.100613
                SP  - 802
                EP  - 812
                PY  - 
                AB  - The activity of the ubiquitin-proteasome system, UPS, declines during aging in several multicellular organisms. The reason behind this decline remains elusive. Here, using yeast as a model system, we show that while the level and potential capacity of the 26S proteasome is maintained in replicatively aged cells, the UPS is not functioning properly in vivo. As a consequence cytosolic UPS substrates, such as ΔssCPY* are stabilized, accumulate, and form inclusions. By integrating a pGPD-HSP104 recombinant gene into the genome, we were able to constitutively elevate protein disaggregase activity, which diminished the accumulation of protein inclusions during aging. Remarkably, this elevated disaggregation restored degradation of a 26S proteasome substrate in aged cells without elevating proteasome levels, demonstrating that age-associated aggregation obstructs UPS function. The data supports the existence of a negative feedback loop that accelerates aging by exacerbating proteostatic decline once misfolded and aggregation-prone proteins reach a critical level.
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Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging

Nan Jiang, Guyu Du, Ethan Tobias, Jason G. Wood, Rachel Whitaker, Nicola Neretti, Stephen L. Helfand,

https://doi.org/10.18632/aging.100614 pp 813—824

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Jiang N, Du G, Tobias E, Wood JG, Whitaker R, Neretti N, Helfand SL, . Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging. . 5:813-824. https://doi.org/10.18632/aging.100614

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                TY  - JOUR
                AU  - Jiang, Nan 
                AU  - Du, Guyu 
                AU  - Tobias, Ethan 
                AU  - Wood, Jason G. 
                AU  - Whitaker, Rachel 
                AU  - Neretti, Nicola 
                AU  - Helfand, Stephen L. 
                TI  - Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging
                JO  - 
                JA  - 
                VL  - 5
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100614
                DO  - 10.18632/aging.100614
                SP  - 813
                EP  - 824
                PY  - 
                AB  - During aging, changes in chromatin state that alter gene transcription have been postulated to result in expression of genes that are normally silenced, leading to deleterious age-related effects on cellular physiology. Despite the prevalence of this hypothesis, it is primarily in yeast that loss of gene silencing with age has been well documented. We use a novel position effect variegation (PEV) reporter in Drosophila melanogaster to show that age-related loss of repressive heterochromatin is associated with loss of gene silencing in metazoans and is affected by Sir2, as it is in yeast. The life span-extending intervention, calorie restriction (CR), delays the age-related loss of gene silencing, indicating that loss of gene silencing is a component of normal aging. Diet switch experiments show that such flies undergo a rapid change in their level of gene silencing, demonstrating the epigenetic plasticity of chromatin during aging and highlighting the potential role of diet and metabolism in chromatin maintenance, Thus, diet and related interventions may be of therapeutic importance for age-related diseases, such as cancer.
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Absence of ductal hyper-keratinization in Mouse age-related meibomian gland dysfunction (ARMGD)

Geraint J. Parfitt, Yilu Xie, Mikhail Geyfman, Donald J. Brown, James V. Jester,

https://doi.org/10.18632/aging.100615 pp 825—834

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Parfitt GJ, Xie Y, Geyfman M, Brown DJ, Jester JV, . Absence of ductal hyper-keratinization in Mouse age-related meibomian gland dysfunction (ARMGD). . 5:825-834. https://doi.org/10.18632/aging.100615

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                TY  - JOUR
                AU  - Parfitt, Geraint J. 
                AU  - Xie, Yilu 
                AU  - Geyfman, Mikhail 
                AU  - Brown, Donald J. 
                AU  - Jester, James V. 
                TI  - Absence of ductal hyper-keratinization in Mouse age-related meibomian gland dysfunction (ARMGD)
                JO  - 
                JA  - 
                VL  - 5
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100615
                DO  - 10.18632/aging.100615
                SP  - 825
                EP  - 834
                PY  - 
                AB  - Meibomian gland dysfunction (MGD) is frequent with aging and is the primary cause of dry eye disease, the most prevalent ocular complaint. We used a novel 3-D reconstruction technique, immunofluorescent computed tomography (ICT), to characterize meibomian gland keratinization and cell proliferation in a mouse model of age-related meibomian gland dysfunction (ARMGD). To visualize the changes associated with ARMGD, 5-month and 2-year old mouse eyelids were 3-D reconstructed by ICT using antibodies to cytokeratin (CK) 1, 5 and 6 and the proliferation marker Ki67. We quantified total gland, ductal and lipid volume from the reconstructions, observing a dramatic decrease in old glands. In young glands, proliferative ductules suggest a potential site of acinar progenitors that were found to be largely absent in aged, atrophic glands. In the aged mouse, we observed an anterior migration of the mucocutaneous junction (MCJ) and an absence of hyper-keratinization with meibomian gland atrophy. Thus, we propose that changes in the MCJ and glandular atrophy through a loss of meibocyte progenitors are most likely responsible for ARMGD and not ductal hyper-keratinization and gland obstruction.
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SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK

Linh Ho, Allen Sam Titus, Kushal Kr Banerjee, Suji George, Wei Lin, Shaunak Deota, Asish K. Saha, Ken Nakamura, Philipp Gut, Eric Verdin, Ullas Kolthur-Seetharam,

https://doi.org/10.18632/aging.100616 pp 835—849

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Ho L, Titus AS, Banerjee KK, George S, Lin W, Deota S, Saha AK, Nakamura K, Gut P, Verdin E, Kolthur-Seetharam U, . SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK. . 5:835-849. https://doi.org/10.18632/aging.100616

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                TY  - JOUR
                AU  - Ho, Linh 
                AU  - Titus, Allen Sam 
                AU  - Banerjee, Kushal Kr 
                AU  - George, Suji 
                AU  - Lin, Wei 
                AU  - Deota, Shaunak 
                AU  - Saha, Asish K. 
                AU  - Nakamura, Ken 
                AU  - Gut, Philipp 
                AU  - Verdin, Eric 
                AU  - Kolthur-Seetharam, Ullas 
                TI  - SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK
                JO  - 
                JA  - 
                VL  - 5
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100616
                DO  - 10.18632/aging.100616
                SP  - 835
                EP  - 849
                PY  - 
                AB  - Efficient coupling of cellular energy production to metabolic demand is crucial to maintain organismal homeostasis. Here, we report that the mitochondrial Sirtuin Sirt4 regulates mitochondrial ATP homeostasis. We find that Sirt4 affects mitochondrial uncoupling via the adenine nucleotide translocator 2 (ANT2). Loss of Sirt4 expression leads to decreased cellular ATP levels in vitro and in vivo while Sirt4 overexpression is associated with increased ATP levels. Further, we provide evidence that lack of Sirt4 activates a retrograde signaling response from the mitochondria to the nucleus that includes AMPK, PGC1α, key regulators of β-oxidation such as Acetyl-CoA carboxylase, and components of the mitochondrial respiratory machinery. This study highlights the ability of Sirt4 to regulate ATP levels via ANT2 and a feedback loop involving AMPK.
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Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells

Scott Maynard, Guido Keijzers, Martin Gram, Claus Desler, Laila Bendix, Esben Budtz-Jørgensen, Drude Molbo, Deborah L. Croteau, Merete Osler, Tinna Stevnsner, Lene Juel Rasmussen, Flemming Dela, Kirsten Avlund, Vilhelm A. Bohr,

https://doi.org/10.18632/aging.100618 pp 850—864

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Maynard S, Keijzers G, Gram M, Desler C, Bendix L, Budtz-Jørgensen E, Molbo D, Croteau DL, Osler M, Stevnsner T, Rasmussen LJ, Dela F, Avlund K, et al, . Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells. . 5:850-864. https://doi.org/10.18632/aging.100618

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                TY  - JOUR
                AU  - Maynard, Scott 
                AU  - Keijzers, Guido 
                AU  - Gram, Martin 
                AU  - Desler, Claus 
                AU  - Bendix, Laila 
                AU  - Budtz-Jørgensen, Esben 
                AU  - Molbo, Drude 
                AU  - Croteau, Deborah L. 
                AU  - Osler, Merete 
                AU  - Stevnsner, Tinna 
                AU  - Rasmussen, Lene Juel 
                AU  - Dela, Flemming 
                AU  - Avlund, Kirsten 
                AU  - Bohr, Vilhelm A. 
                TI  - Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells
                JO  - 
                JA  - 
                VL  - 5
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100618
                DO  - 10.18632/aging.100618
                SP  - 850
                EP  - 864
                PY  - 
                ER  -

Provider: 
                TY  - JOUR
                AU  - Maynard, Scott 
                AU  - Keijzers, Guido 
                AU  - Gram, Martin 
                AU  - Desler, Claus 
                AU  - Bendix, Laila 
                AU  - Budtz-Jørgensen, Esben 
                AU  - Molbo, Drude 
                AU  - Croteau, Deborah L. 
                AU  - Osler, Merete 
                AU  - Stevnsner, Tinna 
                AU  - Rasmussen, Lene Juel 
                AU  - Dela, Flemming 
                AU  - Avlund, Kirsten 
                AU  - Bohr, Vilhelm A. 
                TI  - Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells
                JO  - 
                JA  - 
                VL  - 5
                IS  - 11
                PB  - 
                SN  - 
                UR  - https://doi.org/10.18632/aging.100618
                DO  - 10.18632/aging.100618
                SP  - 850
                EP  - 864
                PY  - 
                AB  - Low vitality (a component of fatigue) in middle-aged and older adults is an important complaint often identified as a symptom of a disease state or side effect of a treatment. No studies to date have investigated the potential link between dysfunctional mitochondrial ATP production and low vitality. Therefore, we measured a number of cellular parameters related to mitochondrial activity in peripheral blood mononuclear cells (PBMCs) isolated from middle-aged men, and tested for association with vitality. These parameters estimate mitochondrial respiration, reactive oxygen species (ROS) production, and deoxyribonucleotide (dNTP) balance in PBMCs. The population was drawn from the Metropolit cohort of men born in 1953. Vitality level was estimated from the Medical Outcomes Study Short Form 36 (SF-36) vitality scale. We found that vitality score had no association with any of the mitochondrial respiration parameters. However, vitality score was inversely associated with cellular ROS production and cellular deoxythymidine triphosphate (dTTP) levels and positively associated with deoxycytidine triphosphate (dCTP) levels. We conclude that self-reported persistent low vitality is not associated with specific aspects of mitochondrial oxidative phosphorylation capacity in PBMCs, but may have other underlying cellular dysfunctions that contribute to dNTP imbalance and altered ROS production.
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Volume 5, Issue 11

Editorials

Repression of Alzheimer's beta-Secretase

Francesca-Fang Liao, Ruishan Wang, Edwards A. Park,

Treating fatty liver and insulin resistance

Rachel J. Perry, Gerald I. Shulman,

Review

Immunostimulatory activity of lifespan-extending agents

José Manuel Bravo-San Pedro, Laura Senovilla,

Research Papers

Enhancing protein disaggregation restores proteasome activity in aged cells

Veronica Andersson, Sarah Hanzén, Beidong Liu, Mikael Molin, Thomas Nyström,

Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging

Nan Jiang, Guyu Du, Ethan Tobias, Jason G. Wood, Rachel Whitaker, Nicola Neretti, Stephen L. Helfand,

Absence of ductal hyper-keratinization in Mouse age-related meibomian gland dysfunction (ARMGD)

Geraint J. Parfitt, Yilu Xie, Mikhail Geyfman, Donald J. Brown, James V. Jester,

SIRT4 regulates ATP homeostasis and mediates a retrograde signaling via AMPK

Linh Ho, Allen Sam Titus, Kushal Kr Banerjee, Suji George, Wei Lin, Shaunak Deota, Asish K. Saha, Ken Nakamura, Philipp Gut, Eric Verdin, Ullas Kolthur-Seetharam,

Relationships between human vitality and mitochondrial respiratory parameters, reactive oxygen species production and dNTP levels in peripheral blood mononuclear cells

Scott Maynard, Guido Keijzers, Martin Gram, Claus Desler, Laila Bendix, Esben Budtz-Jørgensen, Drude Molbo, Deborah L. Croteau, Merete Osler, Tinna Stevnsner, Lene Juel Rasmussen, Flemming Dela, Kirsten Avlund, Vilhelm A. Bohr,

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