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NPJ Aging and Mechanisms of Disease

Ilja L Kruglikov, Philipp E Scherer
Low expression of caveolin-1 (Cav-1) is typical in psoriatic lesions and overexpression of Cav-1 leads to a reduction of inflammation and suppression of epidermal hyperproliferation, thus ameliorating these two well-known hallmarks of psoriasis. At the same time, the interfacial layers of the white adipose tissue (WAT) adjacent to psoriatic lesions demonstrate much higher stiffness, which also points to a modification of Cav-1 expression in this tissue. These processes are connected with each other and regulated via exosomal exchange...
2019: NPJ Aging and Mechanisms of Disease
Jaymie R Voorhees, Matthew T Remy, Claire M Erickson, Laura M Dutca, Daniel J Brat, Andrew A Pieper
Occupational exposure to organophosphate pesticides, such as chlorpyrifos (CPF), increases the risk of Alzheimer's disease (AD), though the mechanism is unclear. To investigate this, we subjected 4-month-old male and female wild-type (WT) and TgF344-AD rats, a transgenic AD model, to an occupational CPF exposure paradigm that recapitulates biomarkers and behavioral impairments experienced by agricultural workers. Subsequent cognition and neuropathology were analyzed over the next 20 months. CPF exposure caused chronic microglial dysregulation and accelerated neurodegeneration in both males and females...
2019: NPJ Aging and Mechanisms of Disease
Sergei Vatolin, Tomas Radivoyevitch, Jaroslaw P Maciejewski
A high-throughput anti-aging drug screen was developed that simultaneously measures senescence-associated β-galactosidase activity and proliferation. Applied to replicatively pre-aged fibroblasts, this screen yielded violuric acid (VA) and 1-naphthoquinone-2-monoxime (N2N1) as its top two hits. These lead compounds extended the replicative life spans of normal and progeroid human cells in a dose-dependent manner and also extended the chronological life spans of mice and C. elegans. They are further shown here to function as redox catalysts in oxidations of NAD(P)H...
2019: NPJ Aging and Mechanisms of Disease
Ryoei Uchida, Yoshimasa Saito, Kazuki Nogami, Yohei Kajiyama, Yukana Suzuki, Yasuhiro Kawase, Toshiaki Nakaoka, Toshihide Muramatsu, Masaki Kimura, Hidetsugu Saito
To understand the molecular features underlying stem cell aging, we established intestinal epithelial organoids derived from both young and aged mice and investigated alterations in their senescence and epigenetic status. Senescence-related changes including accumulation of senescence-associated β-galactosidase and up-regulation of Cdkn1a ( p21) by DNA demethylation were observed in intestinal epithelial organoids derived from aged mice. We also demonstrated that the important stem cell marker Lgr5 was epigenetically silenced by trimethylation of histone H3 lysine 27, inducing suppression of Wnt signaling and a decrease of cell proliferation in organoids from aged mice...
2019: NPJ Aging and Mechanisms of Disease
Mari Yamagami, Motoyuki Otsuka, Takahiro Kishikawa, Kazuma Sekiba, Takahiro Seimiya, Eri Tanaka, Tatsunori Suzuki, Rei Ishibashi, Motoko Ohno, Kazuhiko Koike
During cellular aging, many changes in cellular functions occur. A hallmark of aged cells is secretion of inflammatory mediators, which collectively is referred to as the senescence-associated secretory phenotype (SASP). However, the mechanisms underlying such changes are unclear. Canonically, the expression of interferon (IFN)-stimulated genes (ISGs) is induced by IFNs through the formation of the tripartite transcriptional factor ISGF3, which is composed of IRF9 and the phosphorylated forms of STAT1 and STAT2...
2018: NPJ Aging and Mechanisms of Disease
Sean Johnson, David F Wozniak, S Imai
Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD+ levels are reduced in multiple tissues and organs, including the brain. We found that NAD+ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests...
2018: NPJ Aging and Mechanisms of Disease
Raji R Nair, Shreyas V Madiwale, Deepak Kumar Saini
One of the major pathological outcomes of DNA damage during aging or anticancer therapy is enhanced inflammation. However, the underlying signaling mechanism that drives this is not well understood. Here, we show that in response to DNA damage, ubiquitously expressed GPCR, CXCR4 is upregulated through the ATM kinase-HIF1α dependent DNA damage response (DDR) signaling, and enhances inflammatory response when activated by its ligand, chemokine CXCL12. A pharmacologically active compound screen revealed that this increased inflammation is dependent on reduction in cAMP levels achieved through activation of Gαi through CXCR4 receptor and PDE4A...
2018: NPJ Aging and Mechanisms of Disease
Ryan W Dellinger, Santiago Roel Santos, Mark Morris, Mal Evans, Dan Alminana, Leonard Guarente, Eric Marcotulli
[This corrects the article DOI: 10.1038/s41514-017-0016-9.].
2018: NPJ Aging and Mechanisms of Disease
Yuichi Ikegami, Ikuo Inoue, Kaiji Inoue, Yuichi Shinoda, Shinichiro Iida, Seiichi Goto, Takanari Nakano, Akira Shimada, Mistuhiko Noda
Statins and/or PCSK9 inhibitors cause the regression of coronary atheroma and reduce clinical events. However, it currently remains unclear whether these drugs modulate coronary atheroma calcification in vivo. Coronary artery calcium (CAC) scores (Agatston Units, AUs) were estimated in 120 patients receiving coronary computed tomographic angiography (CCTA) (63% males; median age 56 years). The CAC scores were compared among the three groups: (1) neither statin nor PCSK9 inhibitor therapy, (2) statin monotherapy, and (3) statin and PCSK9 inhibitor combination therapy in an unpaired cross-sectional study...
2018: NPJ Aging and Mechanisms of Disease
Hongyuan Wang, Yuan Zhao, Marina Ezcurra, Alexandre Benedetto, Ann F Gilliat, Josephine Hellberg, Ziyu Ren, Evgeniy R Galimov, Trin Athigapanich, Johannes Girstmair, Maximilian J Telford, Colin T Dolphin, Zhizhou Zhang, David Gems
A long-standing belief is that aging (senescence) is the result of stochastic damage accumulation. Alternatively, senescent pathology may also result from late-life, wild-type gene action (i.e., antagonistic pleiotropy, as argued by Williams) leading to non-adaptive run-on of developmental programs (or quasi-programs ) (as suggested more recently by Blagosklonny). In this study, we use existing and new data to show how uterine tumors, a prominent form of senescent pathology in the nematode Caenorhabditis elegans , likely result from quasi-programs...
2018: NPJ Aging and Mechanisms of Disease
Adam J Dobson, Xiaoli He, Eric Blanc, Ekin Bolukbasi, Yodit Feseha, Mingyao Yang, Matthew D W Piper
Dietary restriction (DR) extends animal lifespan, but imposes fitness costs. This phenomenon depends on dietary essential amino acids (EAAs) and TOR signalling, which exert systemic effects. However, the roles of specific tissues and cell-autonomous transcriptional regulators in diverse aspects of the DR phenotype are unknown. Manipulating relevant transcription factors (TFs) specifically in lifespan-limiting tissues may separate the lifespan benefits of DR from the early-life fitness costs. Here, we systematically analyse transcription across organs of Drosophila subjected to DR or low TOR and predict regulatory TFs...
2018: NPJ Aging and Mechanisms of Disease
Ingo Lämmermann, Lucia Terlecki-Zaniewicz, Regina Weinmüllner, Markus Schosserer, Hanna Dellago, André Dargen de Matos Branco, Dominik Autheried, Benjamin Sevcnikar, Lisa Kleissl, Irina Berlin, Frédérique Morizot, Francois Lejeune, Nicola Fuzzati, Sandra Forestier, Alix Toribio, Anaïs Tromeur, Lionel Weinberg, Juan Carlos Higareda Almaraz, Marcel Scheideler, Marion Rietveld, Abdoel El Ghalbzouri, Erwin Tschachler, Florian Gruber, Johannes Grillari
There is increasing evidence that senescent cells are a driving force behind many age-related pathologies and that their selective elimination increases the life- and healthspan of mice. Senescent cells negatively affect their surrounding tissue by losing their cell specific functionality and by secreting a pro-tumorigenic and pro-inflammatory mixture of growth hormones, chemokines, cytokines and proteases, termed the senescence-associated secretory phenotype (SASP). Here we identified an extract from the plant Solidago virgaurea subsp...
2018: NPJ Aging and Mechanisms of Disease
Paul P Jung, Zhi Zhang, Nicole Paczia, Christian Jaeger, Tomasz Ignac, Patrick May, Carole L Linster
Aging is a complex trait of broad scientific interest, especially because of its intrinsic link with common human diseases. Pioneering work on aging-related mechanisms has been made in Saccharomyces cerevisiae , mainly through the use of deletion collections isogenic to the S288c reference strain. In this study, using a recently published high-throughput approach, we quantified chronological life span (CLS) within a collection of 58 natural strains across seven different conditions. We observed a broad aging variability suggesting the implication of diverse genetic and environmental factors in chronological aging control...
2018: NPJ Aging and Mechanisms of Disease
Hironori Nakagami, Ken Sugimoto, Takahiro Ishikawa, Taku Fujimoto, Toshifumi Yamaoka, Misa Hayashi, Eiji Kiyohara, Hiroshi Ando, Yuta Terabe, Yoichi Takami, Koichi Yamamoto, Yasushi Takeya, Minoru Takemoto, Masaya Koshizaka, Tamotsu Ebihara, Ayumi Nakamura, Mitsunori Nishikawa, Xiang Jing Yao, Hideki Hanaoka, Ichiro Katayama, Koutaro Yokote, Hiromi Rakugi
SR-0379 is a functional peptide that has wound healing effect with anti-microbial action, making it an ideal drug to prevent infection. To evaluate the safety, efficacy, and pharmacokinetics of SR-0379 for the treatment of leg ulcers, a physician-initiated, phase I/IIa, first-in-patient clinical study was designed. A multi-center, double-blind, randomized clinical study was conducted from October 2015 to September 2016. The inclusion criteria for leg ulcers were (1) diabetes or critical limb ischemia and (2) wound size <6 cm in diameter...
2018: NPJ Aging and Mechanisms of Disease
Giuseppe Del Giudice, Jörg J Goronzy, Beatrix Grubeck-Loebenstein, Paul-Henri Lambert, Tomas Mrkvan, Jeffrey J Stoddard, T Mark Doherty
The progressive increase of the aged population worldwide mandates new strategies to ensure sustained health and well-being with age. The development of better and/or new vaccines against pathogens that affect older adults is one pivotal intervention in approaching this goal. However, the functional decline of various physiological systems, including the immune system, requires novel approaches to counteract immunosenescence. Although important progress has been made in understanding the mechanisms underlying the age-related decline of the immune response to infections and vaccinations, knowledge gaps remain, both in the areas of basic and translational research...
2018: NPJ Aging and Mechanisms of Disease
Norimitsu Ban, Yoko Ozawa, Hideto Osada, Jonathan B Lin, Eriko Toda, Mitsuhiro Watanabe, Kenya Yuki, Shunsuke Kubota, Rajendra S Apte, Kazuo Tsubota
SIRT3 is a key regulator of mitochondrial reactive oxygen species as well as mitochondrial function. The retina is one of the highest energy-demanding tissues, in which the regulation of reactive oxygen species is critical to prevent retinal neurodegeneration. Although previous reports have demonstrated that SIRT3 is highly expressed in the retina and important in neuroprotection, function of SIRT3 in regulating reactive oxygen species in the retina is largely unknown. In this study, we investigated the role of retinal SIRT3 in a light-induced retinal degeneration model using SIRT3 knockout mice...
2017: NPJ Aging and Mechanisms of Disease
Xinping Chen, Hana Hall, Jeffrey P Simpson, Walter D Leon-Salas, Donald F Ready, Vikki M Weake
Lipid peroxides are generated by oxidative stress in cells, and contribute to ageing and neurodegenerative disease. The eye is at special risk for lipid peroxidation because photoreceptors possess amplified sensory membranes rich in peroxidation-susceptible polyunsaturated fatty acids. Light-induced lipid peroxidation in the retina contributes to retinal degeneration, and lipid peroxidation has been implicated in the progression of age-associated ocular diseases such as age-related macular degeneration (AMD)...
2017: NPJ Aging and Mechanisms of Disease
Ryan W Dellinger, Santiago Roel Santos, Mark Morris, Mal Evans, Dan Alminana, Leonard Guarente, Eric Marcotulli
NRPT is a combination of nicotinamide riboside (NR), a nicotinamide adenine dinucleotide (NAD+) precursor vitamin found in milk, and pterostilbene (PT), a polyphenol found in blueberries. Here, we report this first-in-humans clinical trial designed to assess the safety and efficacy of a repeat dose of NRPT (commercially known as Basis). NRPT was evaluated in a randomized, double-blind, and placebo-controlled study in a population of 120 healthy adults between the ages of 60 and 80 years. The study consisted of three treatment arms: placebo, recommended dose of NRPT (NRPT 1X), and double dose of NRPT (NRPT 2X)...
2017: NPJ Aging and Mechanisms of Disease
Irene Alfaras, Sarah J Mitchell, Hector Mora, Darisbeth Rosario Lugo, Alessandra Warren, Ignacio Navas-Enamorado, Vickie Hoffmann, Christopher Hine, James R Mitchell, David G Le Couteur, Victoria C Cogger, Michel Bernier, Rafael de Cabo
Chronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure...
2017: NPJ Aging and Mechanisms of Disease
Naoyuki Ishida, Yuichi Ishihara, Kazuto Ishida, Hiroyuki Tada, Yoshiko Funaki-Kato, Makoto Hagiwara, Taslima Ferdous, Mohammad Abdullah, Akio Mitani, Makoto Michikawa, Kenji Matsushita
Periodontitis is a localized infectious disease caused by periodontopathic bacteria, such as Porphyromonas gingivalis . Recently, it has been suggested that bacterial infections may contribute to the onset and the progression of Alzheimer's disease (AD). However, we do not have any evidence about a causative relationship between periodontitis and AD. In this study, we investigated by using a transgenic mouse model of AD whether periodontitis evoked by P. gingivalis modulates the pathological features of AD...
2017: NPJ Aging and Mechanisms of Disease
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