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Publisher: Springer-Verlag (Total: 2355 journals)

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Showing 1 - 200 of 2355 Journals sorted alphabetically
3D Research     Hybrid Journal   (Followers: 19, SJR: 0.214, h-index: 10)
4OR: A Quarterly J. of Operations Research     Hybrid Journal   (Followers: 10, SJR: 1.073, h-index: 25)
AAPS J.     Hybrid Journal   (Followers: 21, SJR: 1.192, h-index: 74)
AAPS PharmSciTech     Hybrid Journal   (Followers: 6, SJR: 0.718, h-index: 54)
Abdominal Imaging     Hybrid Journal   (Followers: 14, SJR: 0.723, h-index: 60)
Abhandlungen aus dem Mathematischen Seminar der Universitat Hamburg     Hybrid Journal   (Followers: 3, SJR: 0.447, h-index: 12)
Academic Psychiatry     Full-text available via subscription   (Followers: 23, SJR: 0.492, h-index: 32)
Academic Questions     Hybrid Journal   (Followers: 8, SJR: 0.135, h-index: 6)
Accreditation and Quality Assurance: J. for Quality, Comparability and Reliability in Chemical Measurement     Hybrid Journal   (Followers: 26, SJR: 0.378, h-index: 30)
Acoustical Physics     Hybrid Journal   (Followers: 11, SJR: 0.355, h-index: 20)
Acoustics Australia     Hybrid Journal  
Acta Analytica     Hybrid Journal   (Followers: 7, SJR: 0.387, h-index: 6)
Acta Applicandae Mathematicae     Hybrid Journal   (Followers: 1, SJR: 0.624, h-index: 34)
Acta Biotheoretica     Hybrid Journal   (Followers: 5, SJR: 0.419, h-index: 25)
Acta Diabetologica     Hybrid Journal   (Followers: 14, SJR: 1.318, h-index: 46)
Acta Endoscopica     Hybrid Journal   (Followers: 1, SJR: 0.113, h-index: 8)
acta ethologica     Hybrid Journal   (Followers: 4, SJR: 0.465, h-index: 23)
Acta Geochimica     Hybrid Journal   (Followers: 6)
Acta Geodaetica et Geophysica     Hybrid Journal   (Followers: 2, SJR: 0.294, h-index: 13)
Acta Geotechnica     Hybrid Journal   (Followers: 7, SJR: 1.818, h-index: 22)
Acta Informatica     Hybrid Journal   (Followers: 5, SJR: 0.524, h-index: 32)
Acta Mathematica     Hybrid Journal   (Followers: 11, SJR: 8.021, h-index: 47)
Acta Mathematica Hungarica     Hybrid Journal   (Followers: 2, SJR: 0.53, h-index: 29)
Acta Mathematica Sinica, English Series     Hybrid Journal   (Followers: 6, SJR: 0.406, h-index: 30)
Acta Mathematica Vietnamica     Hybrid Journal   (SJR: 0.451, h-index: 5)
Acta Mathematicae Applicatae Sinica, English Series     Hybrid Journal   (SJR: 0.22, h-index: 20)
Acta Mechanica     Hybrid Journal   (Followers: 20, SJR: 0.898, h-index: 52)
Acta Mechanica Sinica     Hybrid Journal   (Followers: 5, SJR: 0.426, h-index: 29)
Acta Metallurgica Sinica (English Letters)     Hybrid Journal   (Followers: 5, SJR: 0.525, h-index: 18)
Acta Meteorologica Sinica     Hybrid Journal   (Followers: 3, SJR: 0.524, h-index: 14)
Acta Neurochirurgica     Hybrid Journal   (Followers: 6, SJR: 0.833, h-index: 73)
Acta Neurologica Belgica     Hybrid Journal   (Followers: 1, SJR: 0.348, h-index: 27)
Acta Neuropathologica     Hybrid Journal   (Followers: 5, SJR: 6.61, h-index: 117)
Acta Oceanologica Sinica     Hybrid Journal   (Followers: 3, SJR: 0.295, h-index: 17)
Acta Parasitologica     Hybrid Journal   (Followers: 9, SJR: 0.581, h-index: 28)
Acta Physiologiae Plantarum     Hybrid Journal   (Followers: 2, SJR: 0.551, h-index: 39)
Acta Politica     Hybrid Journal   (Followers: 13, SJR: 0.658, h-index: 20)
Activitas Nervosa Superior     Hybrid Journal  
adhäsion KLEBEN & DICHTEN     Hybrid Journal   (Followers: 5, SJR: 0.103, h-index: 4)
ADHD Attention Deficit and Hyperactivity Disorders     Hybrid Journal   (Followers: 22, SJR: 0.871, h-index: 15)
Adhesion Adhesives & Sealants     Hybrid Journal   (Followers: 8)
Administration and Policy in Mental Health and Mental Health Services Research     Partially Free   (Followers: 15, SJR: 0.795, h-index: 40)
Adsorption     Hybrid Journal   (Followers: 4, SJR: 0.774, h-index: 52)
Advances in Applied Clifford Algebras     Hybrid Journal   (Followers: 3, SJR: 0.319, h-index: 15)
Advances in Atmospheric Sciences     Hybrid Journal   (Followers: 34, SJR: 0.959, h-index: 44)
Advances in Computational Mathematics     Hybrid Journal   (Followers: 15, SJR: 1.255, h-index: 44)
Advances in Contraception     Hybrid Journal   (Followers: 3)
Advances in Data Analysis and Classification     Hybrid Journal   (Followers: 52, SJR: 1.113, h-index: 14)
Advances in Gerontology     Partially Free   (Followers: 8, SJR: 0.141, h-index: 3)
Advances in Health Sciences Education     Hybrid Journal   (Followers: 25, SJR: 1.397, h-index: 42)
Advances in Manufacturing     Hybrid Journal   (Followers: 3, SJR: 0.2, h-index: 4)
Advances in Polymer Science     Hybrid Journal   (Followers: 41, SJR: 0.637, h-index: 89)
Advances in Therapy     Hybrid Journal   (Followers: 5, SJR: 0.79, h-index: 44)
Aegean Review of the Law of the Sea and Maritime Law     Hybrid Journal   (Followers: 7)
Aequationes Mathematicae     Hybrid Journal   (Followers: 2, SJR: 0.882, h-index: 23)
Aerobiologia     Hybrid Journal   (Followers: 2, SJR: 0.511, h-index: 36)
Aesthetic Plastic Surgery     Hybrid Journal   (Followers: 9, SJR: 0.821, h-index: 49)
African Archaeological Review     Hybrid Journal   (Followers: 16, SJR: 0.612, h-index: 24)
Afrika Matematika     Hybrid Journal   (Followers: 1, SJR: 0.248, h-index: 6)
AGE     Hybrid Journal   (Followers: 7, SJR: 1.358, h-index: 33)
Ageing Intl.     Hybrid Journal   (Followers: 7, SJR: 0.337, h-index: 10)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
Aging Clinical and Experimental Research     Hybrid Journal   (Followers: 3, SJR: 0.529, h-index: 55)
Agricultural Research     Hybrid Journal   (Followers: 3)
Agriculture and Human Values     Hybrid Journal   (Followers: 13, SJR: 1.197, h-index: 49)
Agroforestry Systems     Hybrid Journal   (Followers: 19, SJR: 0.64, h-index: 56)
Agronomy for Sustainable Development     Hybrid Journal   (Followers: 10, SJR: 1.732, h-index: 59)
AI & Society     Hybrid Journal   (Followers: 6, SJR: 0.171, h-index: 19)
AIDS and Behavior     Hybrid Journal   (Followers: 13, SJR: 2.006, h-index: 71)
Air Quality, Atmosphere & Health     Hybrid Journal   (Followers: 4, SJR: 0.706, h-index: 19)
Akupunktur & Aurikulomedizin     Full-text available via subscription   (Followers: 1)
Algebra and Logic     Hybrid Journal   (Followers: 4, SJR: 0.566, h-index: 18)
Algebra Universalis     Hybrid Journal   (Followers: 2, SJR: 0.388, h-index: 22)
Algebras and Representation Theory     Hybrid Journal   (Followers: 1, SJR: 0.868, h-index: 20)
Algorithmica     Hybrid Journal   (Followers: 8, SJR: 0.898, h-index: 56)
Allergo J.     Full-text available via subscription   (Followers: 1, SJR: 0.183, h-index: 20)
Allergo J. Intl.     Hybrid Journal   (Followers: 2)
Alpine Botany     Hybrid Journal   (Followers: 5, SJR: 0.729, h-index: 20)
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3, SJR: 1.392, h-index: 32)
AMBIO     Hybrid Journal   (Followers: 15, SJR: 1.094, h-index: 87)
American J. of Cardiovascular Drugs     Hybrid Journal   (Followers: 15, SJR: 0.864, h-index: 39)
American J. of Community Psychology     Hybrid Journal   (Followers: 25, SJR: 1.237, h-index: 83)
American J. of Criminal Justice     Hybrid Journal   (Followers: 8, SJR: 0.634, h-index: 13)
American J. of Cultural Sociology     Hybrid Journal   (Followers: 15, SJR: 0.283, h-index: 3)
American J. of Dance Therapy     Hybrid Journal   (Followers: 4, SJR: 0.175, h-index: 13)
American J. of Potato Research     Hybrid Journal   (Followers: 2, SJR: 0.558, h-index: 35)
American J. of Psychoanalysis     Hybrid Journal   (Followers: 22, SJR: 0.293, h-index: 13)
American Sociologist     Hybrid Journal   (Followers: 14, SJR: 0.18, h-index: 13)
Amino Acids     Hybrid Journal   (Followers: 8, SJR: 1.362, h-index: 83)
AMS Review     Partially Free   (Followers: 4)
Analog Integrated Circuits and Signal Processing     Hybrid Journal   (Followers: 7, SJR: 0.21, h-index: 37)
Analysis and Mathematical Physics     Hybrid Journal   (Followers: 3, SJR: 0.665, h-index: 7)
Analysis in Theory and Applications     Hybrid Journal   (Followers: 1)
Analysis of Verbal Behavior     Hybrid Journal   (Followers: 5)
Analytical and Bioanalytical Chemistry     Hybrid Journal   (Followers: 30, SJR: 1.096, h-index: 123)
Anatomical Science Intl.     Hybrid Journal   (Followers: 2, SJR: 0.301, h-index: 26)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3, SJR: 2.212, h-index: 69)
Animal Cognition     Hybrid Journal   (Followers: 16, SJR: 1.122, h-index: 55)
Annales françaises de médecine d'urgence     Hybrid Journal   (Followers: 1, SJR: 0.156, h-index: 4)
Annales Henri Poincaré     Hybrid Journal   (Followers: 3, SJR: 1.377, h-index: 32)
Annales mathématiques du Québec     Hybrid Journal   (Followers: 4)
Annali dell'Universita di Ferrara     Hybrid Journal   (SJR: 0.504, h-index: 14)
Annali di Matematica Pura ed Applicata     Hybrid Journal   (Followers: 1, SJR: 1.167, h-index: 26)
Annals of Behavioral Medicine     Hybrid Journal   (Followers: 12, SJR: 2.112, h-index: 98)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 18, SJR: 1.182, h-index: 94)
Annals of Combinatorics     Hybrid Journal   (Followers: 3, SJR: 0.849, h-index: 15)
Annals of Data Science     Hybrid Journal   (Followers: 11)
Annals of Dyslexia     Hybrid Journal   (Followers: 10, SJR: 0.857, h-index: 40)
Annals of Finance     Hybrid Journal   (Followers: 28, SJR: 0.686, h-index: 14)
Annals of Forest Science     Hybrid Journal   (Followers: 6, SJR: 0.929, h-index: 57)
Annals of Global Analysis and Geometry     Hybrid Journal   (Followers: 1, SJR: 1.136, h-index: 23)
Annals of Hematology     Hybrid Journal   (Followers: 16, SJR: 1.117, h-index: 62)
Annals of Mathematics and Artificial Intelligence     Hybrid Journal   (Followers: 8, SJR: 0.593, h-index: 42)
Annals of Microbiology     Hybrid Journal   (Followers: 10, SJR: 0.402, h-index: 26)
Annals of Nuclear Medicine     Hybrid Journal   (Followers: 5, SJR: 0.68, h-index: 45)
Annals of Operations Research     Hybrid Journal   (Followers: 10, SJR: 1.186, h-index: 78)
Annals of Ophthalmology     Hybrid Journal   (Followers: 12)
Annals of Regional Science     Hybrid Journal   (Followers: 8, SJR: 0.405, h-index: 42)
Annals of Software Engineering     Hybrid Journal   (Followers: 13)
Annals of Solid and Structural Mechanics     Hybrid Journal   (Followers: 10, SJR: 0.553, h-index: 8)
Annals of Surgical Oncology     Hybrid Journal   (Followers: 14, SJR: 1.902, h-index: 127)
Annals of Telecommunications     Hybrid Journal   (Followers: 7, SJR: 0.315, h-index: 25)
Annals of the Institute of Statistical Mathematics     Hybrid Journal   (Followers: 1, SJR: 0.931, h-index: 31)
Antonie van Leeuwenhoek     Hybrid Journal   (Followers: 5, SJR: 0.992, h-index: 87)
Apidologie     Hybrid Journal   (Followers: 4, SJR: 1.14, h-index: 57)
APOPTOSIS     Hybrid Journal   (Followers: 8, SJR: 1.554, h-index: 87)
Applicable Algebra in Engineering, Communication and Computing     Hybrid Journal   (Followers: 2, SJR: 0.354, h-index: 27)
Applications of Mathematics     Hybrid Journal   (Followers: 1, SJR: 0.274, h-index: 20)
Applied Biochemistry and Biotechnology     Hybrid Journal   (Followers: 42, SJR: 0.575, h-index: 80)
Applied Biochemistry and Microbiology     Hybrid Journal   (Followers: 16, SJR: 0.267, h-index: 26)
Applied Cancer Research     Open Access  
Applied Categorical Structures     Hybrid Journal   (Followers: 2, SJR: 0.361, h-index: 21)
Applied Composite Materials     Hybrid Journal   (Followers: 48, SJR: 0.705, h-index: 35)
Applied Entomology and Zoology     Partially Free   (Followers: 3, SJR: 0.554, h-index: 34)
Applied Geomatics     Hybrid Journal   (Followers: 4, SJR: 0.323, h-index: 9)
Applied Geophysics     Hybrid Journal   (Followers: 8, SJR: 0.541, h-index: 13)
Applied Intelligence     Hybrid Journal   (Followers: 11, SJR: 0.777, h-index: 43)
Applied Magnetic Resonance     Hybrid Journal   (Followers: 4, SJR: 0.358, h-index: 34)
Applied Mathematics & Optimization     Hybrid Journal   (Followers: 4, SJR: 0.955, h-index: 33)
Applied Mathematics - A J. of Chinese Universities     Hybrid Journal   (SJR: 0.275, h-index: 8)
Applied Mathematics and Mechanics     Hybrid Journal   (Followers: 5, SJR: 0.37, h-index: 26)
Applied Microbiology and Biotechnology     Hybrid Journal   (Followers: 61, SJR: 1.262, h-index: 161)
Applied Physics A     Hybrid Journal   (Followers: 7, SJR: 0.535, h-index: 121)
Applied Physics B: Lasers and Optics     Hybrid Journal   (Followers: 23, SJR: 0.983, h-index: 104)
Applied Psychophysiology and Biofeedback     Hybrid Journal   (Followers: 8, SJR: 0.677, h-index: 47)
Applied Research in Quality of Life     Hybrid Journal   (Followers: 11, SJR: 0.288, h-index: 15)
Applied Solar Energy     Hybrid Journal   (Followers: 17, SJR: 0.251, h-index: 6)
Applied Spatial Analysis and Policy     Hybrid Journal   (Followers: 5, SJR: 0.351, h-index: 9)
Aquaculture Intl.     Hybrid Journal   (Followers: 22, SJR: 0.613, h-index: 40)
Aquarium Sciences and Conservation     Hybrid Journal   (Followers: 1)
Aquatic Ecology     Hybrid Journal   (Followers: 32, SJR: 0.646, h-index: 44)
Aquatic Geochemistry     Hybrid Journal   (Followers: 4, SJR: 0.764, h-index: 39)
Aquatic Sciences     Hybrid Journal   (Followers: 13, SJR: 1.172, h-index: 53)
Arabian J. for Science and Engineering     Hybrid Journal   (Followers: 5, SJR: 0.345, h-index: 20)
Arabian J. of Geosciences     Hybrid Journal   (Followers: 1, SJR: 0.417, h-index: 16)
Archaeological and Anthropological Sciences     Hybrid Journal   (Followers: 23, SJR: 1.056, h-index: 15)
Archaeologies     Hybrid Journal   (Followers: 12, SJR: 0.397, h-index: 13)
Archiv der Mathematik     Hybrid Journal   (Followers: 1, SJR: 0.597, h-index: 29)
Archival Science     Hybrid Journal   (Followers: 56, SJR: 0.804, h-index: 22)
Archive for History of Exact Sciences     Hybrid Journal   (Followers: 8, SJR: 0.28, h-index: 15)
Archive for Mathematical Logic     Hybrid Journal   (Followers: 1, SJR: 0.946, h-index: 23)
Archive for Rational Mechanics and Analysis     Hybrid Journal   (SJR: 4.091, h-index: 66)
Archive of Applied Mechanics     Hybrid Journal   (Followers: 5, SJR: 0.865, h-index: 40)
Archives and Museum Informatics     Hybrid Journal   (Followers: 132)
Archives of Computational Methods in Engineering     Hybrid Journal   (Followers: 4, SJR: 2.841, h-index: 40)
Archives of Dermatological Research     Hybrid Journal   (Followers: 7, SJR: 0.9, h-index: 65)
Archives of Environmental Contamination and Toxicology     Hybrid Journal   (Followers: 12, SJR: 0.846, h-index: 84)
Archives of Gynecology and Obstetrics     Hybrid Journal   (Followers: 17, SJR: 0.695, h-index: 47)
Archives of Microbiology     Hybrid Journal   (Followers: 8, SJR: 0.702, h-index: 85)
Archives of Orthopaedic and Trauma Surgery     Hybrid Journal   (Followers: 8, SJR: 1.039, h-index: 56)
Archives of Osteoporosis     Hybrid Journal   (Followers: 2, SJR: 1.092, h-index: 13)
Archives of Sexual Behavior     Hybrid Journal   (Followers: 10, SJR: 1.198, h-index: 74)
Archives of Toxicology     Hybrid Journal   (Followers: 17, SJR: 1.595, h-index: 76)
Archives of Virology     Hybrid Journal   (Followers: 5, SJR: 1.086, h-index: 90)
Archives of Women's Mental Health     Hybrid Journal   (Followers: 14, SJR: 1.264, h-index: 50)
Archivio di Ortopedia e Reumatologia     Hybrid Journal  
Archivum Immunologiae et Therapiae Experimentalis     Hybrid Journal   (Followers: 2, SJR: 1.2, h-index: 42)
ArgoSpine News & J.     Hybrid Journal   (SJR: 0.102, h-index: 3)
Argumentation     Hybrid Journal   (Followers: 5, SJR: 0.295, h-index: 18)
Arid Ecosystems     Hybrid Journal   (Followers: 3)
Arkiv för Matematik     Hybrid Journal   (Followers: 1, SJR: 0.948, h-index: 22)
Arnold Mathematical J.     Hybrid Journal   (Followers: 1)
Arthropod-Plant Interactions     Hybrid Journal   (Followers: 2, SJR: 0.797, h-index: 17)
Arthroskopie     Hybrid Journal   (Followers: 1, SJR: 0.145, h-index: 8)
Artificial Intelligence and Law     Hybrid Journal   (Followers: 11, SJR: 0.288, h-index: 25)
Artificial Intelligence Review     Hybrid Journal   (Followers: 14, SJR: 0.948, h-index: 48)
Artificial Life and Robotics     Hybrid Journal   (Followers: 8, SJR: 0.231, h-index: 14)
Asia Europe J.     Hybrid Journal   (Followers: 5, SJR: 0.247, h-index: 9)
Asia Pacific Education Review     Hybrid Journal   (Followers: 12, SJR: 0.371, h-index: 17)
Asia Pacific J. of Management     Hybrid Journal   (Followers: 16, SJR: 1.676, h-index: 50)
Asia-Pacific Education Researcher     Hybrid Journal   (Followers: 12, SJR: 0.353, h-index: 13)
Asia-Pacific Financial Markets     Hybrid Journal   (Followers: 2, SJR: 0.19, h-index: 15)
Asia-Pacific J. of Atmospheric Sciences     Hybrid Journal   (Followers: 20, SJR: 1.006, h-index: 14)
Asian Business & Management     Hybrid Journal   (Followers: 8, SJR: 0.41, h-index: 10)
Asian J. of Business Ethics     Hybrid Journal   (Followers: 7)
Asian J. of Criminology     Hybrid Journal   (Followers: 5, SJR: 0.263, h-index: 8)
AStA Advances in Statistical Analysis     Hybrid Journal   (Followers: 2, SJR: 0.681, h-index: 15)
AStA Wirtschafts- und Sozialstatistisches Archiv     Hybrid Journal   (Followers: 5, SJR: 0.195, h-index: 5)
ästhetische dermatologie & kosmetologie     Full-text available via subscription  

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Journal Cover AGE
  [SJR: 1.358]   [H-I: 33]   [7 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 1574-4647 - ISSN (Online) 0161-9152
   Published by Springer-Verlag Homepage  [2355 journals]
  • Analysis of DNA modifications in aging research
    • Authors: Dustin R. Masser; Niran Hadad; Hunter Porter; Michael B. Stout; Archana Unnikrishnan; David R. Stanford; Willard M. Freeman
      Abstract: Abstract As geroscience research extends into the role of epigenetics in aging and age-related disease, researchers are being confronted with unfamiliar molecular techniques and data analysis methods that can be difficult to integrate into their work. In this review, we focus on the analysis of DNA modifications, namely cytosine methylation and hydroxymethylation, through next-generation sequencing methods. While older techniques for modification analysis performed relative quantitation across regions of the genome or examined average genome levels, these analyses lack the desired specificity, rigor, and genomic coverage to firmly establish the nature of genomic methylation patterns and their response to aging. With recent methodological advances, such as whole genome bisulfite sequencing (WGBS), bisulfite oligonucleotide capture sequencing (BOCS), and bisulfite amplicon sequencing (BSAS), cytosine modifications can now be readily analyzed with base-specific, absolute quantitation at both cytosine-guanine dinucleotide (CG) and non-CG sites throughout the genome or within specific regions of interest by next-generation sequencing. Additional advances, such as oxidative bisulfite conversion to differentiate methylation from hydroxymethylation and analysis of limited input/single-cells, have great promise for continuing to expand epigenomic capabilities. This review provides a background on DNA modifications, the current state-of-the-art for sequencing methods, bioinformatics tools for converting these large data sets into biological insights, and perspectives on future directions for the field.
      PubDate: 2018-01-11
      DOI: 10.1007/s11357-018-0005-3
  • Oral health in geroscience: animal models and the aging oral cavity
    • Authors: Jonathan Y. An; Richard Darveau; Matt Kaeberlein
      Abstract: Abstract Age is the single greatest risk factor for many diseases, including oral diseases. Despite this, a majority of preclinical oral health research has not adequately considered the importance of aging in research aimed at the mechanistic understanding of oral disease. Here, we have attempted to provide insights from animal studies in the geroscience field and apply them in the context of oral health research. In particular, we discuss the relationship between the biology of aging and mechanisms of oral disease. We also present a framework for defining and utilizing age-appropriate rodents and present experimental design considerations, such as the number of age-points used and the importance of genetic background. While focused primarily on rodent models, alternative animal models that may be particularly useful for studies of oral health during aging, such as companion dogs and marmoset monkeys, are also discussed. We hope that such information will aid in the design of future preclinical studies of geriatric dental health, thus allowing more reliability for translation of such studies to age-associated oral disease in people.
      PubDate: 2017-12-27
      DOI: 10.1007/s11357-017-0004-9
  • The Oxygen Paradox, the French Paradox, and age-related diseases
    • Authors: Joanna M. S. Davies; Josiane Cillard; Bertrand Friguet; Enrique Cadenas; Jean Cadet; Rachael Cayce; Andrew Fishmann; David Liao; Anne-Laure Bulteau; Frédéric Derbré; Amélie Rébillard; Steven Burstein; Etienne Hirsch; Robert A. Kloner; Michael Jakowec; Giselle Petzinger; Delphine Sauce; Florian Sennlaub; Isabelle Limon; Fulvio Ursini; Matilde Maiorino; Christina Economides; Christian J. Pike; Pinchas Cohen; Anne Negre Salvayre; Matthew R. Halliday; Adam J. Lundquist; Nicolaus A. Jakowec; Fatima Mechta-Grigoriou; Mathias Mericskay; Jean Mariani; Zhenlin Li; David Huang; Ellsworth Grant; Henry J. Forman; Caleb E. Finch; Patrick Y. Sun; Laura C. D. Pomatto; Onnik Agbulut; David Warburton; Christian Neri; Mustapha Rouis; Pierre Cillard; Jacqueline Capeau; Jean Rosenbaum; Kelvin J. A. Davies
      Abstract: Abstract A paradox is a seemingly absurd or impossible concept, proposition, or theory that is often difficult to understand or explain, sometimes apparently self-contradictory, and yet ultimately correct or true. How is it possible, for example, that oxygen “a toxic environmental poison” could be also indispensable for life (Beckman and Ames Physiol Rev 78(2):547–81, 1998; Stadtman and Berlett Chem Res Toxicol 10(5):485–94, 1997)': the so-called Oxygen Paradox (Davies and Ursini 1995; Davies Biochem Soc Symp 61:1–31, 1995). How can French people apparently disregard the rule that high dietary intakes of cholesterol and saturated fats (e.g., cheese and paté) will result in an early death from cardiovascular diseases (Renaud and de Lorgeril Lancet 339(8808):1523–6, 1992; Catalgol et al. Front Pharmacol 3:141, 2012; Eisenberg et al. Nat Med 22(12):1428–1438, 2016)': the so-called, French Paradox. Doubtless, the truth is not a duality and epistemological bias probably generates apparently self-contradictory conclusions. Perhaps nowhere in biology are there so many apparently contradictory views, and even experimental results, affecting human physiology and pathology as in the fields of free radicals and oxidative stress, antioxidants, foods and drinks, and dietary recommendations; this is particularly true when issues such as disease-susceptibility or avoidance, “healthspan,” “lifespan,” and ageing are involved. Consider, for example, the apparently paradoxical observation that treatment with low doses of a substance that is toxic at high concentrations may actually induce transient adaptations that protect against a subsequent exposure to the same (or similar) toxin. This particular paradox is now mechanistically explained as “Adaptive Homeostasis” (Davies Mol Asp Med 49:1–7, 2016; Pomatto et al. 2017a; Lomeli et al. Clin Sci (Lond) 131(21):2573–2599, 2017; Pomatto and Davies 2017); the non-damaging process by which an apparent toxicant can activate biological signal transduction pathways to increase expression of protective genes, by mechanisms that are completely different from those by which the same agent induces toxicity at high concentrations. In this review, we explore the influences and effects of paradoxes such as the Oxygen Paradox and the French Paradox on the etiology, progression, and outcomes of many of the major human age-related diseases, as well as the basic biological phenomenon of ageing itself.
      PubDate: 2017-12-21
      DOI: 10.1007/s11357-017-0002-y
  • Pharmacologically induced impairment of neurovascular coupling responses
           alters gait coordination in mice
    • Authors: Stefano Tarantini; Andriy Yabluchanksiy; Gábor A. Fülöp; Peter Hertelendy; M. Noa Valcarcel-Ares; Tamas Kiss; Jonathan M. Bagwell; Daniel O’Connor; Eszter Farkas; Farzaneh Sorond; Anna Csiszar; Zoltan Ungvari
      Abstract: Abstract There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause-and-effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L-NAME, and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns, and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.
      PubDate: 2017-12-14
      DOI: 10.1007/s11357-017-0003-x
  • A longitudinal study of DNA methylation as a potential mediator of
           age-related diabetes risk
    • Authors: Crystal D. Grant; Nadereh Jafari; Lifang Hou; Yun Li; James D. Stewart; Guosheng Zhang; Archana Lamichhane; JoAnn E. Manson; Andrea A. Baccarelli; Eric A. Whitsel; Karen N. Conneely
      Abstract: Abstract DNA methylation (DNAm) has been found to show robust and widespread age-related changes across the genome. DNAm profiles from whole blood can be used to predict human aging rates with great accuracy. We sought to test whether DNAm-based predictions of age are related to phenotypes associated with type 2 diabetes (T2D), with the goal of identifying risk factors potentially mediated by DNAm. Our participants were 43 women enrolled in the Women’s Health Initiative. We obtained methylation data via the Illumina 450K Methylation array on whole blood samples from participants at three timepoints, covering on average 16 years per participant. We employed the method and software of Horvath, which uses DNAm at 353 CpGs to form a DNAm-based estimate of chronological age. We then calculated the epigenetic age acceleration, or Δage, at each timepoint. We fit linear mixed models to characterize how Δage contributed to a longitudinal model of aging and diabetes-related phenotypes and risk factors. For most participants, Δage remained constant, indicating that age acceleration is generally stable over time. We found that Δage associated with body mass index (p = 0.0012), waist circumference (p = 0.033), and fasting glucose (p = 0.0073), with the relationship with BMI maintaining significance after correction for multiple testing. Replication in a larger cohort of 157 WHI participants spanning 3 years was unsuccessful, possibly due to the shorter time frame covered. Our results suggest that DNAm has the potential to act as a mediator between aging and diabetes-related phenotypes, or alternatively, may serve as a biomarker of these phenotypes.
      PubDate: 2017-11-20
      DOI: 10.1007/s11357-017-0001-z
  • Relationships of depressive behavior and sertraline treatment with walking
           speed and activity in older female nonhuman primates
    • Authors: Jamie N. Justice; Marnie G. Silverstein-Metzler; Beth Uberseder; Susan E. Appt; Thomas B. Clarkson; Thomas C. Register; Stephen B. Kritchevsky; Carol A. Shively
      Abstract: Abstract Depression is the most common mental health problem in aging persons and is a leading risk factor for physical disability, especially in women. Though antidepressant drugs such as serotonin reuptake inhibitors (SSRI) are commonly prescribed, epidemiological evidence reveals mixed effects of long-term antidepressant use on physical function and activity, possibly depending on depressive status. The purpose of this preclinical trial was to determine the relationships of depressive behavior and the potential for an SSRI treatment to modulate walking speed and activity patterns in older adult female cynomolgus monkeys (Macaca fascicularis). We evaluated the effects of depression and a commonly prescribed SSRI, sertraline HCl (20 mg/kg/day p.o.), on (a) walking speed, (b) accelerometry-derived activity (counts) and sedentariness (daytime 60-s sedentary epochs), and (c) observed locomotor and sedentary behaviors (% time) in adult female depressed and nondepressed monkeys (n = 42; 17.2 ± 1.8 years) during an 18 month pre-treatment phase and an 18 month treatment phase using a longitudinal, stratified placebo–control study design. Monkeys that were depressed prior to treatment (19/42) subsequently had slower walking speeds (F D [1, 38] = 4.14; p ≤ 0.05) and tended to be more sedentary during the daytime (F D [1, 38] = 3.63; p ≤ 0.06). Sertraline did not affect depressive behaviors, walking speed, accelerometry-derived physical activity or sedentariness, or time observed in total locomotor or sedentary behavior (all p > 0.10). This study provides the first experimental demonstration of relationships between nonhuman primate behavioral depression and walking speed, activity, and sedentariness and provides evidence for a lack of an effect of SSRI treatment on these phenotypes.
      PubDate: 2017-10-28
      DOI: 10.1007/s11357-017-9999-1
  • Chronic curcumin treatment improves spatial working memory but not
           recognition memory in middle-aged rhesus monkeys
    • Authors: Tara L. Moore; Bethany Bowley; Penny Shultz; Samantha Calderazzo; Eli Shobin; Ronald J. Killiany; Douglas L. Rosene; Mark B. Moss
      Abstract: Abstract Studies of both humans and non-human primates have demonstrated that aging is typically characterized by a decline in cognition that can occur as early as the fifth decade of life. Age-related changes in working memory are particularly evident and mediated, in part, by the prefrontal cortex, an area known to evidence age-related changes in myelin that is attributed to inflammation. In recent years, several nutraceuticals, including curcumin, by virtue of their anti-inflammatory and antioxidant effects, have received considerable attention as potential treatments for age-related cognitive decline and inflammation. Accordingly, we assessed for the first time in a non-human primate model of normal aging the efficacy of dietary intervention using the natural phenol curcumin to ameliorate the effects of aging on spatial working and recognition memory. Results revealed that monkeys receiving daily administration of curcumin over 14–18 months demonstrated a greater improvement in performance on repeated administration of a task of spatial working memory compared to monkeys that received a control substance.
      PubDate: 2017-10-18
      DOI: 10.1007/s11357-017-9998-2
  • RHEB1 insufficiency in aged male mice is associated with stress-induced
    • Authors: Qi Tian; Pavel Gromov; Joachim H. Clement; Yingming Wang; Marc Riemann; Falk Weih; Xiao-Xin Sun; Mu-Shui Dai; Lev M. Fedorov
      Abstract: Abstract The mechanistic target of rapamycin (mTOR), a protein kinase, is a central regulator of mammalian metabolism and physiology. Protein mTOR complex 1 (mTORC1) functions as a major sensor for the nutrient, energy, and redox state of a cell and is activated by ras homolog enriched in brain (RHEB1), a GTP-binding protein. Increased activation of mTORC1 pathway has been associated with developmental abnormalities, certain form of epilepsy (tuberous sclerosis), and cancer. Clinically, those mTOR-related disorders are treated with the mTOR inhibitor rapamycin and its rapalogs. Because the effects of chronic interference with mTOR signaling in the aged brain are yet unknown, we used a genetic strategy to interfere with mTORC1 signaling selectively by introducing mutations of Rheb1 into the mouse. We created conventional knockout (Rheb1 +/− ) and gene trap (Rheb1 Δ/+ ) mutant mouse lines. Rheb1-insufficient mice with different combinations of mutant alleles were monitored over a time span of 2 years. The mice did not show any behavioral/neurological changes during the first 18 months of age. However, after aging (> 18 months of age), both the Rheb1 +/− and Rheb1 Δ /− hybrid males developed rare stress-induced seizures, whereas Rheb1 +/− and Rheb1 Δ /− females and Rheb1 Δ/+ and Rheb1 Δ/Δ mice of both genders did not show any abnormality. Our findings suggest that chronic intervention with mTORC1 signaling in the aged brain might be associated with major adverse events.
      PubDate: 2017-09-10
      DOI: 10.1007/s11357-017-9997-3
  • Rapamycin treatment attenuates age-associated periodontitis in mice
    • Authors: Jonathan Y. An; Ellen K. Quarles; Surapat Mekvanich; Alex Kang; Anthony Liu; Danielle Santos; Richard A. Miller; Peter S. Rabinovitch; Timothy C. Cox; Matt Kaeberlein
      Abstract: Abstract Interventions that target biological mechanisms of aging have great potential to enhance quality of life by delaying morbidity and mortality. The FDA-approved drug rapamycin is a compelling candidate for such an intervention. In a previous study, it was reported that 3 months of rapamycin treatment is sufficient to increase life expectancy and remodel the gut microbiome in aged mice. Transient treatment with rapamycin or a rapamycin derivative has also been shown to delay immune stem cell senescence and rejuvenate immune function in aged mice and elderly people. Periodontal disease is an important age-related disease involving altered immune function, pathological changes to the oral microbiome, and systemic inflammation. Periodontal disease is defined clinically by loss of alveolar bone and by connective tissue degeneration. Here, we describe significant alveolar bone loss during aging in two different mouse strain backgrounds and report that rapamycin treatment is sufficient to reverse age-associated periodontal disease in mice. Partial restoration of youthful levels of alveolar bone is observed in 22-month-old rapamycin-treated mice as rapidly as 8 weeks after initiation of treatment. To the best of our knowledge, this represents the first intervention shown to substantially prevent or reverse age-associated alveolar bone loss. These findings suggest the possibility that inhibition of mTOR with rapamycin or other pharmacological agents may be useful to treat a clinically relevant condition for which there is currently no effective treatment.
      PubDate: 2017-09-09
      DOI: 10.1007/s11357-017-9994-6
  • Connective tissue growth factor (CTGF) in age-related vascular pathologies
    • Authors: Zoltan Ungvari; Marta Noa Valcarcel-Ares; Stefano Tarantini; Andriy Yabluchanskiy; Gábor A. Fülöp; Tamas Kiss; Anna Csiszar
      Abstract: Abstract Connective tissue growth factor (CTGF, also known as CCN2) is a matricellular protein expressed in the vascular wall, which regulates diverse cellular functions including cell adhesion, matrix production, structural remodeling, angiogenesis, and cell proliferation and differentiation. CTGF is principally regulated at the level of transcription and is induced by mechanical stresses and a number of cytokines and growth factors, including TGFβ. In this mini-review, the role of age-related dysregulation of CTGF signaling and its role in a range of macro- and microvascular pathologies, including pathogenesis of aorta aneurysms, atherogenesis, and diabetic retinopathy, are discussed. A potential role of CTGF and TGFβ in regulation and non-cell autonomous propagation of cellular senescence is also discussed.
      PubDate: 2017-09-05
      DOI: 10.1007/s11357-017-9995-5
  • A frailty index from common clinical and laboratory tests predicts
           increased risk of death across the life course
    • Authors: Joanna M. Blodgett; Olga Theou; Susan E. Howlett; Kenneth Rockwood
      Abstract: Abstract A frailty index (FI) based entirely on common clinical and laboratory tests might offer scientific advantages in understanding ageing and pragmatic advantages in screening. Our main objective was to compare an FI based on common laboratory tests with an FI based on self-reported data; we additionally investigated if the combination of subclinical deficits with clinical ones increased the ability of the FI to predict mortality. In this secondary analysis of the 2003–2004 and 2005–2006 National Health and Nutrition Examination Survey data, 8888 individuals aged 20+ were evaluated. Three FIs were constructed: a 36-item FI using self-reported questionnaire data (FI-Self-report); a 32-item FI using data from laboratory test values plus pulse and blood pressure measures (FI-Lab); and a 68-item FI that combined all items from each index (FI-Combined). The mean FI-Lab score was 0.15 ± 0.09, the FI-Self-report was 0.11 ± 0.11 and FI-Combined was 0.13 ± 0.08. Each index showed some typical FI characteristics (skewed distribution with long right tail, non-linear increase with age). Even so, there were fewer people with low frailty levels and a slower increase with age for the FI-Lab compared to the FI-Self-report. Higher frailty level was associated with higher risk of death, although it was strongest at older ages. Both FI-Lab and FI-Self-report remained significant in a combined model predicting death. The FI-Lab was feasible and valid, demonstrating that even subclinical deficit accumulation increased mortality risk. This suggests that deficit accumulation, from the subcellular to the clinically visible is a useful construct that may advance our understanding of the ageing process.
      PubDate: 2017-09-02
      DOI: 10.1007/s11357-017-9993-7
  • Hypertension impairs neurovascular coupling and promotes microvascular
           injury: role in exacerbation of Alzheimer’s disease
    • Authors: Anna Csiszar; Stefano Tarantini; Gábor A. Fülöp; Tamas Kiss; M. Noa Valcarcel-Ares; Veronica Galvan; Zoltan Ungvari; Andriy Yabluchanskiy
      Abstract: Abstract Hypertension in the elderly substantially increases both the risk of vascular cognitive impairment (VCI) and Alzheimer’s disease (AD); however, the underlying mechanisms are not completely understood. This review discusses the effects of hypertension on structural and functional integrity of cerebral microcirculation, including hypertension-induced alterations in neurovascular coupling responses, cellular and molecular mechanisms involved in microvascular damage (capillary rarefaction, blood-brain barrier disruption), and the genesis of cerebral microhemorrhages and their potential role in exacerbation of cognitive decline associated with AD. Understanding and targeting the hypertension-induced cerebromicrovascular alterations that are involved in the onset and progression of AD and contribute to cognitive impairment are expected to have a major role in preserving brain health in high-risk older individuals.
      PubDate: 2017-08-29
      DOI: 10.1007/s11357-017-9991-9
  • The application of information theory for the estimation of old-age
    • Authors: David Blokh; Ilia Stambler; Emilia Lubart; Eliyahu H. Mizrahi
      Abstract: Abstract Elderly patients are commonly characterized by the presence of several chronic aging-related diseases at once, or old-age “multimorbidity,” with critical implications for diagnosis and therapy. However, at the present there is no agreed or formal method to diagnose or even define “multimorbidity.” There is also no formal quantitative method to evaluate the effects of individual or combined diagnostic parameters and therapeutic interventions on multimorbidity. The present work outlines a methodology to provide such a measurement and definition, using information theoretical measure of normalized mutual information. A cohort of geriatric patients, suffering from several age-related diseases (multimorbidity), including ischemic heart disease, COPD, and dementia, were evaluated by a variety of diagnostic parameters, including static as well as dynamic biochemical, functional-behavioral, immunological, and hematological parameters. Multimorbidity was formally coded and measured as a composite of several chronic age-related diseases. The normalized mutual information allowed establishing the exact informative value of particular parameters and their combinations about the multimorbidity value. With the currently intensifying attempts to reduce aging-related multimorbidity by therapeutic interventions into its underlying aging processes, the proposed method may outline a valuable direction toward the formal indication and evidence-based evaluation of effectiveness of such interventions.
      PubDate: 2017-08-28
      DOI: 10.1007/s11357-017-9996-4
  • Omega-3 fatty acid levels in red blood cell membranes and physical decline
           over 3 years: longitudinal data from the MAPT study
    • Authors: Bertrand Fougère; MAPT Study Group; Sabine Goisser; Christelle Cantet; Gaëlle Soriano; Sophie Guyonnet; Philipe De Souto Barreto; Matteo Cesari; Sandrine Andrieu; Bruno Vellas
      Abstract: Abstract Studies have shown that omega-3 polyunsaturated fatty acids (PUFAs) are associated with brain, cardiovascular, and immune function, as well as physical performance and bone health in older adults. So far, few studies have investigated the associations between PUFA status and performance-based tests of physical function. The objective of this study was to investigate the associations between the omega-3 PUFA levels (eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA)) in red blood cell (RBC) membranes and physical performance, in a sample of community-dwelling older adults. This is a longitudinal observational study using data from the Multidomain Alzheimer’s Disease Trial (MAPT), a randomized, placebo-controlled trial. Four hundred participants from MAPT placebo group with available PUFA data were included. Omega-3 PUFA levels in RBC membranes were measured at baseline, and their percentage of total RBC membrane fatty acid content was calculated. We dichotomized the standardized omega-3 PUFA levels in RBC membranes as low (lowest quartile) vs. high (three upper quartiles). Gait speed (in m/s) and short physical performance battery (SPPB) score (range from 0 to 12, higher is better) were used to assess physical performance at baseline and after 6, 12, 24, and 36 months. Participants were 75.2 (± 4.3) years old and 68% were female. Bivariate analyses found that the characteristic of the participants in the lowest quartile of omega-3 PUFA levels (Q1) and those in the three upper quartiles (Q2–Q4) was not different at baseline; only those in Q1 were slightly older. In an unadjusted model, the difference in gait speed after 3 years of follow-up was significant (− 0.09 ± 0.03 m/s; p = 0.008) between participants in Q1 and those in Q2–Q4. In a model adjusted for age, gender, educational level, cognitive function, depressive status, body mass index, physical activity, grip strength, and their time interaction, this difference remained clinically relevant (− 0.07 ± 0.04 m/s; p = 0.075). No difference between the two groups was found for the SPPB score development over 3 years. Older adults with subjective memory complaints and in the lower quartile of omega-3 have a faster decline on gait speed compared to people in the three upper quartiles. Other longitudinal studies are needed to explore this association and to examine mechanisms.
      PubDate: 2017-08-22
      DOI: 10.1007/s11357-017-9990-x
  • Association of increased gait variability while dual tasking and cognitive
           decline: results from a prospective longitudinal cohort pilot study
    • Authors: Olivier Beauchet; Cyrille P. Launay; Harmehr Sekhon; Jean-Claude Barthelemy; Frédéric Roche; Julia Chabot; Elise J. Levinoff; Gilles Allali
      Abstract: Abstract Dual task-related changes in gait are considered as a sensitive and a specific marker of adverse effects of cognitive impairment on the highest levels of gait control. No study has examined the longitudinal association between gait performance while dual tasking and the occurrence of cognitive decline. This study aims to examine the association of stride time parameters (i.e., mean value and coefficient of variation (CoV)) during single and dual tasking with the occurrence of cognitive decline in non-demented older community dwellers. A total of 56 non-demented community dwellers were recruited in a longitudinal prospective cohort study. Mini-Mental Status Examination (MMSE) scores at baseline assessment and at 5-year follow-up assessment, and mean value and CoV of stride time at self-selected usual pace, while usual walking and dual tasking (i.e., counting backward and verbal fluency task) at baseline assessment were recorded. Variation (i.e., delta) of MMSE score from baseline to follow-up assessment as well as of stride time parameters from single to dual task was used as outcomes. Worse stride time values were reported while dual tasking compared to single tasking (P < 0.03). An increase of mean value, CoV, and delta of CoV of stride time was associated with an increased delta MMSE while performing verbal fluency task (P < 0.05). Worsening stride time parameters while performing a verbal fluency task at baseline assessment was associated with decline in MMSE score during the 5-year follow-up period in this sample of older community dwellers.
      PubDate: 2017-08-21
      DOI: 10.1007/s11357-017-9992-8
  • Multimodal physical activity increases brain-derived neurotrophic factor
           levels and improves cognition in institutionalized older women
    • Authors: Kelem Vedovelli; Bruno Lima Giacobbo; Márcio Silveira Corrêa; Andréa Wieck; Irani Iracema de Lima Argimon; Elke Bromberg
      Abstract: Abstract Physical activity has been proposed as a promising intervention to improve cognition and decrease the risk of dementia in older adults. Brain-derived neurotrophic factor (BDNF) appears to mediate, at least partially, these effects of exercise. However, intervention studies of the effects of multimodal exercises on cognition and BDNF levels are scarce and composed by small samples. Thus, the generalization of the conclusions of these studies depends on the reproducibility of the results. In order to contribute to the knowledge on the field, the present study evaluated the effects of a physical activity intervention composed by muscle strengthening and aerobic conditioning on BDNF levels and cognition in older women. Independent and non-demented subjects (≥75 years) were assigned to a 3-month physical activity intervention (n = 22, 60 min exercise sessions three times a week) or to a control condition (n = 10, no exercise). Clinical (anxiety and depression symptoms), neuropsychological (Digit Span, Stroop, Trail Making, and Contextual Memory tests), physical (upper and lower limb strength, aerobic conditioning), and physiological (serum BDNF) parameters were evaluated immediately before, 1 month, and 3 months after starting intervention. Results indicated that controls had stable levels for all measured variables, whereas the intervention group improved on physical fitness, depressive symptoms, cognitive performance, and BDNF levels. Moreover, a linear regression identified an association between aerobic conditioning and BDNF levels. In conclusion, combined muscle strengthening and aerobic conditioning was able to improve cognitive performance and increase BDNF levels. Aerobic conditioning seems to be an important mediator of these outcomes.
      PubDate: 2017-07-13
      DOI: 10.1007/s11357-017-9987-5
  • A system to identify inhibitors of mTOR signaling using high-resolution
           growth analysis in Saccharomyces cerevisiae
    • Authors: Mitchell B. Lee; Daniel T. Carr; Michael G. Kiflezghi; Yan Ting Zhao; Deborah B. Kim; Socheata Thon; Margarete D. Moore; Mary Ann K. Li; Matt Kaeberlein
      Abstract: Abstract The mechanistic target of rapamycin (mTOR) is a central regulator of growth and proliferation and mTOR inhibition is a promising therapy for a variety of diseases and disorders. Inhibition of mTOR complex I (mTORC1) with rapamycin delays aging and increases healthy longevity in laboratory animals and is used clinically at high doses to prevent organ transplant rejection and to treat some forms of cancer. Clinical use of rapamycin is associated with several unwanted side effects, however, and several strategies are being taken to identify mTORC1 inhibitors with fewer side effects. We describe here a yeast-based growth assay that can be used to screen for novel inhibitors of mTORC1. By testing compounds using a wild-type strain and isogenic cells lacking either TOR1 or FPR1, we can resolve not only whether a compound is an inhibitor of mTORC1 but also whether the inhibitor acts through a mechanism similar to rapamycin by binding Fpr1. Using this assay, we show that rapamycin derivatives behave similarly to rapamycin, while caffeine and the ATP competitive inhibitors Torin 1 and GSK2126458 are mTORC1 inhibitors in yeast that act independently of Fpr1. Some mTOR inhibitors in mammalian cells do not inhibit mTORC1 in yeast, and several nutraceutical compounds were not found to specifically inhibit mTOR but resulted in a general inhibition of yeast growth. Our screening method holds promise as a means of effectively assaying drug libraries for mTOR-inhibitory molecules in vivo that may be adapted as novel treatments to fight diseases and extend healthy longevity.
      PubDate: 2017-07-13
      DOI: 10.1007/s11357-017-9988-4
  • Hypertension-induced synapse loss and impairment in synaptic plasticity in
           the mouse hippocampus mimics the aging phenotype: implications for the
           pathogenesis of vascular cognitive impairment
    • Authors: Zsuzsanna Tucsek; M. Noa Valcarcel-Ares; Stefano Tarantini; Andriy Yabluchanskiy; Gábor Fülöp; Tripti Gautam; Albert Orock; Anna Csiszar; Ferenc Deak; Zoltan Ungvari
      Abstract: Abstract Strong epidemiological and experimental evidence indicates that hypertension has detrimental effects on the cerebral microcirculation and thereby promotes accelerated brain aging. Hypertension is an independent risk factor for both vascular cognitive impairment (VCI) and Alzheimer’s disease (AD). However, the pathophysiological link between hypertension-induced cerebromicrovascular injury (e.g., blood–brain barrier disruption, increased microvascular oxidative stress, and inflammation) and cognitive decline remains elusive. The present study was designed to characterize neuronal functional and morphological alterations induced by chronic hypertension and compare them to those induced by aging. To achieve that goal, we induced hypertension in young C57BL/6 mice by chronic (4 weeks) infusion of angiotensin II. We found that long-term potentiation (LTP) of performant path synapses following high-frequency stimulation of afferent fibers was decreased in hippocampal slices obtained from hypertensive mice, mimicking the aging phenotype. Hypertension and advanced age were associated with comparable decline in synaptic density in the stratum radiatum of the mouse hippocampus. Hypertension, similar to aging, was associated with changes in mRNA expression of several genes involved in regulation of neuronal function, including down-regulation of Bdnf, Homer1, and Dlg4, which may have a role in impaired synaptic plasticity. Collectively, hypertension impairs synaptic plasticity, reduces synaptic density, and promotes dysregulation of genes involved in synaptic function in the mouse hippocampus mimicking the aging phenotype. These hypertension-induced neuronal alterations may impair establishment of memories in the hippocampus and contribute to the pathogenesis and clinical manifestation of both vascular cognitive impairment (VCI) and Alzheimer’s disease (AD).
      PubDate: 2017-06-29
      DOI: 10.1007/s11357-017-9981-y
  • Androgen supplementation improves some but not all aspects of immune
           senescence in aged male macaques
    • Authors: Maham Rais; Randall M. Wilson; Henryk F. Urbanski; Ilhem Messaoudi
      Abstract: Abstract Aging leads to a progressive decline in immune function commonly referred to as immune senescence, which results in increased incidence and severity of infection. In addition, older males experience a significant disruption in their levels of circulating androgens, notably testosterone and dehydroepiandrosterone (DHEA), which has been linked to sarcopenia, osteoporosis, cardiovascular disease, and diabetes. Since sex steroid levels modulate immune function, it is possible that the age-related decline in androgen levels can also affect immune senescence. Therefore, in this study, we evaluated the pleiotropic effects of physiological androgen supplementation in aged male rhesus macaques (n = 7/group) on immune cell subset frequency and response to vaccination. As expected, frequency of naïve CD4 and CD8 T cells declined in aged non-treated macaques, while that of memory T cells increased. In contrast, frequency of naïve and memory T cells remained stable in androgen-supplemented males. In addition, levels of inflammatory cytokines increased less steeply in supplemented aged males compared to the aged controls. Despite these changes, androgen-supplemented animals only showed modest improvement in antibody responses following vaccination compared to age non-treated controls. These data indicate that short-term physiological androgen supplementation can improve some but not all aspects of immune senescence.
      PubDate: 2017-06-14
      DOI: 10.1007/s11357-017-9979-5
  • Demonstration of impaired neurovascular coupling responses in TG2576 mouse
           model of Alzheimer’s disease using functional laser speckle contrast
    • Authors: Stefano Tarantini; Gabor A. Fulop; Tamas Kiss; Eszter Farkas; Dániel Zölei-Szénási; Veronica Galvan; Peter Toth; Anna Csiszar; Zoltan Ungvari; Andriy Yabluchanskiy
      Abstract: Abstract Increasing evidence from epidemiological, clinical, and experimental studies indicates that cerebromicrovascular dysfunction and microcirculatory damage play critical roles in the pathogenesis of many types of dementia in the elderly, including both vascular cognitive impairment (VCI) and Alzheimer’s disease. Vascular contributions to cognitive impairment and dementia (VCID) include impairment of neurovascular coupling responses/functional hyperemia (“neurovascular uncoupling”). Due to the growing interest in understanding and pharmacologically targeting pathophysiological mechanisms of VCID, there is an increasing need for sensitive, easy-to-establish methods to assess neurovascular coupling responses. Laser speckle contrast imaging (LSCI) is a technique that allows rapid and minimally invasive visualization of changes in regional cerebromicrovascular blood perfusion. This type of imaging technique combines high resolution and speed to provide great spatiotemporal accuracy to measure moment-to-moment changes in cerebral blood flow induced by neuronal activation. Here, we provide detailed protocols for the successful measurement in neurovascular coupling responses in anesthetized mice equipped with a thinned-skull cranial window using LSCI. This method can be used to evaluate the effects of anti-aging or anti-AD treatments on cerebromicrovascular health.
      PubDate: 2017-06-03
      DOI: 10.1007/s11357-017-9980-z
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