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  Subjects -> BIOLOGY (Total: 2995 journals)
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BIOLOGY (1424 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 1720 Journals sorted alphabetically
AAPS Journal     Hybrid Journal   (Followers: 20)
Achievements in the Life Sciences     Open Access   (Followers: 4)
ACS Synthetic Biology     Full-text available via subscription   (Followers: 21)
Acta Biologica Colombiana     Open Access   (Followers: 7)
Acta Biologica Hungarica     Full-text available via subscription   (Followers: 4)
Acta Biologica Sibirica     Open Access  
Acta Biomaterialia     Hybrid Journal   (Followers: 25)
Acta Biotheoretica     Hybrid Journal   (Followers: 5)
Acta Chiropterologica     Full-text available via subscription   (Followers: 6)
acta ethologica     Hybrid Journal   (Followers: 4)
Acta Limnologica Brasiliensia     Open Access   (Followers: 3)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Musei Silesiae, Scientiae Naturales : The Journal of Silesian Museum in Opava     Open Access  
Acta Neurobiologiae Experimentalis     Open Access  
Acta Parasitologica     Hybrid Journal   (Followers: 9)
Acta Scientiarum. Biological Sciences     Open Access   (Followers: 2)
Acta Scientifica Naturalis     Open Access   (Followers: 2)
Actualidades Biológicas     Open Access   (Followers: 1)
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 3)
Advances in Bioinformatics     Open Access   (Followers: 18)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4)
Advances in Biosensors and Bioelectronics     Open Access   (Followers: 6)
Advances in Cell Biology     Open Access   (Followers: 24)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 11)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Ecological Research     Full-text available via subscription   (Followers: 41)
Advances in Environmental Sciences - International Journal of the Bioflux Society     Open Access   (Followers: 20)
Advances in Enzyme Research     Open Access   (Followers: 9)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 7)
Advances in Genome Biology     Full-text available via subscription   (Followers: 11)
Advances in High Energy Physics     Open Access   (Followers: 19)
Advances in Human Biology     Open Access   (Followers: 1)
Advances in Life Science and Technology     Open Access   (Followers: 14)
Advances in Life Sciences     Open Access   (Followers: 4)
Advances in Marine Biology     Full-text available via subscription   (Followers: 16)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 22)
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3)
Advances in Regenerative Biology     Open Access   (Followers: 1)
Advances in Structural Biology     Full-text available via subscription   (Followers: 8)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
African Journal of Range & Forage Science     Hybrid Journal   (Followers: 6)
AFRREV STECH : An International Journal of Science and Technology     Open Access   (Followers: 1)
Ageing Research Reviews     Hybrid Journal   (Followers: 8)
Aging Cell     Open Access   (Followers: 10)
Agrokémia és Talajtan     Full-text available via subscription   (Followers: 2)
Agrokreatif Jurnal Ilmiah Pengabdian kepada Masyarakat     Open Access  
AJP Cell Physiology     Full-text available via subscription   (Followers: 13)
AJP Endocrinology and Metabolism     Full-text available via subscription   (Followers: 22)
AJP Lung Cellular and Molecular Physiology     Full-text available via subscription   (Followers: 3)
Al-Kauniyah : Jurnal Biologi     Open Access  
Alasbimn Journal     Open Access   (Followers: 1)
AMB Express     Open Access   (Followers: 1)
Ambix     Hybrid Journal   (Followers: 3)
American Biology Teacher     Full-text available via subscription   (Followers: 12)
American Fern Journal     Full-text available via subscription   (Followers: 1)
American Journal of Agricultural and Biological Sciences     Open Access   (Followers: 10)
American Journal of Bioethics     Hybrid Journal   (Followers: 10)
American Journal of Biostatistics     Open Access   (Followers: 9)
American Journal of Human Biology     Hybrid Journal   (Followers: 12)
American Journal of Medical and Biological Research     Open Access   (Followers: 5)
American Journal of Plant Sciences     Open Access   (Followers: 19)
American Journal of Primatology     Hybrid Journal   (Followers: 15)
American Malacological Bulletin     Full-text available via subscription   (Followers: 3)
American Naturalist     Full-text available via subscription   (Followers: 65)
Amphibia-Reptilia     Hybrid Journal   (Followers: 6)
Anaerobe     Hybrid Journal   (Followers: 4)
Analytical Methods     Full-text available via subscription   (Followers: 7)
Anatomical Science International     Hybrid Journal   (Followers: 2)
Animal Cells and Systems     Hybrid Journal   (Followers: 4)
Annales de Limnologie - International Journal of Limnology     Hybrid Journal   (Followers: 1)
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3)
Annales UMCS, Biologia     Open Access   (Followers: 1)
Annals of Applied Biology     Hybrid Journal   (Followers: 8)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18)
Annals of Human Biology     Hybrid Journal   (Followers: 4)
Annual Review of Biomedical Engineering     Full-text available via subscription   (Followers: 17)
Annual Review of Biophysics     Full-text available via subscription   (Followers: 25)
Annual Review of Cancer Biology     Full-text available via subscription   (Followers: 1)
Annual Review of Cell and Developmental Biology     Full-text available via subscription   (Followers: 39)
Annual Review of Food Science and Technology     Full-text available via subscription   (Followers: 14)
Annual Review of Genomics and Human Genetics     Full-text available via subscription   (Followers: 19)
Annual Review of Phytopathology     Full-text available via subscription   (Followers: 10)
Anthropological Review     Open Access   (Followers: 25)
Anti-Infective Agents     Hybrid Journal   (Followers: 3)
Antibiotics     Open Access   (Followers: 9)
Antioxidants     Open Access   (Followers: 4)
Antioxidants & Redox Signaling     Hybrid Journal   (Followers: 8)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5)
Anzeiger für Schädlingskunde     Hybrid Journal   (Followers: 1)
Apidologie     Hybrid Journal   (Followers: 4)
Apmis     Hybrid Journal   (Followers: 1)
APOPTOSIS     Hybrid Journal   (Followers: 8)
Applied Bionics and Biomechanics     Open Access   (Followers: 8)
Applied Vegetation Science     Full-text available via subscription   (Followers: 9)
Aquaculture Environment Interactions     Open Access   (Followers: 2)
Aquaculture International     Hybrid Journal   (Followers: 22)
Aquaculture Reports     Open Access   (Followers: 3)
Aquaculture, Aquarium, Conservation & Legislation - International Journal of the Bioflux Society     Open Access   (Followers: 6)
Aquatic Biology     Open Access   (Followers: 4)
Aquatic Ecology     Hybrid Journal   (Followers: 30)
Aquatic Ecosystem Health & Management     Hybrid Journal   (Followers: 13)
Aquatic Science and Technology     Open Access   (Followers: 3)
Aquatic Toxicology     Hybrid Journal   (Followers: 19)
Archaea     Open Access   (Followers: 3)
Archiv für Molluskenkunde: International Journal of Malacology     Full-text available via subscription   (Followers: 3)
Archives of Biomedical Sciences     Open Access   (Followers: 7)
Archives of Microbiology     Hybrid Journal   (Followers: 8)
Archives of Natural History     Hybrid Journal   (Followers: 7)
Archives of Oral Biology     Hybrid Journal   (Followers: 2)
Archives of Virology     Hybrid Journal   (Followers: 5)
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2)
Arid Ecosystems     Hybrid Journal   (Followers: 3)
Arquivos do Instituto Biológico     Open Access   (Followers: 1)
Arquivos do Museu Dinâmico Interdisciplinar     Open Access  
Arthropod Structure & Development     Hybrid Journal   (Followers: 2)
Arthropods     Open Access   (Followers: 1)
Artificial DNA: PNA & XNA     Hybrid Journal   (Followers: 2)
Artificial Photosynthesis     Open Access   (Followers: 1)
Asian Bioethics Review     Full-text available via subscription   (Followers: 1)
Asian Journal of Biodiversity     Open Access   (Followers: 5)
Asian Journal of Biological Sciences     Open Access   (Followers: 3)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Developmental Biology     Open Access   (Followers: 2)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 2)
Asian Journal of Nematology     Open Access   (Followers: 3)
Asian Journal of Poultry Science     Open Access   (Followers: 4)
Australian Life Scientist     Full-text available via subscription   (Followers: 2)
Australian Mammalogy     Hybrid Journal   (Followers: 5)
Autophagy     Hybrid Journal   (Followers: 2)
Avian Biology Research     Full-text available via subscription   (Followers: 4)
Avian Conservation and Ecology     Open Access   (Followers: 11)
Bacteriology Journal     Open Access   (Followers: 2)
Bacteriophage     Full-text available via subscription   (Followers: 3)
Bangladesh Journal of Bioethics     Open Access  
Bangladesh Journal of Plant Taxonomy     Open Access  
Bangladesh Journal of Scientific Research     Open Access   (Followers: 1)
Berita Biologi     Open Access   (Followers: 1)
Between the Species     Open Access   (Followers: 1)
Bio Tribune Magazine     Hybrid Journal  
BIO Web of Conferences     Open Access  
BIO-Complexity     Open Access  
Bio-Grafía. Escritos sobre la Biología y su enseñanza     Open Access  
Bioanalytical Reviews     Hybrid Journal   (Followers: 2)
Biocatalysis and Biotransformation     Hybrid Journal   (Followers: 6)
Biochemistry and Cell Biology     Hybrid Journal   (Followers: 14)
Biochimie     Hybrid Journal   (Followers: 7)
BioControl     Hybrid Journal   (Followers: 5)
Biocontrol Science and Technology     Hybrid Journal   (Followers: 5)
Biodemography and Social Biology     Hybrid Journal   (Followers: 1)
Biodiversidad Colombia     Open Access  
Biodiversity : Research and Conservation     Open Access   (Followers: 26)
Biodiversity and Natural History     Open Access   (Followers: 5)
Biodiversity Data Journal     Open Access   (Followers: 3)
Biodiversity Informatics     Open Access  
Bioedukasi : Jurnal Pendidikan Biologi FKIP UM Metro     Open Access  
Bioeksperimen : Jurnal Penelitian Biologi     Open Access  
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Bioelectromagnetics     Hybrid Journal   (Followers: 1)
Bioenergy Research     Hybrid Journal   (Followers: 2)
Bioengineering and Bioscience     Open Access   (Followers: 1)
BioEssays     Hybrid Journal   (Followers: 10)
Bioethics     Hybrid Journal   (Followers: 14)
BioéthiqueOnline     Open Access  
Biofabrication     Hybrid Journal   (Followers: 3)
Biogeosciences (BG)     Open Access   (Followers: 10)
Biogeosciences Discussions (BGD)     Open Access   (Followers: 1)
Bioinformatics     Hybrid Journal   (Followers: 246)
Bioinformatics and Biology Insights     Open Access   (Followers: 15)
Bioinspiration & Biomimetics     Hybrid Journal   (Followers: 6)
Biointerphases     Open Access   (Followers: 1)
Biojournal of Science and Technology     Open Access  
Biologia     Hybrid Journal  
Biologia on-line : Revista de divulgació de la Facultat de Biologia     Open Access  
Biological Bulletin     Partially Free   (Followers: 4)
Biological Control     Hybrid Journal   (Followers: 5)
Biological Invasions     Hybrid Journal   (Followers: 16)
Biological Journal of the Linnean Society     Hybrid Journal   (Followers: 15)
Biological Letters     Open Access   (Followers: 4)
Biological Procedures Online     Open Access  
Biological Psychiatry     Hybrid Journal   (Followers: 42)
Biological Psychology     Hybrid Journal   (Followers: 6)
Biological Research     Open Access  
Biological Rhythm Research     Hybrid Journal   (Followers: 2)
Biological Theory     Hybrid Journal   (Followers: 1)
Biological Trace Element Research     Hybrid Journal  
Biologicals     Full-text available via subscription   (Followers: 9)
Biologics: Targets & Therapy     Open Access   (Followers: 1)
Biologie Aujourd'hui     Full-text available via subscription  
Biologie in Unserer Zeit (Biuz)     Hybrid Journal   (Followers: 42)
Biologija     Open Access  
Biology     Open Access   (Followers: 5)
Biology and Philosophy     Hybrid Journal   (Followers: 16)
Biology Bulletin     Hybrid Journal   (Followers: 1)
Biology Bulletin Reviews     Hybrid Journal  
Biology Direct     Open Access   (Followers: 7)
Biology Letters     Full-text available via subscription   (Followers: 35)
Biology Methods and Protocols     Hybrid Journal  

        1 2 3 4 5 6 7 8 | Last

Journal Cover Aging Cell
  [SJR: 4.374]   [H-I: 95]   [10 followers]  Follow
    
  This is an Open Access Journal Open Access journal
   ISSN (Print) 1474-9718 - ISSN (Online) 1474-9726
   Published by John Wiley and Sons Homepage  [1577 journals]
  • A multimethod computational simulation approach for investigating
           mitochondrial dynamics and dysfunction in degenerative aging

    • Authors: Timothy E. Hoffman; Katherine J. Barnett, Lyle Wallis, William H. Hanneman
      Abstract: Research in biogerontology has largely focused on the complex relationship between mitochondrial dysfunction and biological aging. In particular, the mitochondrial free radical theory of aging (MFRTA) has been well accepted. However, this theory has been challenged by recent studies showing minimal increases in reactive oxygen species (ROS) as not entirely deleterious in nature, and even beneficial under the appropriate cellular circumstances. To assess these significant and nonintuitive observations in the context of a functional system, we have taken an in silico approach to expand the focus of the MFRTA by including other key mitochondrial stress response pathways, as they have been observed in the nematode Caenorhabditis elegans. These include the mitochondrial unfolded protein response (UPRmt), mitochondrial biogenesis and autophagy dynamics, the relevant DAF-16 and SKN-1 axes, and NAD+-dependent deacetylase activities. To integrate these pathways, we have developed a multilevel hybrid-modeling paradigm, containing agent-based elements among stochastic system-dynamics environments of logically derived ordinary differential equations, to simulate aging mitochondrial phenotypes within a population of energetically demanding cells. The simulation experiments resulted in accurate predictions of physiological parameters over time that accompany normal aging, such as the declines in both NAD+ and ATP and an increase in ROS. Additionally, the in silico system was virtually perturbed using a variety of pharmacological (e.g., rapamycin, pterostilbene, paraquat) and genetic (e.g., skn-1, daf-16, sod-2) schemes to quantitate the temporal alterations of specific mechanistic targets, supporting insights into molecular determinants of aging as well as cytoprotective agents that may improve neurological or muscular healthspan.
      PubDate: 2017-08-16T03:00:55.573049-05:
      DOI: 10.1111/acel.12644
       
  • The valosin-containing protein is a novel repressor of cardiomyocyte
           hypertrophy induced by pressure overload

    • Authors: Ning Zhou; Ben Ma, Shaunrick Stoll, Tristan T. Hays, Hongyu Qiu
      Abstract: Hypertension-induced left ventricular hypertrophy (LVH) is an independent risk factor for heart failure. Regression of LVH has emerged as a major goal in the treatment of hypertensive patients. Here, we tested our hypothesis that the valosin-containing protein (VCP), an ATPase associate protein, is a novel repressor of cardiomyocyte hypertrophy under the pressure overload stress. Left ventricular hypertrophy (LVH) was determined by echocardiography in 4-month male spontaneously hypertensive rats (SHRs) vs. age-matched normotensive Wistar Kyoto (WKY) rats. VCP expression was found to be significantly downregulated in the left ventricle (LV) tissues from SHRs vs. WKY rats. Pressure overload was induced by transverse aortic constriction (TAC) in wild-type (WT) mice. At the end of 2 weeks, mice with TAC developed significant LVH whereas the cardiac function remained unchanged. A significant reduction of VCP at both the mRNA and protein levels in hypertrophic LV tissue was found in TAC WT mice compared to sham controls. Valosin-containing protein VCP expression was also observed to be time- and dose-dependently reduced in vitro in isolated neonatal rat cardiomyocytes upon the treatment of angiotensin II. Conversely, transgenic (TG) mice with cardiac-specific overexpression of VCP showed a significant repression in TAC-induced LVH vs. litter-matched WT controls upon 2-week TAC. TAC-induced activation of the mechanistic target of rapamycin complex 1 (mTORC1) signaling observed in WT mice LVs was also significantly blunted in VCP TG mice. In conclusion, VCP acts as a novel repressor that is able to prevent cardiomyocyte hypertrophy from pressure overload by modulating the mTORC1 signaling pathway.
      PubDate: 2017-08-11T03:21:48.585769-05:
      DOI: 10.1111/acel.12653
       
  • Opposing effects on cardiac function by calorie restriction in
           different-aged mice

    • Authors: Yunlu Sheng; Shan Lv, Min Huang, Yifan Lv, Jing Yu, Juan Liu, Tingting Tang, Hanmei Qi, Wenjuan Di, Guoxian Ding
      Abstract: Calorie restriction (CR) increases average and maximum lifespan and exhibits an apparent beneficial impact on age-related diseases. Several studies have shown that CR initiated either in middle or old age could improve ischemic tolerance and rejuvenate the aging heart; however, the data are not uniform when initiated in young. The accurate time to initiate CR providing maximum benefits for cardiac remodeling and function during aging remains unclear. Thus, whether a similar degree of CR initiated in mice of different ages could exert a similar effect on myocardial protection was investigated in this study. C57BL/6 mice were subjected to a calorically restricted diet (40% less than the ad libitum diet) for 3 months initiated in 3, 12, and 19 months. It was found that CR significantly reversed the aging phenotypes of middle-aged and old mice including cardiac remodeling (cardiomyocyte hypertrophy and cardiac fibrosis), inflammation, mitochondrial damage, telomere shortening, as well as senescence-associated markers but accelerated in young mice. Furthermore, whole-genome microarray demonstrated that the AMP-activated protein kinase (AMPK)–Forkhead box subgroup ‘O’ (FOXO) pathway might be a major contributor to contrasting regulation by CR initiated in different ages; thus, increased autophagy was seen in middle-aged and old mice but decreased in young mice. Together, the findings demonstrated promising myocardial protection by 40% CR should be initiated in middle or old age that may have vital implications for the practical nutritional regimen.
      PubDate: 2017-08-11T03:21:22.270866-05:
      DOI: 10.1111/acel.12652
       
  • Reduced expression of PMCA1 is associated with increased blood pressure
           with age which is preceded by remodelling of resistance arteries

    • Authors: Robert Little; Min Zi, Sally K. Hammad, Loan Nguyen, Alexandra Njegic, Sathishkumar Kurusamy, Sukhpal Prehar, Angel L. Armesilla, Ludwig Neyses, Clare Austin, Elizabeth J. Cartwright
      Abstract: Hypertension is a well-established risk factor for adverse cardiovascular events, and older age is a risk factor for the development of hypertension. Genomewide association studies have linked ATP2B1, the gene for the plasma membrane calcium ATPase 1 (PMCA1), to blood pressure (BP) and hypertension. Here, we present the effects of reduction in the expression of PMCA1 on BP and small artery structure and function when combined with advancing age. Heterozygous PMCA1 null mice (PMCA1Ht) were generated and conscious BP was measured at 6 to 18 months of age. Passive and active properties of isolated small mesenteric arteries were examined by pressure myography. PMCA1Ht mice exhibited normal BP at 6 and 9 months of age but developed significantly elevated BP when compared to age-matched wild-type controls at ≥12 months of age. Decreased lumen diameter, increased wall thickness and increased wall:lumen ratio were observed in small mesenteric arteries from animals 9 months of age and older, indicative of eutrophic remodelling. Increases in mesenteric artery intrinsic tone and global intracellular calcium were evident in animals at both 6 and 18 months of age. Thus, decreased expression of PMCA1 is associated with increased BP when combined with advancing age. Changes in arterial structure precede the elevation of BP. Pathways involving PMCA1 may be a novel target for BP regulation in the elderly.
      PubDate: 2017-08-09T23:07:32.991907-05:
      DOI: 10.1111/acel.12637
       
  • Autophagy in stem cell aging

    • Authors: Miren Revuelta; Ander Matheu
      Abstract: Aging is responsible for changes in mammalian tissues that result in an imbalance to tissue homeostasis and a decline in the regeneration capacity of organs due to stem cell exhaustion. Autophagy is a constitutive pathway necessary to degrade damaged organelles and protein aggregates. Autophagy is one of the hallmarks of aging, which involves a decline in the number and functionality of stem cells. Recent studies show that stem cells require autophagy to get rid of cellular waste produced during the quiescent stage. In particular, two independent studies in muscle and hematopoietic stem cells demonstrate the relevance of the autophagy impairment for stem cell exhaustion and aging. In this review, we summarize the main results of these works, which helped to elucidate the impact of autophagy in stem cell activity as well as in age-associated diseases.
      PubDate: 2017-08-07T04:25:20.582883-05:
      DOI: 10.1111/acel.12655
       
  • In vivo imaging reveals mitophagy independence in the maintenance of
           axonal mitochondria during normal aging

    • Authors: Xu Cao; Haiqiong Wang, Zhao Wang, Qingyao Wang, Shuang Zhang, Yuanping Deng, Yanshan Fang
      Abstract: Mitophagy is thought to be a critical mitochondrial quality control mechanism in neurons and has been extensively studied in neurological disorders such as Parkinson's disease. However, little is known about how mitochondria are maintained in the lengthy neuronal axons in the context of physiological aging. Here, we utilized the unique Drosophila wing nerve model and in vivo imaging to rigorously profile changes in axonal mitochondria during aging. We revealed that mitochondria became fragmented and accumulated in aged axons. However, lack of Pink1 or Parkin did not lead to the accumulation of axonal mitochondria or axonal degeneration. Further, unlike in in vitro cultured neurons, we found that mitophagy rarely occurred in intact axons in vivo, even in aged animals. Furthermore, blocking overall mitophagy by knockdown of the core autophagy genes Atg12 or Atg17 had little effect on the turnover of axonal mitochondria or axonal integrity, suggesting that mitophagy is not required for axonal maintenance; this is regardless of whether the mitophagy is PINK1-Parkin dependent or independent. In contrast, downregulation of mitochondrial fission–fusion genes caused age-dependent axonal degeneration. Moreover, Opa1 expression in the fly head was significantly decreased with age, which may underlie the accumulation of fragmented mitochondria in aged axons. Finally, we showed that adult-onset, neuronal downregulation of the fission–fusion, but not mitophagy genes, dramatically accelerated features of aging. We propose that axonal mitochondria are maintained independently of mitophagy and that mitophagy-independent mechanisms such as fission–fusion may be central to the maintenance of axonal mitochondria and neural integrity during normal aging.
      PubDate: 2017-08-07T04:21:02.075181-05:
      DOI: 10.1111/acel.12654
       
  • Dyrk1 inhibition improves Alzheimer's disease-like pathology

    • Authors: Caterina Branca; Darren M. Shaw, Ramona Belfiore, Vijay Gokhale, Arthur Y. Shaw, Christopher Foley, Breland Smith, Christopher Hulme, Travis Dunckley, Bessie Meechoovet, Antonella Caccamo, Salvatore Oddo
      Abstract: There is an urgent need for the development of new therapeutic strategies for Alzheimer's disease (AD). The dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD-like pathology developed by 3xTg-AD mice, a widely used animal model of AD. We dosed 10-month-old 3xTg-AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1-inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg-AD mice. These effects were associated with a reduction in amyloid-β (Aβ) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Aβ levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.
      PubDate: 2017-08-04T23:05:47.943226-05:
      DOI: 10.1111/acel.12648
       
  • HDAC3 negatively regulates spatial memory in a mouse model of Alzheimer's
           disease

    • Authors: Xiaolei Zhu; Sulei Wang, Linjie Yu, Jiali Jin, Xing Ye, Yi Liu, Yun Xu
      Abstract: The accumulation and deposition of beta-amyloid (Aβ) is a key neuropathological hallmark of Alzheimer's disease (AD). Histone deacetylases (HDACs) are promising therapeutic targets for the treatment of AD, while the specific HDAC isoforms associated with cognitive improvement are poorly understood. In this study, we investigate the role of HDAC3 in the pathogenesis of AD. Nuclear HDAC3 is significantly increased in the hippocampus of 6- and 9-month-old APPswe/PS1dE9 (APP/PS1) mice compared with that in age-matched wild-type C57BL/6 (B6) mice. Lentivirus -mediated inhibition or overexpression of HDAC3 was used in the hippocampus of APP/PS1 mice to investigate the role of HDAC3 in spatial memory, amyloid burden, dendritic spine density, glial activation and tau phosphorylation. Inhibition of HDAC3 in the hippocampus attenuates spatial memory deficits, as indicated in the Morris water maze test, and decreases amyloid plaque load and Aβ levels in the brains of APP/PS1 mice. Dendritic spine density is increased, while microglial activation is alleviated after HDAC3 inhibition in the hippocampus of 9-month-old APP/PS1 mice. Furthermore, HDAC3 overexpression in the hippocampus increases Aβ levels, activates microglia, and decreases dendritic spine density in 6-month-old APP/PS1 mice. In conclusion, our results indicate that HDAC3 negatively regulates spatial memory in APP/PS1 mice and HDAC3 inhibition might represent a potential therapy for the treatment of AD.
      PubDate: 2017-08-03T01:07:00.643617-05:
      DOI: 10.1111/acel.12642
       
  • The ω-3 fatty acid α-linolenic acid extends Caenorhabditis elegans
           lifespan via NHR-49/PPARα and oxidation to oxylipins

    • Authors: Wenbo Qi; Gloria E. Gutierrez, Xiaoli Gao, Hong Dixon, Joe A. McDonough, Ann M. Marini, Alfred L. Fisher
      Abstract: The dietary intake of ω-3 polyunsaturated fatty acids has been linked to a reduction in the incidence of aging-associated disease including cardiovascular disease and stroke. Additionally, long-lived Caenorhabditis elegans glp-1 germ line-less mutant animals show a number of changes in lipid metabolism including the increased production of the ω-3 fatty acid, α-linolenic acid (ALA). Here, we show that the treatment of C. elegans with ALA produces a dose-dependent increase in lifespan. The increased longevity of the glp-1 mutant animals is known to be dependent on both the NHR-49/PPARα and SKN-1/Nrf2 transcription factors, although the mechanisms involved are incompletely understood. We find that ALA treatment increased the lifespan of wild-type worms and that these effects required both of these transcription factors. Specifically, NHR-49 was activated by ALA to promote the expression of genes involved in the β-oxidation of lipids, whereas SKN-1 is not directly activated by ALA, but instead, the exposure of ALA to air results in the oxidation of ALA to a group of compounds termed oxylipins. At least one of the oxylipins activates SKN-1 and enhances the increased longevity resulting from ALA treatment. The results show that ω-3 fatty acids inhibit aging and that these effects could reflect the combined effects of the ω-3 fatty acid and the oxylipin metabolites. The benefits of ω-3 fatty acid consumption on human health may similarly involve the production of oxylipins, and differences in oxylipin conversion could account for at least part of the variability found between observational vs. interventional clinical trials.
      PubDate: 2017-08-03T01:02:59.23575-05:0
      DOI: 10.1111/acel.12651
       
  • Evidence for reduced neurogenesis in the aging human hippocampus despite
           stable stem cell markers

    • Authors: Kathryn J. Mathews; Katherine M. Allen, Danny Boerrigter, Helen Ball, Cynthia Shannon Weickert, Kay L. Double
      Abstract: Reduced neurogenesis in the aging mammalian hippocampus has been linked to cognitive deficits and increased risk of dementia. We utilized postmortem human hippocampal tissue from 26 subjects aged 18–88 years to investigate changes in expression of six genes representing different stages of neurogenesis across the healthy adult lifespan. Progressive and significant decreases in mRNA levels of the proliferation marker Ki67 (MKI67) and the immature neuronal marker doublecortin (DCX) were found in the healthy human hippocampus over the lifespan. In contrast, expression of genes for the stem cell marker glial fibrillary acidic protein delta and the neuronal progenitor marker eomesodermin was unchanged with age. These data are consistent with a persistence of the hippocampal stem cell population with age. Age-associated expression of the proliferation and immature neuron markers MKI67 and DCX, respectively, was unrelated, suggesting that neurogenesis-associated processes are independently altered at these points in the development from stem cell to neuron. These data are the first to demonstrate normal age-related decreases at specific stages of adult human hippocampal neurogenesis.
      PubDate: 2017-08-01T23:08:10.852462-05:
      DOI: 10.1111/acel.12641
       
  • The path from mitochondrial ROS to aging runs through the mitochondrial
           permeability transition pore

    • Authors: Hagai Rottenberg; Jan B. Hoek
      Abstract: Excessive production of mitochondrial reactive oxygen species (mROS) is strongly associated with mitochondrial and cellular oxidative damage, aging, and degenerative diseases. However, mROS also induces pathways of protection of mitochondria that slow aging, inhibit cell death, and increase lifespan. Recent studies show that the activation of the mitochondrial permeability transition pore (mPTP), which is triggered by mROS and mitochondrial calcium overloading, is enhanced in aged animals and humans and in aging-related degenerative diseases. mPTP opening initiates further production and release of mROS that damage both mitochondrial and nuclear DNA, proteins, and phospholipids, and also releases matrix NAD that is hydrolyzed in the intermembrane space, thus contributing to the depletion of cellular NAD that accelerates aging. Oxidative damage to calcium transporters leads to calcium overload and more frequent opening of mPTP. Because aging enhances the opening of the mPTP and mPTP opening accelerates aging, we suggest that mPTP opening drives the progression of aging. Activation of the mPTP is regulated, directly and indirectly, not only by the mitochondrial protection pathways that are induced by mROS, but also by pro-apoptotic signals that are induced by DNA damage. We suggest that the integration of these contrasting signals by the mPTP largely determines the rate of cell aging and the initiation of cell death, and thus animal lifespan. The suggestion that the control of mPTP activation is critical for the progression of aging can explain the conflicting and confusing evidence regarding the beneficial and deleterious effects of mROS on health and lifespan.
      PubDate: 2017-07-31T03:00:54.086459-05:
      DOI: 10.1111/acel.12650
       
  • Mitofusin 1 and optic atrophy 1 shift metabolism to mitochondrial
           respiration during aging

    • Authors: Jyung Mean Son; Ehab H. Sarsour, Anurag Kakkerla Balaraju, Jenna Fussell, Amanda L. Kalen, Brett A. Wagner, Garry R. Buettner, Prabhat C. Goswami
      Abstract: Replicative and chronological lifespan are two different modes of cellular aging. Chronological lifespan is defined as the duration during which quiescent normal cells retain their capacity to re-enter the proliferative cycle. This study investigated whether changes in metabolism occur during aging of quiescent normal human fibroblasts (NHFs) and the mechanisms that regulate these changes. Bioenergetics measurements were taken in quiescent NHFs from younger (newborn, 3-day, 5-month, and 1-year) and older (58-, 61-, 63-, 68-, and 70-year) healthy donors as well as NHFs from the same individual at different ages (29, 36, and 46 years). Results show significant changes in cellular metabolism during aging of quiescent NHFs: Old NHFs exhibit a significant decrease in glycolytic flux and lactate levels, and increase in oxygen consumption rate (OCR) and ATP levels compared to young NHFs. Results from the Seahorse XF Cell Mito Stress Test show that old NHFs with a lower Bioenergetic Health Index (BHI) are more prone to oxidative stress compared to young NHFs with a higher BHI. The increase in OCR in old NHFs is associated with a shift in mitochondrial dynamics more toward fusion. Genetic knockdown of mitofusin 1 (MFN1) and optic atrophy 1 (OPA1) in old NHFs decreased OCR and shifted metabolism more toward glycolysis. Downregulation of MFN1 and OPA1 also suppressed the radiation-induced increase in doubling time of NHFs. In summary, results show that a metabolic shift from glycolysis in young to mitochondrial respiration in old NHFs occurs during chronological lifespan, and MFN1 and OPA1 regulate this process.
      PubDate: 2017-07-31T02:45:31.982873-05:
      DOI: 10.1111/acel.12649
       
  • Combined deficiency of the Cnr1 and Cnr2 receptors protects against
           age-related bone loss by osteoclast inhibition

    • Authors: Antonia Sophocleous; Silvia Marino, Dilruba Kabir, Stuart H. Ralston, Aymen I. Idris
      Abstract: The endocannabinoid system plays a role in regulating bone mass and bone cell activity and inactivation of the type 1 (Cnr1) or type 2 (Cnr2) cannabinoid receptors influences peak bone mass and age-related bone loss. As the Cnr1 and Cnr2 receptors have limited homology and are activated by different ligands, we have evaluated the effects of combined deficiency of Cnr1 and 2 receptors (Cnr1/2−/−) on bone development from birth to old age and studied ovariectomy induced bone loss in female mice. The Cnr1/2−/− mice had accelerated bone accrual at birth when compared with wild type littermates, and by 3 months of age, they had higher trabecular bone mass. They were also significantly protected against ovariectomy-induced bone loss due to a reduction in osteoclast number. The Cnr1/2−/− mice had reduced age-related bone loss when compared with wild-type due to a reduction in osteoclast number. Although bone formation was reduced and bone marrow adiposity increased in Cnr1/2−/− mice, the osteoclast defect outweighed the reduction in bone formation causing preservation of bone mass with aging. This contrasts with the situation previously reported in mice with inactivation of the Cnr1 or Cnr2 receptors individually where aged-related bone loss was greater than in wild-type. We conclude that the Cnr1 and Cnr2 receptors have overlapping but nonredundant roles in regulating osteoclast and osteoblast activities. These observations indicate that combined inhibition of Cnr1 and Cnr2 receptors may be beneficial in preventing age-related bone loss, whereas blockade of individual receptors may be detrimental.
      PubDate: 2017-07-28T03:22:17.898405-05:
      DOI: 10.1111/acel.12638
       
  • Serpine 1 induces alveolar type II cell senescence through activating
           p53-p21-Rb pathway in fibrotic lung disease

    • Authors: Chunsun Jiang; Gang Liu, Tracy Luckhardt, Veena Antony, Yong Zhou, A. Brent Carter, Victor J. Thannickal, Rui-Ming Liu
      Abstract: Senescence of alveolar type 2 (ATII) cells, progenitors of the alveolar epithelium, is implicated in the pathogeneses of idiopathic pulmonary fibrosis (IPF), an aging-related progressive fatal lung disorder with unknown etiology. The mechanism underlying ATII cell senescence in fibrotic lung diseases, however, remains poorly understood. In this study, we report that ATII cells in IPF lungs express higher levels of serpine 1, also known as plasminogen activator inhibitor 1 (PAI-1), and cell senescence markers p21 and p16, compared to ATII cells in control lungs. Silencing PAI-1 or inhibition of PAI-1 activity in cultured rat ATII (L2) cells leads to decreases in p53 serine 18 phosphorylation (p53S18P), p53 and p21 protein expressions; an increase in retinoblastoma protein phosphorylation (ppRb); and a reduction in the sensitivity to bleomycin- and doxorubicin-induced senescence. Silencing p53, on the other hand, abrogates PAI-1 protein-stimulated p21 expression and cell senescence. In vivo studies, using ATII cell-specific PAI-1 conditional knockout mouse model generated recently in this laboratory, further support the role of PAI-1 in the activation of p53-p21-Rb cell cycle repression pathway, ATII cell senescence, and lung fibrosis induced by bleomycin. This study reveals a novel function of PAI-1 in regulation of cell cycle and suggests that elevation of PAI-1 contributes importantly to ATII cell senescence in fibrotic lung diseases.
      PubDate: 2017-07-19T01:47:16.134657-05:
      DOI: 10.1111/acel.12643
       
  • Nrf2 as a target for prevention of age-related and diabetic cataracts by
           against oxidative stress

    • Authors: Xiu-Fen Liu; Ji-Long Hao, Tian Xie, Tayyab Hamid Malik, Cheng-Bo Lu, Cong Liu, Chang Shu, Cheng-Wei Lu, Dan-Dan Zhou
      Abstract: Cataract is one of the most important causes of blindness worldwide, with age-related cataract being the most common one. Agents preventing cataract formation are urgently required. Substantial evidences point out aggravated oxidative stress as a vital factor for cataract formation. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Kelch-like erythroid-cell-derived protein with CNC homology (ECH)-associated protein 1 (Keap1) system is considered as one of the main cellular defense mechanisms against oxidative stresses. This review discusses the role of Nrf2 pathway in the prevention of cataracts and highlights that Nrf2 suppressors may augment oxidative stress of the lens, and Nrf2 inducers may decrease the oxidative stress and prevent the cataract formation. Thus, Nrf2 may serve as a promising therapeutic target for cataract treatment.
      PubDate: 2017-07-19T01:10:39.465703-05:
      DOI: 10.1111/acel.12645
       
  • FOXO3 longevity interactome on chromosome 6

    • Authors: Timothy A. Donlon; Brian J. Morris, Randi Chen, Kamal H. Masaki, Richard C. Allsopp, D. Craig Willcox, Ayako Elliott, Bradley J. Willcox
      Abstract: FOXO3 has been implicated in longevity in multiple populations. By DNA sequencing in long-lived individuals, we identified all single nucleotide polymorphisms (SNPs) in FOXO3 and showed 41 were associated with longevity. Thirteen of these had predicted alterations in transcription factor binding sites. Those SNPs appeared to be in physical contact, via RNA polymerase II binding chromatin looping, with sites in the FOXO3 promoter, and likely function together as a cis-regulatory unit. The SNPs exhibited a high degree of LD in the Asian population, in which they define a specific longevity haplotype that is relatively common. The haplotype was less frequent in whites and virtually nonexistent in Africans. We identified distant contact points between FOXO3 and 46 neighboring genes, through long-range physical contacts via CCCTC-binding factor zinc finger protein (CTCF) binding sites, over a 7.3 Mb distance on chromosome 6q21. When activated by cellular stress, we visualized movement of FOXO3 toward neighboring genes. FOXO3 resides at the center of this early-replicating and highly conserved syntenic region of chromosome 6. Thus, in addition to its role as a transcription factor regulating gene expression genomewide, FOXO3 may function at the genomic level to help regulate neighboring genes by virtue of its central location in chromatin conformation via topologically associated domains. We believe that the FOXO3 ‘interactome’ on chromosome 6 is a chromatin domain that defines an aging hub. A more thorough understanding of the functions of these neighboring genes may help elucidate the mechanisms through which FOXO3 variants promote longevity and healthy aging.
      PubDate: 2017-07-19T01:02:17.671811-05:
      DOI: 10.1111/acel.12625
       
  • Translation fidelity coevolves with longevity

    • Authors: Zhonghe Ke; Pramit Mallik, Adam B. Johnson, Facundo Luna, Eviatar Nevo, Zhengdong D. Zhang, Vadim N. Gladyshev, Andrei Seluanov, Vera Gorbunova
      Abstract: Whether errors in protein synthesis play a role in aging has been a subject of intense debate. It has been suggested that rare mistakes in protein synthesis in young organisms may result in errors in the protein synthesis machinery, eventually leading to an increasing cascade of errors as organisms age. Studies that followed generally failed to identify a dramatic increase in translation errors with aging. However, whether translation fidelity plays a role in aging remained an open question. To address this issue, we examined the relationship between translation fidelity and maximum lifespan across 17 rodent species with diverse lifespans. To measure translation fidelity, we utilized sensitive luciferase-based reporter constructs with mutations in an amino acid residue critical to luciferase activity, wherein misincorporation of amino acids at this mutated codon re-activated the luciferase. The frequency of amino acid misincorporation at the first and second codon positions showed strong negative correlation with maximum lifespan. This correlation remained significant after phylogenetic correction, indicating that translation fidelity coevolves with longevity. These results give new life to the role of protein synthesis errors in aging: Although the error rate may not significantly change with age, the basal rate of translation errors is important in defining lifespan across mammals.
      PubDate: 2017-07-13T23:05:33.625806-05:
      DOI: 10.1111/acel.12628
       
  • The emerging role of alternative splicing in senescence and aging

    • Authors: Mathieu Deschênes; Benoit Chabot
      Abstract: Deregulation of precursor mRNA splicing is associated with many illnesses and has been linked to age-related chronic diseases. Here we review recent progress documenting how defects in the machinery that performs intron removal and controls splice site selection contribute to cellular senescence and organismal aging. We discuss the functional association linking p53, IGF-1, SIRT1, and ING-1 splice variants with senescence and aging, and review a selection of splicing defects occurring in accelerated aging (progeria), vascular aging, and Alzheimer's disease. Overall, it is becoming increasingly clear that changes in the activity of splicing factors and in the production of key splice variants can impact cellular senescence and the aging phenotype.
      PubDate: 2017-07-13T04:26:54.119195-05:
      DOI: 10.1111/acel.12646
       
  • Analysis of individual cells identifies cell-to-cell variability following
           induction of cellular senescence

    • Authors: Christopher D. Wiley; James M. Flynn, Christapher Morrissey, Ronald Lebofsky, Joe Shuga, Xiao Dong, Marc A. Unger, Jan Vijg, Simon Melov, Judith Campisi
      Abstract: Senescent cells play important roles in both physiological and pathological processes, including cancer and aging. In all cases, however, senescent cells comprise only a small fraction of tissues. Senescent phenotypes have been studied largely in relatively homogeneous populations of cultured cells. In vivo, senescent cells are generally identified by a small number of markers, but whether and how these markers vary among individual cells is unknown. We therefore utilized a combination of single-cell isolation and a nanofluidic PCR platform to determine the contributions of individual cells to the overall gene expression profile of senescent human fibroblast populations. Individual senescent cells were surprisingly heterogeneous in their gene expression signatures. This cell-to-cell variability resulted in a loss of correlation among the expression of several senescence-associated genes. Many genes encoding senescence-associated secretory phenotype (SASP) factors, a major contributor to the effects of senescent cells in vivo, showed marked variability with a subset of highly induced genes accounting for the increases observed at the population level. Inflammatory genes in clustered genomic loci showed a greater correlation with senescence compared to nonclustered loci, suggesting that these genes are coregulated by genomic location. Together, these data offer new insights into how genes are regulated in senescent cells and suggest that single markers are inadequate to identify senescent cells in vivo.
      PubDate: 2017-07-11T23:06:07.370995-05:
      DOI: 10.1111/acel.12632
       
  • Cooperation between p21 and Akt is required for p53-dependent cellular
           senescence

    • Authors: Young Yeon Kim; Hye Jin Jee, Jee-Hyun Um, Young Mi Kim, Sun Sik Bae, Jeanho Yun
      Abstract: Cellular senescence has been implicated in normal aging, tissue homeostasis, and tumor suppression. Although p53 has been shown to be a central mediator of cellular senescence, the signaling pathway by which it induces senescence remains incompletely understood. In this study, we have shown that both Akt and p21 are required to induce cellular senescence in response to p53 expression. In a p53-induced senescence model, we found that Akt activation was essential for inducing a cellular senescence phenotype. Surprisingly, Akt inhibition did not abolish p53-induced cell cycle arrest, but it suppressed the increase in intracellular reactive oxygen species (ROS) levels. The results of the cell cycle and morphological analysis suggest that p53 induced quiescence, not senescence, following Akt inhibition. Conversely, the inhibition of p21 induction abolished cell cycle arrest but did not affect the p53-induced increase in ROS levels. Additionally, p21 and Akt separately controlled cell cycle arrest and ROS levels, respectively, during H-Ras-induced senescence in human normal fibroblasts. The mechanistic analysis revealed that Akt increased ROS levels through NOX4 induction, and increased Akt-dependent NF-κB binding to the NOX4 promoter is responsible for NOX4 induction upon p53 expression. We further showed that Akt activation upon p53 expression is mediated by mammalian target of rapamycin complex 2. In addition, p53-mediated IL6 and IL8 induction was abrogated by Akt inhibition, suggesting that Akt activation is also required for the senescence-associated secretory phenotype. Collectively, these results suggest that p53 simultaneously controls multiple pathways to induce cellular senescence through p21 and Akt.
      PubDate: 2017-07-09T21:35:33.018543-05:
      DOI: 10.1111/acel.12639
       
  • Akt2 ablation prolongs life span and improves myocardial contractile
           function with adaptive cardiac remodeling: role of Sirt1-mediated
           autophagy regulation

    • Authors: Jun Ren; Lifang Yang, Li Zhu, Xihui Xu, Asli F. Ceylan, Wei Guo, Jian Yang, Yingmei Zhang
      Abstract: Aging is accompanied with unfavorable geometric and functional changes in the heart involving dysregulation of Akt and autophagy. This study examined the impact of Akt2 ablation on life span and cardiac aging as well as the mechanisms involved with a focus on autophagy and mitochondrial integrity. Cardiac geometry, contractile, and intracellular Ca2+ properties were evaluated using echocardiography, IonOptix® edge-detection and fura-2 techniques. Levels of Sirt1, mitochondrial integrity, autophagy, and mitophagy markers were evaluated using Western blot. Our results revealed that Akt2 ablation prolonged life span (by 9.1%) and alleviated aging (24 months)-induced unfavorable changes in myocardial function and intracellular Ca2+ handling (SERCA2a oxidation) albeit with more pronounced cardiac hypertrophy (58.1%, 47.8%, and 14.5% rises in heart weight, wall thickness, and cardiomyocyte cross-sectional area). Aging downregulated levels of Sirt1, increased phosphorylation of Akt, and the nuclear transcriptional factor Foxo1, as well as facilitated acetylation of Foxo1, the effects of which (except Sirt1 and Foxo1 acetylation) were significantly attenuated or negated by Akt2 ablation. Advanced aging disturbed autophagy, mitophagy, and mitochondrial integrity as evidenced by increased p62, decreased levels of beclin-1, Atg7, LC3B, BNIP3, PTEN-induced putative kinase 1 (PINK1), Parkin, UCP-2, PGC-1α, and aconitase activity, the effects of which were reversed by Akt2 ablation. Aging-induced cardiomyocyte contractile dysfunction and loss of mitophagy were improved by rapamycin and the Sirt1 activator SRT1720. Activation of Akt using insulin or Parkin deficiency prevented SRT1720-induced beneficial effects against aging. In conclusion, our data indicate that Akt2 ablation protects against cardiac aging through restored Foxo1-related autophagy and mitochondrial integrity.
      PubDate: 2017-07-05T23:07:16.823263-05:
      DOI: 10.1111/acel.12616
       
  • Caloric restriction impacts plasma microRNAs in rhesus monkeys

    • Authors: Augusto Schneider; Joseph M. Dhahbi, Hani Atamna, Josef P. Clark, Ricki J. Colman, Rozalyn M. Anderson
      Abstract: Caloric restriction (CR) is one of the most robust interventions shown to delay aging in diverse species, including rhesus monkeys (Macaca mulatta). Identification of factors involved in CR brings a promise of translatability to human health and aging. Here, we show that CR induced a profound change in abundance of circulating microRNAs (miRNAs) linked to growth and insulin signaling pathway, suggesting that miRNAs are involved in CR's mechanisms of action in primates. Deep sequencing of plasma RNA extracts enriched for short species revealed a total of 243 unique species of miRNAs including 47 novel species. Approximately 70% of the plasma miRNAs detected were conserved between rhesus monkeys and humans. CR induced or repressed 24 known and 10 novel miRNA species. Regression analysis revealed correlations between bodyweight, adiposity, and insulin sensitivity for 10 of the CR-regulated known miRNAs. Sequence alignment and target identification for these 10 miRNAs identify a role in signaling downstream of the insulin receptor. The highly abundant miR-125a-5p correlated positively with adiposity and negatively with insulin sensitivity and was negatively regulated by CR. Putative target pathways of CR-associated miRNAs were highly enriched for growth and insulin signaling that have previously been implicated in delayed aging. Clustering analysis further pointed to CR-induced miRNA regulation of ribosomal, mitochondrial, and spliceosomal pathways. These data are consistent with a model where CR recruits miRNA-based homeostatic mechanisms to coordinate a program of delayed aging.
      PubDate: 2017-07-05T01:00:30.643652-05:
      DOI: 10.1111/acel.12636
       
  • Anti-aging pharmacology in cutaneous wound healing: effects of metformin,
           resveratrol, and rapamycin by local application

    • Authors: Pan Zhao; Bing-Dong Sui, Nu Liu, Ya-Jie Lv, Chen-Xi Zheng, Yong-Bo Lu, Wen-Tao Huang, Cui-Hong Zhou, Ji Chen, Dan-Lin Pang, Dong-Dong Fei, Kun Xuan, Cheng-Hu Hu, Yan Jin
      Abstract: Cutaneous wounds are among the most common soft tissue injuries and are particularly hard to heal in aging. Caloric restriction (CR) is well documented to extend longevity; pharmacologically, profound rejuvenative effects of CR mimetics have been uncovered, especially metformin (MET), resveratrol (RSV), and rapamycin (RAPA). However, locally applied impacts and functional differences of these agents on wound healing remain to be established. Here, we discovered that chronic topical administration of MET and RSV, but not RAPA, accelerated wound healing with improved epidermis, hair follicles, and collagen deposition in young rodents, and MET exerted more profound effects. Furthermore, locally applied MET and RSV improved vascularization of the wound beds, which were attributed to stimulation of adenosine monophosphate-activated protein kinase (AMPK) pathway, the key mediator of wound healing. Notably, in aged skin, AMPK pathway was inhibited, correlated with impaired vasculature and reduced healing ability. As therapeutic approaches, local treatments of MET and RSV prevented age-related AMPK suppression and angiogenic inhibition in wound beds. Moreover, in aged rats, rejuvenative effects of topically applied MET and RSV on cell viability of wound beds were confirmed, of which MET showed more prominent anti-aging effects. We further verified that only MET promoted wound healing and cutaneous integrity in aged skin. These findings clarified differential effects of CR-based anti-aging pharmacology in wound healing, identified critical angiogenic and rejuvenative mechanisms through AMPK pathway in both young and aged skin, and unraveled chronic local application of MET as the optimal and promising regenerative agent in treating cutaneous wound defects.
      PubDate: 2017-07-05T00:51:17.224549-05:
      DOI: 10.1111/acel.12635
       
  • Epigenetic regulation by G9a/GLP complex ameliorates amyloid-beta 1-42
           induced deficits in long-term plasticity and synaptic tagging/capture in
           hippocampal pyramidal neurons

    • Authors: Mahima Sharma; Tobias Dierkes, Sreedharan Sajikumar
      Abstract: Altered epigenetic mechanisms are implicated in the cognitive decline associated with neurodegenerative diseases such as in Alzheimer's disease (AD). AD is the most prevalent form of dementia worldwide; amyloid plaques and neurofibrillary tangles are the histopathological hallmarks of AD. We have recently reported that the inhibition of G9a/GLP complex promotes long-term potentiation (LTP) and its associative mechanisms such as synaptic tagging and capture (STC). However, the role of this complex in plasticity impairments remains elusive. Here, we investigated the involvement of G9a/GLP complex in alleviating the effects of soluble Amyloid-β 1-42 oligomers (oAβ) on neuronal plasticity and associativity in the CA1 region of acute hippocampal slices from 5- to 7-week-old male Wistar rats. Our findings demonstrate that the regulation of G9a/GLP complex by inhibiting its catalytic activity reverses the amyloid-β oligomer-induced deficits in late-LTP and STC. This is achieved by releasing the transcription repression of the brain-derived neurotrophic factor (Bdnf) gene. The catalytic inhibition of G9a/GLP complex leads to the upregulation of Bdnf expression in the slices treated with oAβ. This further ensures the availability of BDNF that subsequently binds its receptor tyrosine kinase B (TrkB) and maintains the late-LTP. Furthermore, the capture of BDNF by weakly activated synapses re-establishes STC. Our findings regarding the reinstatement of functional plasticity and associativity in AD-like conditions provide the first evidence for the role of G9a/GLP complex in AD. We propose G9a/GLP complex as the possible target for preventing oAβ-induced plasticity deficits in hippocampal neurons.
      PubDate: 2017-06-30T05:25:39.558285-05:
      DOI: 10.1111/acel.12634
       
  • Small RNAs induce the activation of the pro-inflammatory TLR7 signaling
           pathway in aged rat kidney

    • Authors: Eun Kyeong Lee; Ki Wung Chung, Ye Ra Kim, Sugyeong Ha, Sung Dae Kim, Dae Hyun Kim, Kyung Jin Jung, Bonggi Lee, Eunok Im, Byung Pal Yu, Hae Young Chung
      Abstract: We have recently reported that TLR-related genes, including TLR7, are upregulated during aging. However, the role of TLR7 and its endogenous ligand in inflammation related to aging is not well defined. Here, we established that small RNAs trigger age-related renal inflammation via TLR7 signaling pathway. We first investigated the expression changes of nine different TLRs in kidney of 6-month-old young rats and 20-month-old aged rats. The results revealed that the expression of TLR7 was the highest among nine TLRs in kidney of old rats compared to the young aged rats. Next, to assess the role of cellular RNA as a TLR7 ligand, we treated a renal tubular epithelial cell line with total RNA isolated from the kidney of young and old rats. The results showed that RNA isolated from old rats showed higher expression of TLR7, IL1β, and TNFα compared to that from young rats. Furthermore, RNA isolated from old rats induced IKKα/β/JNK/NF-κB activation. To identify RNA that activates TLR7, we isolated small and large RNAs from old rat kidney and found that small RNAs increased TLR7 expression in cells. Finally, to investigate the local inflammatory response by small RNA, C57B/L6 mice were intraperitoneally injected with small RNAs isolated from young and old rats; thereby, RNA isolated from old rats induced higher inflammatory responses. Our study demonstrates that renal small RNAs from aged rats induce pro-inflammatory processes via the activation of the TLR7/IKKα/β/JNK/NF-κB signaling pathway, and highlights its causative role as a possible therapeutic target in age-related chronic renal inflammation.
      PubDate: 2017-06-30T05:06:04.626576-05:
      DOI: 10.1111/acel.12629
       
  • The Piwi-piRNA pathway: road to immortality

    • Authors: Ádám Sturm; András Perczel, Zoltán Ivics, Tibor Vellai
      Abstract: Despite its medical, social, and economic significance, understanding what primarily causes aging, that is, the mechanisms of the aging process, remains a fundamental and fascinating problem in biology. Accumulating evidence indicates that a small RNA-based gene regulatory machinery, the Piwi-piRNA pathway, represents a shared feature of nonaging (potentially immortal) biological systems, including the germline, somatic cancer stem cells, and certain ‘lower’ eukaryotic organisms like the planarian flatworm and freshwater hydra. The pathway primarily functions to repress the activity of mobile genetic elements, also called transposable elements (TEs) or ‘jumping genes’, which are capable of moving from one genomic locus to another, thereby causing insertional mutations. TEs become increasingly active and multiply in the genomes of somatic cells as the organism ages. These characteristics of TEs highlight their decisive mutagenic role in the progressive disintegration of genetic information, a molecular hallmark associated with aging. Hence, TE-mediated genomic instability may substantially contribute to the aging process.
      PubDate: 2017-06-27T04:12:37.666252-05:
      DOI: 10.1111/acel.12630
       
  • Methylation of the ribosomal RNA gene promoter is associated with aging
           and age-related decline

    • Authors: Patrizia D'Aquila; Alberto Montesanto, Maurizio Mandalà, Sabrina Garasto, Vincenzo Mari, Andrea Corsonello, Dina Bellizzi, Giuseppe Passarino
      Abstract: The transcription of ribosomal RNA genes (rDNA) is subject to epigenetic regulation, as it is abrogated by the methylation of CpG dinucleotides within their promoter region. Here, we investigated, through Sequenom platform, the age-related methylation status of the CpG island falling into the rDNA promoter in 472 blood samples from 20- to 105-year-old humans and in different tissues (blood, heart, liver, kidney, and testis) of 15 rats 3–96 weeks old. In humans, we did not find a consistently significant correlation between CpG site methylation and chronological age. Furthermore, the methylation levels of one of the analyzed CpG sites were negatively associated with both cognitive performance and survival chance measured in a 9-year follow-up study. We consistently confirmed such result in a replication sample. In rats, the analysis of the homologous region in the tissues revealed the existence of increased methylation in old rats. rRNA expression data, in both humans and rats, were consistent with observed methylation patterns, with a lower expression of rRNA in highly methylated samples. As chronological and biological ages in rats of a given strain are likely to be much closer to each other than in humans, these results seem to provide the first evidence that epigenetic modifications of rDNA change over time according to the aging decline. Thus, the methylation profile of rDNA may represent a potential biomarker of aging.
      PubDate: 2017-06-17T23:05:39.780868-05:
      DOI: 10.1111/acel.12603
       
  • Drug repurposing for aging research using model organisms

    • Authors: Matthias Ziehm; Satwant Kaur, Dobril K. Ivanov, Pedro J. Ballester, David Marcus, Linda Partridge, Janet M. Thornton
      Abstract: Many increasingly prevalent diseases share a common risk factor: age. However, little is known about pharmaceutical interventions against aging, despite many genes and pathways shown to be important in the aging process and numerous studies demonstrating that genetic interventions can lead to a healthier aging phenotype. An important challenge is to assess the potential to repurpose existing drugs for initial testing on model organisms, where such experiments are possible. To this end, we present a new approach to rank drug-like compounds with known mammalian targets according to their likelihood to modulate aging in the invertebrates Caenorhabditis elegans and Drosophila. Our approach combines information on genetic effects on aging, orthology relationships and sequence conservation, 3D protein structures, drug binding and bioavailability. Overall, we rank 743 different drug-like compounds for their likelihood to modulate aging. We provide various lines of evidence for the successful enrichment of our ranking for compounds modulating aging, despite sparse public data suitable for validation. The top ranked compounds are thus prime candidates for in vivo testing of their effects on lifespan in C. elegans or Drosophila. As such, these compounds are promising as research tools and ultimately a step towards identifying drugs for a healthier human aging.
      PubDate: 2017-06-16T03:10:31.565446-05:
      DOI: 10.1111/acel.12626
       
  • TORC1-mediated sensing of chaperone activity alters glucose metabolism and
           extends lifespan

    • Authors: Matea Perić; Anita Lovrić, Ana Šarić, Marina Musa, Peter Bou Dib, Marina Rudan, Andrea Nikolić, Sandra Sobočanec, Ana-Matea Mikecin, Sven Dennerlein, Ira Milošević, Kristian Vlahoviček, Nuno Raimundo, Anita Kriško
      Abstract: Protein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activity and consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age-related diseases.
      PubDate: 2017-06-14T04:36:02.593499-05:
      DOI: 10.1111/acel.12623
       
  • Transcriptional coactivator with PDZ-binding motif is required to sustain
           testicular function on aging

    • Authors: Mi Gyeong Jeong; Hyuna Song, Ji Hyun Shin, Hana Jeong, Hyo Kyeong Kim, Eun Sook Hwang
      Abstract: Transcriptional coactivator with PDZ-binding motif (TAZ) directly interacts with transcription factors and regulates their transcriptional activity. Extensive functional studies have shown that TAZ plays critical regulatory roles in stem cell proliferation, differentiation, and survival and also modulates the development of organs such as the lung, kidney, heart, and bone. Despite the importance of TAZ in stem cell maintenance, TAZ function has not yet been evaluated in spermatogenic stem cells of the male reproductive system. Here, we investigated the expression and functions of TAZ in mouse testis. TAZ was expressed in spermatogenic stem cells; however, its deficiency caused significant structural abnormalities, including atrophied tubules, widened interstitial space, and abnormal Leydig cell expansion, thereby resulting in lowered sperm counts and impaired fertility. Furthermore, TAZ deficiency increased the level of apoptosis and senescence in spermatogenic cells and Leydig cells upon aging. The expression of senescence-associated β-galactosidase (SA-βgal), secretory phenotypes, and cyclin-dependent kinase inhibitors (p16, p19, and p21) significantly increased in the absence of TAZ. TAZ downregulation in testicular cells further increased SA-βgal and p21 expression induced by oxidative stress, whereas TAZ overexpression decreased p21 induction and prevented senescence. Mechanistic studies showed that TAZ suppressed DNA-binding activity of p53 through a direct interaction and thus attenuated p53-induced p21 gene transcription. Our results suggested that TAZ may suppress apoptosis and premature senescence in spermatogenic cells by inhibiting the p53-p21 signaling pathway, thus playing important roles in the maintenance and control of reproductive function.
      PubDate: 2017-06-14T04:31:51.14111-05:0
      DOI: 10.1111/acel.12631
       
  • The SKN-1/Nrf2 transcription factor can protect against oxidative stress
           and increase lifespan in C. elegans by distinct mechanisms

    • Authors: Jennifer M.A. Tullet; James W. Green, Catherine Au, Alexandre Benedetto, Maximillian A. Thompson, Emily Clark, Ann F. Gilliat, Adelaide Young, Kathrin Schmeisser, David Gems
      Abstract: In C. elegans, the skn-1 gene encodes a transcription factor that resembles mammalian Nrf2 and activates a detoxification response. skn-1 promotes resistance to oxidative stress (Oxr) and also increases lifespan, and it has been suggested that the former causes the latter, consistent with the theory that oxidative damage causes aging. Here, we report that effects of SKN-1 on Oxr and longevity can be dissociated. We also establish that skn-1 expression can be activated by the DAF-16/FoxO transcription factor, another central regulator of growth, metabolism, and aging. Notably, skn-1 is required for Oxr but not increased lifespan resulting from over-expression of DAF-16; concomitantly, DAF-16 over-expression rescues the short lifespan of skn-1 mutants but not their hypersensitivity to oxidative stress. These results suggest that SKN-1 promotes longevity by a mechanism other than protection against oxidative damage.
      PubDate: 2017-06-14T04:31:34.998074-05:
      DOI: 10.1111/acel.12627
       
  • HIV and drug abuse mediate astrocyte senescence in a β-catenin-dependent
           manner leading to neuronal toxicity

    • Authors: Chunjiang Yu; Srinivas D. Narasipura, Maureen H. Richards, Xiu-Ti Hu, Bryan Yamamoto, Lena Al-Harthi
      Abstract: Emerging evidence suggests that cell senescence plays an important role in aging-associated diseases including neurodegenerative diseases. HIV leads to a spectrum of neurologic diseases collectively termed HIV-associated neurocognitive disorders (HAND). Drug abuse, particularly methamphetamine (meth), is a frequently abused psychostimulant among HIV+ individuals and its abuse exacerbates HAND. The mechanism by which HIV and meth lead to brain cell dysregulation is not entirely clear. In this study, we evaluated the impact of HIV and meth on astrocyte senescence using in vitro and several animal models. Astrocytes constitute up to 50% of brain cells and play a pivotal role in marinating brain homeostasis. We show here that HIV and meth induce significant senescence of primary human fetal astrocytes, as evaluated by induction of senescence markers (β-galactosidase and p16INK4A), senescence-associated morphologic changes, and cell cycle arrest. HIV- and meth-mediated astrocyte senescence was also demonstrated in three small animal models (humanized mouse model of HIV/NSG-huPBMCs, HIV-transgenic rats, and in a meth administration rat model). Senescent astrocytes in turn mediated neuronal toxicity. Further, we show that β-catenin, a pro-survival/proliferation transcriptional co-activator, is downregulated by HIV and meth in human astrocytes and this downregulation promotes astrocyte senescence while induction of β-catenin blocks HIV- and meth-mediated astrocyte senescence. These studies, for the first time, demonstrate that HIV and meth induce astrocyte senescence and implicate the β-catenin pathway as potential therapeutic target to overcome astrocyte senescence.
      PubDate: 2017-06-13T23:07:25.855523-05:
      DOI: 10.1111/acel.12593
       
  • Inducible knockdown of pregnancy-associated plasma protein-A gene
           expression in adult female mice extends life span

    • Authors: Laurie K. Bale; Sally A. West, Cheryl A. Conover
      Abstract: Pregnancy-associated plasma protein-A (PAPP-A) knockout (KO) mice, generated through homologous recombination in embryonic stem cells, have a significantly increased lifespan compared to wild-type littermates. However, it is unknown whether this longevity advantage would pertain to PAPP-A gene deletion in adult animals. In the present study, we used tamoxifen (Tam)-inducible Cre recombinase-mediated excision of the floxed PAPP-A (fPAPP-A) gene in mice at 5 months of age. fPAPP-A mice, which were either positive (pos) or negative (neg) for Tam-Cre, received Tam treatment with quarterly boosters. Only female mice could be used with this experimental design. fPAPP-A/neg and fPAPP-A/pos mice had similar weights at the start of the experiment and showed equivalent weight gain. We found that fPAPP-A/pos mice had a significant extension of life span (P = 0.005). The median life span was increased by 21% for fPAPP-A/pos compared to fPAPP-A/neg mice. Analysis of mortality in life span quartiles indicated that the proportion of deaths of fPAPP-A/pos mice were lower than fPAPP-A/neg mice at young adult ages (P = 0.002 for 601–800 days) and higher than fPAPP-A/neg mice at older ages (P = 0.004 for>1000 days). Thus, survival curves and age-specific mortality indicate that female mice with knockdown of PAPP-A gene expression as adults have an extended healthy life span.
      PubDate: 2017-06-09T23:05:25.615213-05:
      DOI: 10.1111/acel.12624
       
  • Cross-sectional relations of whole-blood miRNA expression levels and hand
           grip strength in a community sample

    • Authors: Joanne M. Murabito; Jian Rong, Kathryn L. Lunetta, Tianxiao Huan, Honghuang Lin, Qiang Zhao, Jane E. Freedman, Kahraman Tanriverdi, Daniel Levy, Martin G. Larson
      Abstract: MicroRNAs (miRNAs) regulate gene expression with emerging data suggesting miRNAs play a role in skeletal muscle biology. We sought to examine the association of miRNAs with grip strength in a community-based sample. Framingham Heart Study Offspring and Generation 3 participants (n = 5668 54% women, mean age 55 years, range 24, 90 years) underwent grip strength measurement and miRNA profiling using whole blood from fasting morning samples. Linear mixed-effects regression modeling of grip strength (kg) versus continuous miRNA ‘Cq’ values and versus binary miRNA expression was performed. We conducted an integrative miRNA–mRNA coexpression analysis and examined the enrichment of biologic pathways for the top miRNAs associated with grip strength. Grip strength was lower in women than in men and declined with age with a mean 44.7 (10.0) kg in men and 26.5 (6.3) kg in women. Among 299 miRNAs interrogated for association with grip strength, 93 (31%) had FDR q value 
      PubDate: 2017-06-08T22:49:37.390416-05:
      DOI: 10.1111/acel.12622
       
  • Reprogramming progeria fibroblasts re-establishes a normal epigenetic
           landscape

    • Authors: Zhaoyi Chen; Wing Y. Chang, Alton Etheridge, Hilmar Strickfaden, Zhigang Jin, Gareth Palidwor, Ji-Hoon Cho, Kai Wang, Sarah Y. Kwon, Carole Doré, Angela Raymond, Akitsu Hotta, James Ellis, Rita A. Kandel, F. Jeffrey Dilworth, Theodore J. Perkins, Michael J. Hendzel, David J. Galas, William L. Stanford
      Abstract: Ideally, disease modeling using patient-derived induced pluripotent stem cells (iPSCs) enables analysis of disease initiation and progression. This requires any pathological features of the patient cells used for reprogramming to be eliminated during iPSC generation. Hutchinson–Gilford progeria syndrome (HGPS) is a segmental premature aging disorder caused by the accumulation of the truncated form of Lamin A known as Progerin within the nuclear lamina. Cellular hallmarks of HGPS include nuclear blebbing, loss of peripheral heterochromatin, defective epigenetic inheritance, altered gene expression, and senescence. To model HGPS using iPSCs, detailed genome-wide and structural analysis of the epigenetic landscape is required to assess the initiation and progression of the disease. We generated a library of iPSC lines from fibroblasts of patients with HGPS and controls, including one family trio. HGPS patient-derived iPSCs are nearly indistinguishable from controls in terms of pluripotency, nuclear membrane integrity, as well as transcriptional and epigenetic profiles, and can differentiate into affected cell lineages recapitulating disease progression, despite the nuclear aberrations, altered gene expression, and epigenetic landscape inherent to the donor fibroblasts. These analyses demonstrate the power of iPSC reprogramming to reset the epigenetic landscape to a revitalized pluripotent state in the face of widespread epigenetic defects, validating their use to model the initiation and progression of disease in affected cell lineages.
      PubDate: 2017-06-08T22:49:26.617665-05:
      DOI: 10.1111/acel.12621
       
  • Deletion of ghrelin prevents aging-associated obesity and muscle
           dysfunction without affecting longevity

    • Authors: Bobby Guillory; Ji-an Chen, Shivam Patel, Jiaohua Luo, Andres Splenser, Avni Mody, Michael Ding, Shiva Baghaie, Barbara Anderson, Blaga Iankova, Tripti Halder, Yamileth Hernandez, Jose M. Garcia
      Abstract: During aging, decreases in energy expenditure and locomotor activity lead to body weight and fat gain. Aging is also associated with decreases in muscle strength and endurance leading to functional decline. Here, we show that lifelong deletion of ghrelin prevents development of obesity associated with aging by modulating food intake and energy expenditure. Ghrelin deletion also attenuated the decrease in phosphorylated adenosine monophosphate-activated protein kinase (pAMPK) and downstream mediators in muscle, and increased the number of type IIa (fatigue resistant, oxidative) muscle fibers, preventing the decline in muscle strength and endurance seen with aging. Longevity was not affected by ghrelin deletion. Treatment of old mice with pharmacologic doses of ghrelin increased food intake, body weight, and muscle strength in both ghrelin wild-type and knockout mice. These findings highlight the relevance of ghrelin during aging and identify a novel AMPK-dependent mechanism for ghrelin action in muscle.
      PubDate: 2017-06-06T03:50:40.642431-05:
      DOI: 10.1111/acel.12618
       
  • Advances in Therapeutic Approaches to Extend Healthspan: a perspective
           from the 2nd Scripps Symposium on the Biology of Aging

    • Authors: Paul D. Robbins; Laura J. Niedernhofer
      Abstract: The 2nd Scripps Florida Symposium on The Biology of Aging entitled ‘Advances in Therapeutic Approaches to Extend Healthspan’ was held on January 22nd–25th, 2017 at The Scripps Research Institute in Jupiter, Florida. The meeting highlighted a variety of therapeutic approaches in animal models of aging that either are or soon will be in clinic trials. For example, drugs targeting senescent cells, metformin, rapalogs, NAD precursors, young plasma, mitochondrial-targeted free radical scavengers, stem cells, and stem cell factors all have shown significant preclinical efficacy. This perspective, based on presentations and discussions at the symposium, outlines the current and future state of development of therapeutic approaches to extend human healthspan.
      PubDate: 2017-06-06T03:50:23.910542-05:
      DOI: 10.1111/acel.12620
       
  • The replicative lifespan-extending deletion of SGF73 results in altered
           ribosomal gene expression in yeast

    • Authors: Amanda G. Mason; Renee M. Garza, Mark A. McCormick, Bhumil Patel, Brian K. Kennedy, Lorraine Pillus, Albert R. La Spada
      Abstract: Sgf73, a core component of SAGA, is the yeast orthologue of ataxin-7, which undergoes CAG–polyglutamine repeat expansion leading to the human neurodegenerative disease spinocerebellar ataxia type 7 (SCA7). Deletion of SGF73 dramatically extends replicative lifespan (RLS) in yeast. To further define the basis for Sgf73-mediated RLS extension, we performed ChIP-Seq, identified 388 unique genomic regions occupied by Sgf73, and noted enrichment in promoters of ribosomal protein (RP)-encoding genes. Of 388 Sgf73 binding sites, 33 correspond to 5′ regions of genes implicated in RLS extension, including 20 genes encoding RPs. Furthermore, half of Sgf73-occupied, RLS-linked RP genes displayed significantly reduced expression in sgf73Δ mutants, and double null strains lacking SGF73 and a Sgf73-regulated, RLS-linked RP gene exhibited no further increase in replicative lifespan. We also found that sgf73Δ mutants display altered acetylation of Ifh1, an important regulator of RP gene transcription. These findings implicate altered ribosomal protein expression in sgf73Δ yeast RLS and highlight altered acetylation as a pathway of relevance for SCA7 neurodegeneration.
      PubDate: 2017-05-31T21:55:43.829123-05:
      DOI: 10.1111/acel.12611
       
  • Transcription factors CEP-1/p53 and CEH-23 collaborate with AAK-2/AMPK to
           modulate longevity in Caenorhabditis elegans.

    • Authors: Hsin-Wen Chang; Steve Pisano, Amaresh Chaturbedi, Jennifer Chen, Sarah Gordon, Aiswarya Baruah, Siu Sylvia Lee
      Abstract: A decline in mitochondrial electron transport chain (ETC) function has long been implicated in aging and various diseases. Recently, moderate mitochondrial ETC dysfunction has been found to prolong lifespan in diverse organisms, suggesting a conserved and complex role of mitochondria in longevity determination. Several nuclear transcription factors have been demonstrated to mediate the lifespan extension effect associated with partial impairment of the ETC, suggesting that compensatory transcriptional response to be crucial. In this study, we showed that the transcription factors CEP-1/p53 and CEH-23 act through a similar mechanism to modulate longevity in response to defective ETC in Caenorhabditis elegans. Genomewide gene expression profiling comparison revealed a new link between these two transcription factors and AAK-2/AMP kinase (AMPK) signaling. Further functional analyses suggested that CEP-1/p53 and CEH-23 act downstream of AAK-2/AMPK signaling and CRTC-1 transcriptional coactivator to promote stress resistance and lifespan. As AAK-2, CEP-1, and CEH-23 are all highly conserved, our findings likely provide important insights for understanding the organismal adaptive response to mitochondrial dysfunction in diverse organisms and will be relevant to aging and pathologies with a mitochondrial etiology in human.
      PubDate: 2017-05-30T21:50:37.178994-05:
      DOI: 10.1111/acel.12619
       
  • Sustained NFκB inhibition improves insulin sensitivity but is
           detrimental to muscle health

    • Authors: Ning Zhang; Joseph M. Valentine, You Zhou, Mengyao E. Li, Yiqiang Zhang, Arunabh Bhattacharya, Michael E. Walsh, Katherine E. Fischer, Steven N. Austad, Pawel Osmulski, Maria Gaczynska, Steven E. Shoelson, Holly Van Remmen, Hung I. Chen, Yidong Chen, Hanyu Liang, Nicolas Musi
      Abstract: Older adults universally suffer from sarcopenia and approximately 60–70% are diabetic or prediabetic. Nonetheless, the mechanisms underlying these aging-related metabolic disorders are unknown. NFκB has been implicated in the pathogenesis of several aging-related pathologies including sarcopenia and type 2 diabetes and has been proposed as a target against them. NFκB also is thought to mediate muscle wasting seen with disuse, denervation, and some systemic diseases (e.g., cancer, sepsis). We tested the hypothesis that lifelong inhibition of the classical NFκB pathway would protect against aging-related sarcopenia and insulin resistance. Aged mice with muscle-specific overexpression of a super-repressor IκBα mutant (MISR) were protected from insulin resistance. However, MISR mice were not protected from sarcopenia; to the contrary, these mice had decreases in muscle mass and strength compared to wild-type mice. In MISR mice, NFκB suppression also led to an increase in proteasome activity and alterations in several genes and pathways involved in muscle growth and atrophy (e.g., myostatin). We conclude that the mechanism behind aging-induced sarcopenia is NFκB independent and differs from muscle wasting due to pathologic conditions. Our findings also indicate that, while suppressing NFκB improves insulin sensitivity in aged mice, this transcription factor is important for normal muscle mass maintenance and its sustained inhibition is detrimental to muscle function.
      PubDate: 2017-05-29T02:00:29.876218-05:
      DOI: 10.1111/acel.12613
       
  • Identification of tissue-specific transcriptional markers of caloric
           restriction in the mouse and their use to evaluate caloric restriction
           mimetics

    • Authors: Jamie L. Barger; James M. Vann, Nicole L. Cray, Thomas D. Pugh, Angela Mastaloudis, Shelly N. Hester, Steven M. Wood, Michael A. Newton, Richard Weindruch, Tomas A. Prolla
      Abstract: Caloric restriction (CR) without malnutrition has been shown to retard several aspects of the aging process and to extend lifespan in different species. There is strong interest in the identification of CR mimetics (CRMs), compounds that mimic the beneficial effects of CR on lifespan and healthspan without restriction of energy intake. Identification of CRMs in mammals is currently inefficient due to the lack of screening tools. We have performed whole-genome transcriptional profiling of CR in seven mouse strains (C3H/HeJ, CBA/J, DBA/2J, B6C3F1/J, 129S1/SvImJ, C57BL/6J, and BALB/cJ) in white adipose tissue (WAT), gastrocnemius muscle, heart, and brain neocortex. This analysis has identified tissue-specific panels of genes that change in expression in multiple mouse strains with CR. We validated a subset of genes with qPCR and used these to evaluate the potential CRMs bezafibrate, pioglitazone, metformin, resveratrol, quercetin, 2,4-dinitrophenol, and L-carnitine when fed to C57BL/6J 2-month-old mice for 3 months. Compounds were also evaluated for their ability to modulate previously characterized biomarkers of CR, including mitochondrial enzymes citrate synthase and SIRT3, plasma inflammatory cytokines TNF-α and IFN-γ, glycated hemoglobin (HbA1c) levels and adipocyte size. Pioglitazone, a PPAR-γ agonist, and L-carnitine, an amino acid involved in lipid metabolism, displayed the strongest effects on both the novel transcriptional markers of CR and the additional CR biomarkers tested. Our findings provide panels of tissue-specific transcriptional markers of CR that can be used to identify novel CRMs, and also represent the first comparative molecular analysis of several potential CRMs in multiple tissues in mammals.
      PubDate: 2017-05-26T23:05:34.562612-05:
      DOI: 10.1111/acel.12608
       
  • Kallistatin reduces vascular senescence and aging by regulating
           microRNA-34a-SIRT1 pathway

    • Authors: Youming Guo; Pengfei Li, Lin Gao, Jingmei Zhang, Zhirong Yang, Grant Bledsoe, Eugene Chang, Lee Chao, Julie Chao
      Abstract: Kallistatin, an endogenous protein, protects against vascular injury by inhibiting oxidative stress and inflammation in hypertensive rats and enhancing the mobility and function of endothelial progenitor cells (EPCs). We aimed to determine the role and mechanism of kallistatin in vascular senescence and aging using cultured EPCs, streptozotocin (STZ)-induced diabetic mice, and Caenorhabditis elegans (C. elegans). Human kallistatin significantly decreased TNF-α-induced cellular senescence in EPCs, as indicated by reduced senescence-associated β-galactosidase activity and plasminogen activator inhibitor-1 expression, and elevated telomerase activity. Kallistatin blocked TNF-α-induced superoxide levels, NADPH oxidase activity, and microRNA-21 (miR-21) and p16INK4a synthesis. Kallistatin prevented TNF-α-mediated inhibition of SIRT1, eNOS, and catalase, and directly stimulated the expression of these antioxidant enzymes. Moreover, kallistatin inhibited miR-34a synthesis, whereas miR-34a overexpression abolished kallistatin-induced antioxidant gene expression and antisenescence activity. Kallistatin via its active site inhibited miR-34a, and stimulated SIRT1 and eNOS synthesis in EPCs, which was abolished by genistein, indicating an event mediated by tyrosine kinase. Moreover, kallistatin administration attenuated STZ-induced aortic senescence, oxidative stress, and miR-34a and miR-21 synthesis, and increased SIRT1, eNOS, and catalase levels in diabetic mice. Furthermore, kallistatin treatment reduced superoxide formation and prolonged wild-type C. elegans lifespan under oxidative or heat stress, although kallistatin's protective effect was abolished in miR-34 or sir-2.1 (SIRT1 homolog) mutant C. elegans. Kallistatin inhibited miR-34, but stimulated sir-2.1 and sod-3 synthesis in C. elegans. These in vitro and in vivo studies provide significant insights into the role and mechanism of kallistatin in vascular senescence and aging by regulating miR-34a-SIRT1 pathway.
      PubDate: 2017-05-24T04:40:28.991669-05:
      DOI: 10.1111/acel.12615
       
  • Biochemical isolation of myonuclei employed to define changes to the
           myonuclear proteome that occur with aging

    • Authors: Alicia A. Cutler; Eric B. Dammer, Duc M. Doung, Nicholas T. Seyfried, Anita H. Corbett, Grace K. Pavlath
      Abstract: Skeletal muscle aging is accompanied by loss of muscle mass and strength. Examining changes in myonuclear proteins with age would provide insight into molecular processes which regulate these profound changes in muscle physiology. However, muscle tissue is highly adapted for contraction and thus comprised largely of contractile proteins making the nuclear proteins difficult to identify from whole muscle samples. By developing a method to purify myonuclei from whole skeletal muscle, we were able to collect myonuclei for analysis by flow cytometry, biochemistry, and mass spectrometry. Nuclear purification dramatically increased the number and intensity of nuclear proteins detected by mass spectrometry compared to whole tissue. We exploited this increased proteomic depth to investigate age-related changes to the myonuclear proteome. Nuclear levels of 54 of 779 identified proteins (7%) changed significantly with age; these proteins were primarily involved in chromatin maintenance and RNA processing. To determine whether the changes we detected were specific to myonuclei or were common to nuclei of excitatory tissues, we compared aging in myonuclei to aging in brain nuclei. Although several of the same processes were affected by aging in both brain and muscle nuclei, the specific proteins involved in these alterations differed between the two tissues. Isolating myonuclei allowed a deeper view into the myonuclear proteome than previously possible facilitating identification of novel age-related changes in skeletal muscle. Our technique will enable future studies into a heretofore underrepresented compartment of skeletal muscle.
      PubDate: 2017-05-23T04:55:27.639453-05:
      DOI: 10.1111/acel.12604
       
  • Molecular and physiological manifestations and measurement of aging in
           humans

    • Authors: Sadiya S. Khan; Benjamin D. Singer, Douglas E. Vaughan
      Abstract: Biological aging is associated with a reduction in the reparative and regenerative potential in tissues and organs. This reduction manifests as a decreased physiological reserve in response to stress (termed homeostenosis) and a time-dependent failure of complex molecular mechanisms that cumulatively create disorder. Aging inevitably occurs with time in all organisms and emerges on a molecular, cellular, organ, and organismal level with genetic, epigenetic, and environmental modulators. Individuals with the same chronological age exhibit differential trajectories of age-related decline, and it follows that we should assess biological age distinctly from chronological age. In this review, we outline mechanisms of aging with attention to well-described molecular and cellular hallmarks and discuss physiological changes of aging at the organ-system level. We suggest methods to measure aging with attention to both molecular biology (e.g., telomere length and epigenetic marks) and physiological function (e.g., lung function and echocardiographic measurements). Finally, we propose a framework to integrate these molecular and physiological data into a composite score that measures biological aging in humans. Understanding the molecular and physiological phenomena that drive the complex and multifactorial processes underlying the variable pace of biological aging in humans will inform how researchers assess and investigate health and disease over the life course. This composite biological age score could be of use to researchers seeking to characterize normal, accelerated, and exceptionally successful aging as well as to assess the effect of interventions aimed at modulating human aging.
      PubDate: 2017-05-23T04:30:40.972734-05:
      DOI: 10.1111/acel.12601
       
  • Short-term rapamycin treatment increases ovarian lifespan in young
           and middle-aged female mice

    • Authors: Xiaowei Dou; Yan Sun, Jiazhao Li, Jing Zhang, Dandan Hao, Wenwen Liu, Rui Wu, Feifei Kong, Xiaoxu Peng, Jing Li
      Abstract: Although age-related ovarian failure in female mammals cannot be reversed, recent strategies have focused on improving reproductive capacity with age, and rapamycin is one such intervention that has shown a potential for preserving the ovarian follicle pool and preventing premature ovarian failure. However, the application is limited because of its detrimental effects on follicular development and ovulation during long-term treatment. Herein, we shortened the rapamycin administration to 2 weeks and applied the protocol to both young (8 weeks) and middle-aged (8 months) mouse models. Results showed disturbances in ovarian function during and shortly after treatment; however, all the treated animals returned to normal fertility 2 months later. Following natural mating, we observed prolongation of ovarian lifespan in both mouse models, with the most prominent effect occurring in mice older than 12 months. The effects of transient rapamycin treatment on ovarian lifespan were reflected in the preservation of primordial follicles, increases in oocyte quality, and improvement in the ovarian microenvironment. These data indicate that short-term rapamycin treatment exhibits persistent effects on prolonging ovarian lifespan no matter the age at initiation of treatment. In order not to disturb fertility in young adults, investigators should in the future consider applying the protocol later in life so as to delay menopause in women, and at the same time increase ovarian lifespan.
      PubDate: 2017-05-22T05:00:53.309133-05:
      DOI: 10.1111/acel.12617
       
  • Impairment of insulin signalling in peripheral tissue fails to extend
           murine lifespan

    • Authors: Troy L. Merry; Doreen Kuhlow, Beate Laube, Doris Pöhlmann, Andreas F. H. Pfeiffer, C. Ronald Kahn, Michael Ristow, Kim Zarse
      Abstract: Impaired insulin/IGF1 signalling has been shown to extend lifespan in model organisms ranging from yeast to mammals. Here we sought to determine the effect of targeted disruption of the insulin receptor (IR) in non-neuronal tissues of adult mice on the lifespan. We induced hemizygous (PerIRKO+/−) or homozygous (PerIRKO−/−) disruption of the IR in peripheral tissue of 15-weeks-old mice using a tamoxifen-inducible Cre transgenic mouse with only peripheral tissue expression, and subsequently monitored glucose metabolism, insulin signalling and spontaneous death rates over 4 years. Complete peripheral IR disruption resulted in a diabetic phenotype with increased blood glucose and plasma insulin levels in young mice. Although blood glucose levels returned to normal, and fat mass was reduced in aged PerIRKO−/− mice, their lifespan was reduced. By contrast, heterozygous disruption had no effect on lifespan. This was despite young male PerIRKO+/− mice showing reduced fat mass and mild increase in hepatic insulin sensitivity. In conflict with findings in metazoans like Caenorhabditis elegans and Drosophila melanogaster, our results suggest that heterozygous impairment of the insulin signalling limited to peripheral tissues of adult mice fails to extend lifespan despite increased systemic insulin sensitivity, while homozygous impairment shortens lifespan.
      PubDate: 2017-05-22T04:55:33.251803-05:
      DOI: 10.1111/acel.12610
       
  • Anti-aging drugs reduce hypothalamic inflammation in a sex-specific manner

    • Authors: Marianna Sadagurski; Gillian Cady, Richard A. Miller
      Abstract: Aging leads to hypothalamic inflammation, but does so more slowly in mice whose lifespan has been extended by mutations that affect GH/IGF-1 signals. Early-life exposure to GH by injection, or to nutrient restriction in the first 3 weeks of life, also modulate both lifespan and the pace of hypothalamic inflammation. Three drugs extend lifespan of UM-HET3 mice in a sex-specific way: acarbose (ACA), 17-α-estradiol (17αE2), and nordihydroguaiaretic acid (NDGA), with more dramatic longevity increases in males in each case. In this study, we examined the effect of these anti-aging drugs on neuro-inflammation in hypothalamus and hippocampus. We found that age-associated hypothalamic inflammation is reduced in males but not in females at 12 months of age by ACA and 17αE2 and at 22 months of age in NDGA-treated mice. The three drugs blocked indices of hypothalamic reactive gliosis associated with aging, such as Iba-1-positive microglia and GFAP-positive astrocytes, as well as age-associated overproduction of TNF-α. This effect was not observed in drug-treated female mice or in the hippocampus of the drug-treated animals. On the other hand, caloric restriction (CR; an intervention that extends the lifespan in both sexes) significantly reduced hypothalamic microglia and TNF-α in both sexes at 12 months of age. Together, these results suggest that the extent of drug-induced changes in hypothalamic inflammatory processes is sexually dimorphic in a pattern that parallels the effects of these agents on mouse longevity and that mimics the changes seen, in both sexes, of long-lived nutrient restricted or mutant mice.
      PubDate: 2017-05-20T23:05:53.051596-05:
      DOI: 10.1111/acel.12590
       
  • The PPARγ-SETD8 axis constitutes an epigenetic, p53-independent
           checkpoint on p21-mediated cellular senescence

    • Authors: Chieh-Tien Shih; Yi-Feng Chang, Yi-Tung Chen, Chung-Pei Ma, Hui-Wen Chen, Chang-Ching Yang, Juu-Chin Lu, Yau-Sheng Tsai, Hua-Chien Chen, Bertrand Chin-Ming Tan
      Abstract: Cellular senescence is a permanent proliferative arrest triggered by genome instability or aberrant growth stresses, acting as a protective or even tumor-suppressive mechanism. While several key aspects of gene regulation have been known to program this cessation of cell growth, the involvement of the epigenetic regulation has just emerged but remains largely unresolved. Using a systems approach that is based on targeted gene profiling, we uncovered known and novel chromatin modifiers with putative link to the senescent state of the cells. Among these, we identified SETD8 as a new target as well as a key regulator of the cellular senescence signaling. Knockdown of SETD8 triggered senescence induction in proliferative culture, irrespectively of the p53 status of the cells; ectopic expression of this epigenetic writer alleviated the extent doxorubicin-induced cellular senescence. This repressive effect of SETD8 in senescence was mediated by directly maintaining the silencing mark H4K20me1 at the locus of the senescence switch gene p21. Further in support of this regulatory link, depletion of p21 reversed this SETD8-mediated cellular senescence. Additionally, we found that PPARγ acts upstream and regulates SETD8 expression in proliferating cells. Downregulation of PPARγ coincided with the senescence induction, while its activation inhibited the progression of this process. Viewed together, our findings delineated a new epigenetic pathway through which the PPARγ-SETD8 axis directly silences p21 expression and consequently impinges on its senescence-inducing function. This implies that SETD8 may be part of a cell proliferation checkpoint mechanism and has important implications in antitumor therapeutics.
      PubDate: 2017-05-17T04:25:44.606816-05:
      DOI: 10.1111/acel.12607
       
  • Caveolin-1 deficiency induces premature senescence with mitochondrial
           dysfunction

    • Authors: Dong-Min Yu; Seung Hee Jung, Hyoung-Tae An, Sungsoo Lee, Jin Hong, Jun Sub Park, Hyun Lee, Hwayeon Lee, Myeong-Suk Bahn, Hyung Chul Lee, Na-Kyung Han, Jesang Ko, Jae-Seon Lee, Young-Gyu Ko
      Abstract: Paradoxical observations have been made regarding the role of caveolin-1 (Cav-1) during cellular senescence. For example, caveolin-1 deficiency prevents reactive oxygen species-induced cellular senescence despite mitochondrial dysfunction, which leads to senescence. To resolve this paradox, we re-addressed the role of caveolin-1 in cellular senescence in human diploid fibroblasts, A549, HCT116, and Cav-1−/− mouse embryonic fibroblasts. Cav-1 deficiency (knockout or knockdown) induced cellular senescence via a p53-p21-dependent pathway, downregulating the expression level of the cardiolipin biosynthesis enzymes and then reducing the content of cardiolipin, a critical lipid for mitochondrial respiration. Our results showed that Cav-1 deficiency decreased mitochondrial respiration, reduced the activity of oxidative phosphorylation complex I (CI), inactivated SIRT1, and decreased the NAD+/NADH ratio. From these results, we concluded that Cav-1 deficiency induces premature senescence via mitochondrial dysfunction and silent information regulator 2 homologue 1 (SIRT1) inactivation.
      PubDate: 2017-05-17T04:16:45.01602-05:0
      DOI: 10.1111/acel.12606
       
  • The space where aging acts: focus on the GABAergic synapse

    • Authors: Aleksandra Rozycka; Monika Liguz-Lecznar
      Abstract: As it was established that aging is not associated with massive neuronal loss, as was believed in the mid-20th Century, scientific interest has addressed the influence of aging on particular neuronal subpopulations and their synaptic contacts, which constitute the substrate for neural plasticity. Inhibitory neurons represent the most complex and diverse group of neurons, showing distinct molecular and physiological characteristics and possessing a compelling ability to control the physiology of neural circuits. This review focuses on the aging of GABAergic neurons and synapses. Understanding how aging affects synapses of particular neuronal subpopulations may help explain the heterogeneity of aging-related effects. We reviewed the literature concerning the effects of aging on the numbers of GABAergic neurons and synapses as well as aging-related alterations in their presynaptic and postsynaptic components. Finally, we discussed the influence of those changes on the plasticity of the GABAergic system, highlighting our results concerning aging in mouse somatosensory cortex and linking them to plasticity impairments and brain disorders. We posit that aging-induced impairments of the GABAergic system lead to an inhibitory/excitatory imbalance, thereby decreasing neuron's ability to respond with plastic changes to environmental and cellular challenges, leaving the brain more vulnerable to cognitive decline and damage by synaptopathic diseases.
      PubDate: 2017-05-12T02:20:27.368405-05:
      DOI: 10.1111/acel.12605
       
  • Enhanced NOLC1 promotes cell senescence and represses hepatocellular
           carcinoma cell proliferation by disturbing the organization of nucleolus

    • Authors: Fuwen Yuan; Yu Zhang, Liwei Ma, Qian Cheng, Guodong Li, Tanjun Tong
      Abstract: The nucleolus is a key organelle that is responsible for the synthesis of rRNA and assembly of ribosomal subunits, which is also the center of metabolic control because of the critical role of ribosomes in protein synthesis. Perturbations of rRNA biogenesis are closely related to cell senescence and tumor progression; however, the underlying molecular mechanisms are not well understood. Here, we report that cellular senescence-inhibited gene (CSIG) knockdown up-regulated NOLC1 by stabilizing the 5′UTR of NOLC1 mRNA, and elevated NOLC1 induced the retention of NOG1 in the nucleolus, which is responsible for rRNA processing. Besides, the expression of NOLC1 was negatively correlated with CSIG in the aged mouse tissue and replicative senescent 2BS cells, and the down-regulation of NOLC1 could rescue CSIG knockdown-induced 2BS senescence. Additionally, NOLC1 expression was decreased in human hepatocellular carcinoma (HCC) tissue, and the ectopic expression of NOLC1 repressed the proliferation of HCC cells and tumor growth in a HCC xenograft model.
      PubDate: 2017-05-10T23:11:01.937446-05:
      DOI: 10.1111/acel.12602
       
  • Mitochondrial thioredoxin reductase 2 is elevated in long-lived primate as
           well as rodent species and extends fly mean lifespan

    • Authors: Andrew M. Pickering; Marcus Lehr, Christi M. Gendron, Scott D. Pletcher, Richard A. Miller
      Abstract: In a survey of enzymes related to protein oxidation and cellular redox state, we found activity of the redox enzyme thioredoxin reductase (TXNRD) to be elevated in cells from long-lived species of rodents, primates, and birds. Elevated TXNRD activity in long-lived species reflected increases in the mitochondrial form, TXNRD2, rather than the cytosolic forms TXNRD1 and TXNRD3. Analysis of published RNA-Seq data showed elevated TXNRD2 mRNA in multiple organs of longer-lived primates, suggesting that the phenomenon is not limited to skin-derived fibroblasts. Elevation of TXNRD2 activity and protein levels was also noted in liver of three different long-lived mutant mice, and in normal male mice treated with a drug that extends lifespan in males. Overexpression of mitochondrial TXNRD2 in Drosophila melanogaster extended median (but not maximum) lifespan in female flies with a small lifespan extension in males; in contrast, overexpression of the cytosolic form, TXNRD1, did not produce a lifespan extension.
      PubDate: 2017-05-05T02:00:36.748008-05:
      DOI: 10.1111/acel.12596
       
  • Quantitative identification of senescent cells in aging and disease

    • Authors: Anat Biran; Lior Zada, Paula Abou Karam, Ezra Vadai, Lior Roitman, Yossi Ovadya, Ziv Porat, Valery Krizhanovsky
      Abstract: Senescent cells are present in premalignant lesions and sites of tissue damage and accumulate in tissues with age. In vivo identification, quantification and characterization of senescent cells are challenging tasks that limit our understanding of the role of senescent cells in diseases and aging. Here, we present a new way to precisely quantify and identify senescent cells in tissues on a single-cell basis. The method combines a senescence-associated beta-galactosidase assay with staining of molecular markers for cellular senescence and of cellular identity. By utilizing technology that combines flow cytometry with high-content image analysis, we were able to quantify senescent cells in tumors, fibrotic tissues, and tissues of aged mice. Our approach also yielded the finding that senescent cells in tissues of aged mice are larger than nonsenescent cells. Thus, this method provides a basis for quantitative assessment of senescent cells and it offers proof of principle for combination of different markers of senescence. It paves the way for screening of senescent cells for identification of new senescence biomarkers, genes that bypass senescence or senolytic compounds that eliminate senescent cells, thus enabling a deeper understanding of the senescent state in vivo.
      PubDate: 2017-04-28T23:22:09.691772-05:
      DOI: 10.1111/acel.12592
       
  • Autophagy compensates impaired energy metabolism in CLPXP-deficient
           Podospora anserina strains and extends healthspan

    • Authors: Laura Knuppertz; Heinz D. Osiewacz
      Abstract: The degradation of nonfunctional mitochondrial proteins is of fundamental relevance for maintenance of cellular homeostasis. The heteromeric CLPXP protein complex in the mitochondrial matrix is part of this process. In the fungal aging model Podospora anserina, ablation of CLPXP leads to an increase in healthy lifespan. Here, we report that this counterintuitive increase depends on a functional autophagy machinery. In PaClpXP mutants, autophagy is involved in energy conservation and the compensation of impairments in respiration. Strikingly, despite the impact on mitochondrial function, it is not mitophagy but general autophagy that is constitutively induced and required for longevity. In contrast, in another long-lived mutant ablated for the mitochondrial PaIAP protease, autophagy is neither induced nor required for lifespan extension. Our data provide novel mechanistic insights into the capacity of different forms of autophagy to compensate impairments of specific components of the complex mitochondrial quality control network and about the biological role of mitochondrial CLPXP in the control of cellular energy metabolism.
      PubDate: 2017-04-27T12:20:53.684724-05:
      DOI: 10.1111/acel.12600
       
  • DNA damage and senescence in osteoprogenitors expressing Osx1 may cause
           their decrease with age

    • Authors: Ha-Neui Kim; Jianhui Chang, Lijian Shao, Li Han, Srividhya Iyer, Stavros C. Manolagas, Charles A. O'Brien, Robert L. Jilka, Daohong Zhou, Maria Almeida
      Abstract: Age-related bone loss in mice results from a decrease in bone formation and an increase in cortical bone resorption. The former is accounted by a decrease in the number of postmitotic osteoblasts which synthesize the bone matrix and is thought to be the consequence of age-dependent changes in mesenchymal osteoblast progenitors. However, there are no specific markers for these progenitors, and conclusions rely on results from in vitro cultures of mixed cell populations. Moreover, the culprits of such changes remain unknown. Here, we have used Osx1-Cre;TdRFP mice in which osteoprogenitors express the TdRFP fluorescent protein. We report that the number of TdRFP-Osx1 cells, freshly isolated from the bone marrow, declines by more than 50% between 6 and 24 months of age in both female and male mice. Moreover, TdRFP-Osx1 cells from old mice exhibited markers of DNA damage and senescence, such as γH2AX foci, G1 cell cycle arrest, phosphorylation of p53, increased p21CIP1 levels, as well as increased levels of GATA4 and activation of NF-κB – two major stimulators of the senescence-associated secretory phenotype (SASP). Bone marrow stromal cells from old mice also exhibited elevated expression of SASP genes, including several pro-osteoclastogenic cytokines, and increased capacity to support osteoclast formation. These changes were greatly attenuated by the senolytic drug ABT263. Together, these findings suggest that the decline in bone mass with age is the result of intrinsic defects in osteoprogenitor cells, leading to decreased osteoblast numbers and increased support of osteoclast formation.
      PubDate: 2017-04-12T03:42:10.859643-05:
      DOI: 10.1111/acel.12597
       
  • Caenorhabditis elegans orthologs of human genes differentially expressed
           with age are enriched for determinants of longevity

    • Authors: George L. Sutphin; Grant Backer, Susan Sheehan, Shannon Bean, Caroline Corban, Teresa Liu, Marjolein J. Peters, Joyce B. J. Meurs, Joanne M. Murabito, Andrew D. Johnson, Ron Korstanje,
      Abstract: We report a systematic RNAi longevity screen of 82 Caenorhabditis elegans genes selected based on orthology to human genes differentially expressed with age. We find substantial enrichment in genes for which knockdown increased lifespan. This enrichment is markedly higher than published genomewide longevity screens in C. elegans and similar to screens that preselected candidates based on longevity-correlated metrics (e.g., stress resistance). Of the 50 genes that affected lifespan, 46 were previously unreported. The five genes with the greatest impact on lifespan (>20% extension) encode the enzyme kynureninase (kynu-1), a neuronal leucine-rich repeat protein (iglr-1), a tetraspanin (tsp-3), a regulator of calcineurin (rcan-1), and a voltage-gated calcium channel subunit (unc-36). Knockdown of each gene extended healthspan without impairing reproduction. kynu-1(RNAi) alone delayed pathology in C. elegans models of Alzheimer's disease and Huntington's disease. Each gene displayed a distinct pattern of interaction with known aging pathways. In the context of published work, kynu-1, tsp-3, and rcan-1 are of particular interest for immediate follow-up. kynu-1 is an understudied member of the kynurenine metabolic pathway with a mechanistically distinct impact on lifespan. Our data suggest that tsp-3 is a novel modulator of hypoxic signaling and rcan-1 is a context-specific calcineurin regulator. Our results validate C. elegans as a comparative tool for prioritizing human candidate aging genes, confirm age-associated gene expression data as valuable source of novel longevity determinants, and prioritize select genes for mechanistic follow-up.
      PubDate: 2017-04-12T03:35:55.838489-05:
      DOI: 10.1111/acel.12595
       
  • Impact of early personal-history characteristics on the Pace of Aging:
           implications for clinical trials of therapies to slow aging and extend
           healthspan

    • Authors: Daniel W. Belsky; Avshalom Caspi, Harvey J. Cohen, William E. Kraus, Sandhya Ramrakha, Richie Poulton, Terrie E. Moffitt
      Abstract: Therapies to extend healthspan are poised to move from laboratory animal models to human clinical trials. Translation from mouse to human will entail challenges, among them the multifactorial heterogeneity of human aging. To inform clinical trials about this heterogeneity, we report how humans’ pace of biological aging relates to personal-history characteristics. Because geroprotective therapies must be delivered by midlife to prevent age-related disease onset, we studied young-adult members of the Dunedin Study 1972–73 birth cohort (n = 954). Cohort members’ Pace of Aging was measured as coordinated decline in the integrity of multiple organ systems, by quantifying rate of decline across repeated measurements of 18 biomarkers assayed when cohort members were ages 26, 32, and 38 years. The childhood personal-history characteristics studied were known predictors of age-related disease and mortality, and were measured prospectively during childhood. Personal-history characteristics of familial longevity, childhood social class, adverse childhood experiences, and childhood health, intelligence, and self-control all predicted differences in cohort members’ adulthood Pace of Aging. Accumulation of more personal-history risks predicted faster Pace of Aging. Because trials of anti-aging therapies will need to ascertain personal histories retrospectively, we replicated results using cohort members’ retrospective personal-history reports made in adulthood. Because many trials recruit participants from clinical settings, we replicated results in the cohort subset who had recent health system contact according to electronic medical records. Quick, inexpensive measures of trial participants’ early personal histories can enable clinical trials to study who volunteers for trials, who adheres to treatment, and who responds to anti-aging therapies.
      PubDate: 2017-04-12T03:16:11.47942-05:0
      DOI: 10.1111/acel.12591
       
  • Issue Information

    • Pages: 607 - 609
      PubDate: 2017-07-12T03:34:26.75556-05:0
      DOI: 10.1111/acel.12534
       
  • Endoplasmic reticulum proteostasis impairment in aging

    • Authors: Gabriela Martínez; Claudia Duran-Aniotz, Felipe Cabral-Miranda, Juan P. Vivar, Claudio Hetz
      First page: 615
      Abstract: Perturbed neuronal proteostasis is a salient feature shared by both aging and protein misfolding disorders. The proteostasis network controls the health of the proteome by integrating pathways involved in protein synthesis, folding, trafficking, secretion, and their degradation. A reduction in the buffering capacity of the proteostasis network during aging may increase the risk to undergo neurodegeneration by enhancing the accumulation of misfolded proteins. As almost one-third of the proteome is synthetized at the endoplasmic reticulum (ER), maintenance of its proper function is fundamental to sustain neuronal function. In fact, ER stress is a common feature of most neurodegenerative diseases. The unfolded protein response (UPR) operates as central player to maintain ER homeostasis or the induction of cell death of chronically damaged cells. Here, we discuss recent evidence placing ER stress as a driver of brain aging, and the emerging impact of neuronal UPR in controlling global proteostasis at the whole organismal level. Finally, we discuss possible therapeutic interventions to improve proteostasis and prevent pathological brain aging.
      PubDate: 2017-04-23T20:10:32.178017-05:
      DOI: 10.1111/acel.12599
       
  • Genetic interplay between human longevity and metabolic pathways — a
           large-scale eQTL study

    • Authors: Robert Häsler; Geetha Venkatesh, Qihua Tan, Friederike Flachsbart, Anupam Sinha, Philip Rosenstiel, Wolfgang Lieb, Stefan Schreiber, Kaare Christensen, Lene Christiansen, Almut Nebel
      First page: 716
      Abstract: Human longevity is a complex phenotype influenced by genetic and environmental components. Unraveling the contribution of genetic vs. nongenetic factors to longevity is a challenging task. Here, we conducted a large-scale RNA-sequencing-based expression quantitative trait loci study (eQTL) with subsequent heritability analysis. The investigation was performed on blood samples from 244 individuals from Germany and Denmark, representing various age groups including long-lived subjects up to the age of 104 years. Our eQTL-based approach revealed for the first time that human longevity is associated with a depletion of metabolic pathways in a genotype-dependent and independent manner. Further analyses indicated that 20% of the differentially expressed genes are influenced by genetic variants in cis. The subsequent study of twins showed that the transcriptional activity of a third of the differentially regulated genes is heritable. These findings suggest that longevity-associated biological processes such as altered metabolism are, to a certain extent, also the driving force of longevity rather than just a consequence of old age.
      PubDate: 2017-04-19T01:00:38.870491-05:
      DOI: 10.1111/acel.12598
       
  • Erratum

    • Pages: 898 - 898
      PubDate: 2017-07-12T03:34:26.170327-05:
      DOI: 10.1111/acel.12612
       
  • Erratum

    • Pages: 899 - 899
      PubDate: 2017-07-12T03:34:20.099802-05:
      DOI: 10.1111/acel.12633
       
  • Corrigendum

    • Pages: 900 - 900
      PubDate: 2017-07-12T03:34:18.30073-05:0
      DOI: 10.1111/acel.12609
       
  • Announcement

    • Pages: 901 - 901
      PubDate: 2017-07-12T03:34:23.486975-05:
      DOI: 10.1111/acel.12647
       
 
 
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