Fat tissue, aging, and cellular senescence

Abstract

Summary Fat tissue, frequently the largest organ in humans, is at the nexus of mechanisms involved in longevity and age‐related metabolic dysfunction. Fat distribution and function change dramatically throughout life. Obesity is associated with accelerated onset of diseases common in old age, while fat ablation and certain mutations affecting fat increase life span. Fat cells turn over throughout the life span. Fat cell progenitors, preadipocytes, are abundant, closely related to macrophages, and dysdifferentiate in old age, switching into a pro‐inflammatory, tissue‐remodeling, senescent‐like state. Other mesenchymal progenitors also can acquire a pro‐inflammatory, adipocyte‐like phenotype with aging. We propose a hypothetical model in which cellular stress and preadipocyte overutilization with aging induce cellular senescence, leading to impaired adipogenesis, failure to sequester lipotoxic fatty acids, inflammatory cytokine and chemokine generation, and innate and adaptive immune response activation. These pro‐inflammatory processes may amplify each other and have systemic consequences. This model is consistent with recent concepts about cellular senescence as a stress‐responsive, adaptive phenotype that develops through multiple stages, including major metabolic and secretory readjustments, which can spread from cell to cell and can occur at any point during life. Senescence could be an alternative cell fate that develops in response to injury or metabolic dysfunction and might occur in nondividing as well as dividing cells. Consistent with this, a senescent‐like state can develop in preadipocytes and fat cells from young obese individuals. Senescent, pro‐inflammatory cells in fat could have profound clinical consequences because of the large size of the fat organ and its central metabolic role.

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    Kintscher U, Hartge M, Hess K, Foryst-Ludwig A, Clemenz M, Wabitsch M, Fischer-Posovszky P, Barth TF, Dragun D, Skurk T, Hauner H, Bluher M, Unger T, Wolf AM, Knippschild U, Hombach V, Marx N. T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance. Arterioscler. Thromb. Vasc. Biol. 2008;28:1304-1310.

    Not in our library10.1161/atvbaha.108.165100

92. 92.

    Kirkland JL, Dax EM. Adipose hormone responsiveness and aging in the rat. J. Am. Geriatr. Soc. 1984;32:219-228.

    Not in our library10.1111/j.1532-5415.1984.tb02006.x

93. 93.

    Kirkland JL, Dobson DE. Preadipocyte function and aging: links between age-related changes in cell dynamics and altered fat cell function. J. Am. Geriatr. Soc. 1997;45:959-967.

    Not in our library10.1111/j.1532-5415.1997.tb02967.x

94. 94.

    Kirkland JL, Hollenberg CH. Inhibitors of preadipocyte replication: opportunities for the treatment of obesity. Prog. Mol. Subcell. Biol. 1998;22:177-195.

    Not in our library10.1007/978-3-642-72149-6_9

95. 95.

    Kirkland JL, Hollenberg CH, Gillon WS. Age, anatomic site, and the replication and differentiation of adipocyte precursors. Am. J. Physiol. 1990;258:C206-C210.

    Not in our library10.1152/ajpcell.1990.258.2.c206

96. 96.

    Kirkland JL, Hollenberg CH, Gillon WS. Ageing, differentiation, and gene expression in rat epididymal preadipocytes. Biochem. Cell Biol. 1993;71:556-561.

    Not in our library10.1139/o93-079

97. 97.

    Kirkland JL, Hollenberg CH, Kindler S, Gillon WS. Effects of age and anatomic site on preadipocyte number in rat fat depots. J. Gerontol. 1994;49:B31-B35.

    Not in our library10.1093/geronj/49.1.b31

98. 98.

    Kirkland JL, Cummins P, Steppan C, Dobson DE, Cladaras MH. Decreasing preadipocyte differentiation capacity with aging is associated with blunted expression of the transcription factor, CCAAT enhancer binding protein a. Obes. Res. 1997;5(Suppl. 1):22S.

    Not in our library

99. 99.

    Kirkland JL, Tchkonia T, Pirtskhalava T, Han J, Karagiannides I. Adipogenesis and aging: does aging make fat go MAD? Exp. Gerontol. 2002;37:757-767.

    Not in our library10.1016/s0531-5565(02)00014-1

100. 100.

     Kirkland JL, Tchkonia T, Giorgadze N, Pirtskhalava T. Adipose tissue as an endocrine organ: regional differences in adipocyte endocrine function. Prog. Obes. Res. 2003;9:87-95.

     Not in our library

101. 101.

     Klein S, Fontana L, Young VL, Coggan AR, Kilo C, Patterson BW, Mohammed BS. Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N. Engl. J. Med. 2004;350:2549-2557.

     Not in our library10.1056/nejmoa033179

102. 102.

     Koster A, Stenholm S, Alley DE, Kim LJ, Simonsick EM, Kanaya AM, Visser M, Houston DK, Nicklas BJ, Tylavsky FA, Satterfield S, Goodpaster BH, Ferrucci L, Harris TB. Body fat distribution and inflammation among obese older adults with and without metabolic syndrome. Obesity (Silver Spring). 2010.

     Not in our library10.1038/oby.2010.86

103. 103.

     Kotani K, Tokunaga K, Fujioka S, Kobatake T, Keno Y, Yoshida S, Shimomura I, Tarui S, Matsuzawa Y. Sexual dimorphism of age-related changes in whole-body fat distribution in the obese. Int. J. Obes. Relat. Metab. Disord. 1994;18:207-212.

     Not in our library

104. 104.

     Koutsari C, Ali AH, Nair KS, Rizza RA, O’Brien P, Khosla S, Jensen MD. Fatty acid metabolism in the elderly: effects of dehydroepiandrosterone and testosterone replacement in hormonally deficient men and women. J. Clin. Endocrinol. Metab. 2009;94:3414-3423.

     Not in our library10.1210/jc.2009-0165

105. 105.

     Kralisch S, Weise S, Sommer G, Lipfert J, Lossner U, Bluher M, Stumvoll M, Fasshauer M. Interleukin-1beta induces the novel adipokine chemerin in adipocytes in vitro. Regul. Pept. 2009;154:102-106.

     Not in our library10.1016/j.regpep.2009.02.010

106. 106.

     Krishnamurthy J, Torrice C, Ramsey MR, Kovalev GI, Al-Regaiey K, Su L, Sharpless NE. Ink4a/Arf expression is a biomarker of aging. J. Clin. Invest. 2004;114:1299-1307.

     Not in our library10.1172/jci22475

107. 107.

     Krtolica A, Campisi J. Cancer and aging: a model for the cancer promoting effects of the aging stroma. Int. J. Cell Biol. 2002;34:1401-1414.

     Not in our library10.1016/s1357-2725(02)00053-5

108. 108.

     Kuilman T, Peeper DS. Senescence-messaging secretome: SMS-ing cellular stress. Nat. Rev. Cancer. 2009;9:81-94.

     Not in our library10.1038/nrc2560

109. 109.

     Kuilman T, Michaloglou C, Vredeveld LC, Douma S, van Doorn R, Desmet CJ, Aarden LA, Mooi WJ, Peeper DS. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133:958-961.

     Not in our library10.1016/j.cell.2008.03.039

110. 110.

     Kuk JL, Saunders TJ, Davidson LE, Ross R. Age-related changes in total and regional fat distribution. Ageing Res. Rev. 2009;8:339-348.

     Not in our library10.1016/j.arr.2009.06.001

111. 111.

     Kyle UG, Genton L, Hans D, Karsegard L, Slosman DO, Pichard C. Age-related differences in fat-free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years. Eur. J. Clin. Nutr. 2001;55:663-672.

     Not in our library10.1038/sj.ejcn.1601198

112. 112.

     Lacasa D, Taleb S, Keophiphath M, Miranville A, Clement K. Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes. Endocrinology. 2007;148:868-877.

     Not in our library10.1210/en.2006-0687

113. 113.

     Lean ME. Pathophysiology of obesity. Proc. Nutr. Soc. 2000;59:331-336.

     Not in our library10.1017/s0029665100000379

114. 114.

     Lelliott C, Vidal-Puig AJ. Lipotoxicity, an imbalance between lipogenesis de novo and fatty acid oxidation. Int. J. Obes. Relat. Metab. Disord. 2004;28(Suppl. 4):S22-S28.

     Not in our library10.1038/sj.ijo.0802854

115. 115.

     Lim S, Yoon JW, Choi SH, Park YJ, Lee JJ, Park JH, Lee SB, Kim KW, Lim JY, Kim YB, Park KS, Lee HK, Cho SI, Jang HC. Combined impact of adiponectin and retinol-binding protein 4 on metabolic syndrome in elderly people: the Korean Longitudinal Study on Health and Aging. Obesity (Silver Spring). 2010;18:826-832.

     Not in our library10.1038/oby.2009.232

116. 116.

     Lin FT, Lane MD. CCAAT/enhancer binding protein a is sufficient to initiate the 3T3-L1 adipocyte differentiation program. Proc. Natl Acad. Sci. USA. 1994;91:8757-8761.

     Not in our library10.1073/pnas.91.19.8757

117. 117.

     Lin Y, Lee H, Berg AH, Listani MP, Shapiro L, Scherer PE. LPS activated TLR-4 receptor induces the synthesis of the closely related receptor TLR-2 in adipocytes. J. Biol. Chem. 2000;275:24255-24263.

     Not in our library10.1074/jbc.m002137200

118. 118.

     Listenberger LL, Han H, Lewis SE, Cases S, Farese RV, Ory DS. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl Acad. Sci. USA. 2003;100:3077-3082.

     Not in our library10.1073/pnas.0630588100

119. 119.

     Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ, Doria A, Libby P, Blumberg RS, Kahn BB, Hotamisligil GS, Shi GP. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat. Med. 2009;15:940-945.

     Not in our library10.1038/nm.1994

120. 120.

     Loffreda S, Yang SQ, Lin HZ, Karp CL, Brengman ML, Wang DJ, Klein AS, Bulkley GB, Bao C, Noble PW, Lane MD, Diehl AM. Leptin regulates proinflammatory immune responses. FASEB J. 1998;12:57-65.

     Not in our library

121. 121.

     Lowell BB. PPARg: an essential regulator of adipogenesis and modulator of fat cell function. Cell. 1999;99:239-242.

     Not in our library10.1016/s0092-8674(00)81654-2

122. 122.

     Lumeng CN, Maillard I, Saltiel AR. T-ing up inflammation in fat. Nat. Med. 2009;15:846-847.

     Not in our library10.1038/nm0809-846

123. 123.

     Lutz W, Sanderson W, Scherbov S. The coming acceleration of global population ageing. Nature. 2008;451:716-719.

     Not in our library10.1038/nature06516

124. 124.

     Mack I, BelAiba RS, Djordjevic T, Gorlach A, Hauner H, Bader BL. Functional analyses reveal the greater potency of preadipocytes compared with adipocytes as endothelial cell activator under normoxia, hypoxia, and TNFalpha exposure. Am. J. Physiol. Endocrinol. Metab. 2009;297:E735-E748.

     Not in our library10.1152/ajpendo.90851.2008

125. 125.

     Martin GM. Epigenetic gambling and epigenetic drift as an antagonistic pleiotropic mechanism of aging. Aging Cell. 2009;8:761-764.

     Not in our library10.1111/j.1474-9726.2009.00515.x

126. 126.

     Martin-Ruiz C, Saretzki G, Petrie J, Ladhoff J, Jeyapalan J, Wei W, Sedivy J, von Zglinicki T. Stochastic variation in telomere shortening rate causes heterogeneity of human fibroblast replicative lifespan. J. Biol. Chem. 2004;279:17826-17833.

     Not in our library10.1074/jbc.m311980200

127. 127.

     Masoro EJ. Caloric restriction and aging: controversial issues. J. Gerontol. A Biol. Sci. Med. Sci. 2006;61:14-19.

     Not in our library10.1093/gerona/61.1.14

128. 128.

     Matsuzawa Y, Shimomura I, Nakamura T, Keno Y, Kotani K, Tokunaga K. Pathophysiology and pathogenesis of visceral fat obesity. Obes. Res. 1995;3(Suppl. 2):187S-194S.

     Not in our library10.1002/j.1550-8528.1995.tb00462.x

129. 129.

     McDonald RB, Horwitz BA. Brown adipose tissue thermogenesis during aging and senescence. J. Bioenerg. Biomembr. 1999;31:507-516.

     Not in our library10.1023/a:1005404708710

130. 130.

     Meunier P, Aaron J, Edouard C, Vignon G. Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. Clin. Orthop. Relat. Res. 1971;80:147-154.

     Not in our library10.1097/00003086-197110000-00021

131. 131.

     Miard S, Picard F. Obesity and aging have divergent genomic fingerprints. Int. J. Obes. (Lond.). 2008;32:1873-1874.

     Not in our library10.1038/ijo.2008.214

132. 132.

     Mimura T, Joyce NC. Replication competence and senescence in central and peripheral human corneal endothelium. Invest. Ophthalmol. Vis. Sci. 2006;47:1387-1396.

     Not in our library10.1167/iovs.05-1199

133. 133.

     Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, Nojima A, Nabetani A, Oike Y, Matsubara H, Ishikawa F, Komuro I. A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat. Med. 2009;15:1082-1087.

     Not in our library10.1038/nm.2014

134. 134.

     Morin CL, Pagliassotti MJ, Windmiller D, Eckel RH. Adipose tissue-derived tumor necrosis factor-a activity is elevated in older rats. J. Gerontol. 1997;52A:B190-B195.

     Not in our library10.1093/gerona/52a.4.b190

135. 135.

     Morley JE. The metabolic syndrome and aging. J. Gerontol. A Biol. Sci. Med. Sci. 2004;59:139-142.

     Not in our library10.1093/gerona/59.2.m139

136. 136.

     Mu XC, Higgins PJ. Differential growth state-dependent regulation of plasminogen activator inhibitor type-1 expression in senescent IMR-90 human diploid fibroblasts. J. Cell. Physiol. 1995;165:647-657.

     Not in our library10.1002/jcp.1041650324

137. 137.

     Muzumdar R, Allison DB, Huffman DM, Ma X, Atzmon G, Einstein FH, Fishman S, Poduval AD, McVei T, Keith SW, Barzilai N. Visceral adipose tissue modulates mammalian longevity. Aging Cell. 2008;7:438-440.

     Not in our library10.1111/j.1474-9726.2008.00391.x

138. 138.
     The expression of adipogenic genes is decreased in obesity and diabetes mellitus · 2000

     Not checked
139. 139.

     Nair S, Lee YH, Rousseau E, Cam M, Tataranni PA, Baier LJ, Bogardus C, Permana PA. Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with non-obese Pima Indians. Diabetologia. 2005;48:1784-1788.

     Not in our library10.1007/s00125-005-1868-2

140. 140.

     Narita M, Lowe SW. Senescence comes of age. Nat. Med. 2005;11:920-922.

     Not in our library10.1038/nm0905-920

141. 141.

     Narita M, Nunez S, Heard E, Narita M, Lin AW, Hearn SA, Spector DL, Hannon GJ, Lowe SW. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell. 2003;113:703-716.

     Not in our library10.1016/s0092-8674(03)00401-x

142. 142.

     Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 2009;15:914-920.

     Not in our library10.1038/nm.1964

143. 143.

     Noer A, Lindeman LC, Collas P. Histone H3 modifications associated with differentiation and long-term culture of mesenchymal adipose stem cells. Stem Cells Dev. 2009;18:725-736.

     Not in our library10.1089/scd.2008.0189

144. 144.

     Palmer AJ, Chung MY, List EO, Walker J, Okada S, Kopchick JJ, Berryman DE. Age-related changes in body composition of bovine growth hormone transgenic mice. Endocrinology. 2009;150:1353-1360.

     Not in our library10.1210/en.2008-1199

145. 145.

     Parrinello S, Coppe JP, Krtolica A, Campisi J. Stromal-epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 2005;118:485-496.

     Not in our library10.1242/jcs.01635

146. 146.

     Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, Miwa S, Olijslagers S, Hallinan J, Wipat A, Saretzki G, Rudolph KL, Kirkwood TB, von Zglinicki T. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol. Syst. Biol. 2010;6:347.

     Not in our library10.1038/msb.2010.5

147. 147.
     Mitochondrial Dysfunction Accounts for the Stochastic Heterogeneity in Telomere-Dependent Senescence · 2007

     No notice
148. 148.

     Passos JF, Simillion C, Hallinan J, Wipat A, von Zglinicki T. Cellular senescence: unravelling complexity. Age (Dordr.). 2009.

     Not in our library10.1007/s11357-009-9108-1

149. 149.

     Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG. Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 2008;8:301-309.

     Not in our library10.1016/j.cmet.2008.08.015

150. 150.

     Permana PA, Nair S, Lee YH, Luczy-Bachman G, Vozarova de Courten B, Tataranni PA. Subcutaneous abdominal preadipocyte differentiation in vitro inversely correlates with central obesity. Am. J. Physiol. 2004;286:E958-E962.

     Not in our library10.1152/ajpendo.00544.2003

151. 151.

     Perreault M, Marette A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat. Med. 2001;7:1138-1143.

     Not in our library10.1038/nm1001-1138

152. 152.

     Pischon T, Boeing H, Hoffmann K, Bergmann M, Schulze MB, Overvad K, van der Schouw YT, Spencer E, Moons KG, Tjonneland A, Halkjaer J, Jensen MK, Stegger J, Clavel-Chapelon F, Boutron-Ruault MC, Chajes V, Linseisen J, Kaaks R, Trichopoulou A, Trichopoulos D, Bamia C, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, May AM, Bueno-de-Mesquita HB, van Duijnhoven FJ, Hallmans G, Weinehall L, Manjer J, Hedblad B, Lund E, Agudo A, Arriola L, Barricarte A, Navarro C, Martinez C, Quiros JR, Key T, Bingham S, Khaw KT, Boffetta P, Jenab M, Ferrari P, Riboli E. General and abdominal adiposity and risk of death in Europe. N. Engl. J. Med. 2008;359:2105-2120.

     Not in our library10.1056/nejmoa0801891

153. 153.

     Poehls J, Wassel CL, Harris TB, Havel PJ, Swarbrick MM, Cummings SR, Newman AB, Satterfield S, Kanaya AM. Association of adiponectin with mortality in older adults: the Health, Aging, and Body Composition Study. Diabetologia. 2009;52:591-595.

     Not in our library10.1007/s00125-009-1261-7

154. 154.

     Rabkin SW. Epicardial fat: properties, function and relationship to obesity. Obes. Rev. 2007;8:253-261.

     Not in our library10.1111/j.1467-789x.2006.00293.x

155. 155.

     Raguso CA, Kyle U, Kossovsky MP, Roynette C, Paoloni-Giacobino A, Hans D, Genton L, Pichard C. A 3-year longitudinal study on body composition changes in the elderly: role of physical exercise. Clin. Nutr. 2006;25:573-580.

     Not in our library10.1016/j.clnu.2005.10.013

156. 156.

     Rizza S, Gigli F, Galli A, Micchelini B, Lauro D, Lauro R, Federici M. Adiponectin isoforms in elderly patients with or without coronary artery disease. J. Am. Geriatr. Soc. 2010;58:702-706.

     Not in our library10.1111/j.1532-5415.2010.02773.x

157. 157.

     Rosen ED. The transcriptional basis of adipocyte development. Prost. Leu. Essential FA. 2005;73:31-34.

     Not in our library10.1016/j.plefa.2005.04.004

158. 158.

     Rosen CJ, Ackert-Bicknell C, Rodriguez JP, Pino AM. Marrow fat and the bone microenvironment: developmental, functional, and pathological implications. Crit. Rev. Eukaryot. Gene Expr. 2009;19:109-124.

     Not in our library10.1615/critreveukargeneexpr.v19.i2.20

159. 159.

     Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, Bandyopadhyay G, Verma IM, Olefsky JM. Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab. 2009;10:419-429.

     Not in our library10.1016/j.cmet.2009.09.006

160. 160.

     Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide. J. Clin. Invest. 1996;97:37-46.

     Not in our library10.1172/jci118404

161. 161.

     Samad F, Yamamoto K, Pandey M, Loskutoff DJ. Elevated expression of transforming growth factor-beta in adipose tissue from obese mice. Mol. Med. 1997;3:37-48.

     Not in our library

162. 162.

     Samad F, Pandey M, Loskutoff DJ. Tissue factor gene expression in the adipose tissues of obese mice. Proc. Natl Acad. Sci. USA. 1998;95:7591-7596.

     Not in our library10.1073/pnas.95.13.7591

163. 163.

     Samaras K, Botelho NK, Chisholm DJ, Lord RV. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes. Obesity (Silver Spring). 2010;18:884-889.

     Not in our library10.1038/oby.2009.443

164. 164.

     Sartipy P, Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc. Natl Acad. Sci. USA. 2003;100:7265-7270.

     Not in our library10.1073/pnas.1133870100

165. 165.

     Schipper BM, Marra KG, Zhang W, Donnenberg AD, Rubin JP. Regional anatomic and age effects on cell function of human adipose-derived stem cells. Ann. Plast. Surg. 2008;60:538-544.

     Not in our library10.1097/sap.0b013e3181723bbe

166. 166.

     Sebastian C, Lloberas J, Celada A, Fulop T. Molecular and cellular aspects of macrophage aging. Handbook on Immunosenescence. 2009;919-945.

     Not in our library

167. 167.

     Sekimoto H, Eipper-Mains J, Pond-Tor S, Boney CM. (alpha)v(beta)3 integrins and Pyk2 mediate insulin-like growth factor I activation of Src and mitogen-activated protein kinase in 3T3-L1 cells. Mol. Endocrinol. 2005;19:1859-1867.

     Not in our library10.1210/me.2004-0481

168. 168.

     Selman C, Lingard S, Choudhury AI, Batterham RL, Claret M, Clements M, Ramadani F, Okkenhaug K, Schuster E, Blanc E, Piper MD, Al-Qassab H, Speakman JR, Carmignac D, Robinson IC, Thornton JM, Gems D, Partridge L, Withers DJ. Evidence for lifespan extension and delayed age-related biomarkers in insulin receptor substrate 1 null mice. FASEB J. 2008;22:807-818.

     Not in our library10.1096/fj.07-9261com

169. 169.

     Selman C, Tullet JM, Wieser D, Irvine E, Lingard SJ, Choudhury AI, Claret M, Al-Qassab H, Carmignac D, Ramadani F, Woods A, Robinson IC, Schuster E, Batterham RL, Kozma SC, Thomas G, Carling D, Okkenhaug K, Thornton JM, Partridge L, Gems D, Withers DJ. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science. 2009;326:140-144.

     Not in our library10.1126/science.1177221

170. 170.

     Semple RK, Crowley VC, Sewter CP, Laudes M, Christodoulides C, Considine RV, Vidal-Puig A, O’Rahilly S. Expression of the thermogenic nuclear hormone receptor coactivator PGC-1alpha is reduced in the adipose tissue of morbidly obese subjects. Int. J. Obes. Relat. Metab. Disord. 2004;28:176-179.

     Not in our library10.1038/sj.ijo.0802482

171. 171.

     Sherr CJ, DePinho RA. Cellular senescence: mitotic clock or culture shock? Cell. 2000;102:407-410.

     Not in our library10.1016/s0092-8674(00)00046-5

172. 172.

     Shillabeer G, Forden JM, Russell JC, Lau DC. Paradoxically slow preadipocyte replication and differentiation in corpulent rats. Am. J. Physiol. 1990;258:E368-E376.

     Not in our library10.1152/ajpendo.1990.258.2.e368

173. 173.

     Silver AJ, Guillen CP, Kahl MJ, Morley JE. Effect of aging on body fat. J. Am. Geriatr. Soc. 1993;41:211-213.

     Not in our library10.1111/j.1532-5415.1993.tb06693.x

174. 174.

     Slawik M, Vidal-Puig AJ. Lipotoxicity, overnutrition and energy metabolism in aging. Ageing Res. Rev. 2006;5:144-164.

     Not in our library10.1016/j.arr.2006.03.004

175. 175.

     Sokolov MV, Dickey JS, Bonner WM, Sedelnikova OA. gamma-H2AX in bystander cells: not just a radiation-triggered event, a cellular response to stress mediated by intercellular communication. Cell Cycle. 2007;6:2210-2212.

     Not in our library10.4161/cc.6.18.4682

176. 176.

     Starr ME, Evers BM, Saito H. Age-associated increase in cytokine production during systemic inflammation: adipose tissue as a major source of IL-6. J. Gerontol. A Biol. Sci. Med. Sci. 2009;64:723-730.

     Not in our library10.1093/gerona/glp046

177. 177.

     Stenholm S, Koster A, Alley DE, Visser M, Maggio M, Harris TB, Egan JM, Bandinelli S, Guralnik JM, Ferrucci L. Adipocytokines and the metabolic syndrome among older persons with and without obesity – the InCHIANTI Study. Clin. Endocrinol. (Oxf.). 2009.

     Not in our library10.1111/j.1365-2265.2009.03742.x

178. 178.

     Stout RD, Suttles J. Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes. Immunol. Rev. 2005;205:60-71.

     Not in our library10.1111/j.0105-2896.2005.00260.x

179. 179.

     Strissel K, Stancheva Z, Miyoshi H, Perfield JW, Defuria J, Jick Z, Greenberg AS, Obin MS. Adipocyte death, adipose tissue remodeling and obesity complications. Diabetes. 2007;56:2910-2918.

     Not in our library10.2337/db07-0767

180. 180.

     Suganami T, Nishida J, Ogawa Y. A paracrine loop between adipocytes and macrophages aggravates inflammatory changes: role of free fatty acids and tumor necrosis factor alpha. Arterioscler. Thromb. Vasc. Biol. 2005;25:2062-2068.

     Not in our library10.1161/01.atv.0000183883.72263.13

181. 181.

     Takahashi K, Mizuarai S, Araki H, Mashiko S, Ishihara A, Kanatani A, Itadani H, Kotani H. Adiposity elevates plasma MCP-1 levels leading to the increased CD11b-positive monocytes in mice. J. Biol. Chem. 2003;278:46654-46660.

     Not in our library10.1074/jbc.m309895200

182. 182.

     Tang W, Zeve D, Suh JM, Bosnakovski D, Kyba M, Hammer RE, Tallquist MD, Graff JM. White fat progenitor cells reside in the adipose vasculature. Science. 2008;322:583-586.

     Not in our library10.1126/science.1156232

183. 183.

     Taylor-Jones JM, McGehee RE, Rando TA, Lecka-Czernik B, Lipschitz D, Peterson CA. Activation of an adipogenic program in adult skeletal muscle myoblasts with age. Mech. Ageing Dev. 2002;123:649-661.

     Not in our library10.1016/s0047-6374(01)00411-0

184. 184.

     Tchkonia T, Karagiannides I, Forse RA, Kirkland JL. Different fat depots are distinct mini-organs. Curr. Opin. Endocrinol. Diabetes. 2001;8:227-234.

     Not in our library

185. 185.

     Tchkonia T, Giorgadze N, Pirtskhalava T, Tchoukalova Y, Karagiannides I, Forse RA, DePonte M, Stevenson M, Guo W, Han J, Waloga G, Lash TL, Jensen MD, Kirkland JL. Fat depot origin affects adipogenesis in primary cultured and cloned human preadipocytes. Am. J. Physiol. 2002;282:R1286-R1296.

     Not in our library10.1152/ajpregu.00653.2001

186. 186.

     Tchkonia T, Tchoukalova YD, Giorgadze N, Pirtskhalava T, Karagiannides I, Forse RA, Koo A, Stevenson M, Chinnappan D, Cartwright A, Jensen MD, Kirkland JL. Abundance of two human preadipocyte subtypes with distinct capacities for replication, adipogenesis, and apoptosis varies among fat depots. Am. J. Physiol. 2005;288:E267-E277.

     Not in our library10.1152/ajpendo.00265.2004

187. 187.

     Tchkonia T, Corkey BE, Kirkland JL. Current views of the fat cell as an endocrine cell: lipotoxicity. Endocr. Updates. 2006a;26:105-118.

     Not in our library

188. 188.

     Tchkonia T, Giorgadze N, Pirtskhalava T, Thomou T, DePonte M, Koo A, Forse RA, Chinnappan D, Carmen Martin-Ruiz C, von Zglinicki T, Kirkland JL. Fat depot-specific characteristics are retained in strains derived from single human preadipocytes. Diabetes. 2006b;55:2571-2578.

     Not in our library10.2337/db06-0540

189. 189.

     Tchkonia T, Cartwright M, Wise B, Pirtskhalava T, Karagiannides I, Shpilman A, Beckerer D, Kirkland JL. Increased TNFa and CCAAT/enhancer binding protein homologous protein (CHOP) with aging predispose preadipocytes to resist adipogenesis. Am. J. Physiol. 2007a;293:E1810-E1819.

     Not in our library10.1152/ajpendo.00295.2007

190. 190.

     Tchkonia T, Lenburg M, Thomou T, Giorgadze N, Frampton G, Pirtskhalava T, Cartwright A, Cartwright M, Flanagan J, Karagiannides I, Gerry N, Forse RA, Tchoukalova Y, Jensen MD, Pothoulakis C, Kirkland JL. Identification of depot-specific human fat cell progenitors through distinct expression profiles and developmental gene patterns. Am. J. Physiol. 2007b;292:E298-E307.

     Not in our library10.1152/ajpendo.00202.2006

191. 191.

     Tchkonia T, Giorgadze N, Pirtskhalava T, Thomou T, Villaret A, Bouloumie A, von Zglinicki T, Kirkland JL. Cellular senescence and inflammation in obesity. Obesity. 2009;17(Suppl. 2):S57.

     Not in our library

192. 192.

     Tchoukalova Y, Koutsari C, Jensen M. Committed subcutaneous preadipocytes are reduced in human obesity. Diabetologia. 2007;50:151-157.

     Not in our library10.1007/s00125-006-0496-9

193. 193.

     Thomou T, Tchkonia T, Kirkland JL, Leff TA, Granneman JG. The cellular and molecular basis of functional differences among fat depots. Adipose Tissue in Health and Disease. 2010;21-47.

     Not in our library

194. 194.

     Tran TT, Yamamoto Y, Gesta S, Kahn CR. Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 2008;7:410-420.

     Not in our library10.1016/j.cmet.2008.04.004

195. 195.

     Turkenkopf IJ, Chow G, East-Palmer J, Greenwood MR, Johnson PR. Regional and genotypic differences in stromal-vascular cells from obese and lean Zucker rats. Int. J. Obes. Relat. Metab. Disord. 1988;12:515-524.

     Not in our library

196. 196.

     Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004;431:200-205.

     Not in our library10.1038/nature02866

197. 197.

     Unger RH. Lipotoxic diseases. Annu. Rev. Med. 2002;53:319-336.

     Not in our library10.1146/annurev.med.53.082901.104057

198. 198.

     Unger RH. Longevity, lipotoxicity and leptin: the adipocyte defense against feasting and famine. Biochimie. 2005;87:57-64.

     Not in our library10.1016/j.biochi.2004.11.014

199. 199.

     Uranga AP, Levine J, Jensen M. Isotope tracer measures of meal fatty acid metabolism: reproducibility and effects of the menstrual cycle. Am. J. Physiol. Endocrinol. Metab. 2005;288:E547-E555.

     Not in our library10.1152/ajpendo.00340.2004

200. 200.

     Valle A, Guevara R, Garcia-Palmer FJ, Roca P, Oliver J. Caloric restriction retards the age-related decline in mitochondrial function of brown adipose tissue. Rejuvenation Res. 2008;11:597-604.

     Not in our library10.1089/rej.2007.0626

201. 201.

     Vasile E, Tomita Y, Brown LF, Kocher O, Dvorak HF. Differential expression of thymosin beta-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: evidence for senescent endothelial cells in vivo at sites of atherosclerosis. FASEB J. 2001;15:458-466.

     Not in our library10.1096/fj.00-0051com

202. 202.

     Vgontzas AN, Papanicolaou DA, Bixler EO, Kales A, Tyson K, Chrousos GP. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J. Clin. Endocrinol. Metab. 1997;82:1313-1316.

     Not in our library10.1210/jcem.82.5.3950

203. 203.

     Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB. Elevated C-reactive protein levels in overweight and obese adults. J. Am. Med. Assoc. 1999;282:2131-2135.

     Not in our library10.1001/jama.282.22.2131

204. 204.

     Visser M, Pahor M, Tylavsky F, Kritchevsky SB, Cauley JA, Newman AB, Blunt BA, Harris TB. One- and two-year change in body composition as measured by DXA in a population-based cohort of older men and women. J. Appl. Physiol. 2003;94:2368-2374.

     Not in our library10.1152/japplphysiol.00124.2002

205. 205.

     Vitseva OI, Tanriverdi K, Tchkonia TT, Kirkland JL, McDonnell ME, Apovian CM, Freedman J, Gokce N. Inducible Toll-like receptor and NF-kappaB regulatory pathway expression in human adipose tissue. Obesity (Silver Spring). 2008;16:932-937.

     Not in our library10.1038/oby.2008.25

206. 206.

     Wang H, Kirkland JL, Hollenberg CH. Varying capacities for replication of rat adipocyte precursor clones and adipose tissue growth. J. Clin. Invest. 1989;83:1741-1746.

     Not in our library10.1172/jci114075

207. 207.

     Wang C, Jurk D, Maddick M, Nelson G, Martin-Ruiz C, von Zglinicki T. DNA damage response and cellular senescence in tissues of aging mice. Aging Cell. 2009a;8:311-323.

     Not in our library10.1111/j.1474-9726.2009.00481.x

208. 208.

     Wang CY, Kim HH, Hiroi Y, Sawada N, Salomone S, Benjamin LE, Walsh K, Moskowitz MA, Liao JK. Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR. Sci. Signal. 2009b;2:ra11.

     Not in our library10.1126/scisignal.2000143

209. 209.

     Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Decreased muscle mass and increased central adiposity are independently related to mortality in older men. Am. J. Clin. Nutr. 2007;86:1339-1346.

     Not in our library10.1093/ajcn/86.5.1339

210. 210.

     Weber RV, Buckley MC, Fried SK, Kral JG. Subcutaneous lipectomy causes a metabolic syndrome in hamsters. Am. J. Physiol. 2000;279:R936-R943.

     Not in our library10.1152/ajpregu.2000.279.3.r936

211. 211.

     Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 2003;112:1796-1808.

     Not in our library10.1172/jci19246

212. 212.

     Weyer C, Yudkin JS, Stehouwer CD, Schalkwijk CG, Pratley RE, Tataranni PA. Humoral markers of inflammation and endothelial dysfunction in relation to adiposity and in vivo insulin action in Pima Indians. Atherosclerosis. 2002;161:233-242.

     Not in our library10.1016/s0021-9150(01)00626-8

213. 213.

     Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 2009;15:921-929.

     Not in our library10.1038/nm.2001

214. 214.

     Wu Z, Xie Y, Bucher NLR, Farmer SR. Conditional ectopic expression of C/EBPb in NIH-3T3 cells induces PPARg and stimulates adipogenesis. Genes Dev. 1995;9:2350-2363.

     Not in our library10.1101/gad.9.19.2350

215. 215.

     Wu Z, Bucher NLR, Farmer SR. Induction of peroxisome proliferator-activated receptor g during the conversion of 3T3 fibroblasts into adipocytes is mediated by C/EBPb, C/EBPd and glucocorticoids. Mol. Cell. Biol. 1996;16:4128-4136.

     Not in our library10.1128/mcb.16.8.4128

216. 216.

     Wu Z, Rosen ED, Brun R, Hauser S, Adelmant G, Troy AE, McKeon C, Darlington GJ, Spiegelman BM. Cross-regulation of C/EBPa and PPARg controls the transcriptional pathway of adipogenesis and insulin sensitivity. Mol. Cell. 1999;3:151-158.

     Not in our library10.1016/s1097-2765(00)80306-8

217. 217.

     Wu D, Ren Z, Pae M, Guo W, Cui X, Merrill AH, Meydani SN. Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J. Immunol. 2007;179:4829-4839.

     Not in our library10.4049/jimmunol.179.7.4829

218. 218.

     Xie W, Hamilton JA, Kirkland JL, Corkey BE, Guo W. Oleate-induced formation of fat cells with impaired insulin sensitivity. Lipids. 2006;41:267-271.

     Not in our library10.1007/s11745-006-5096-4

219. 219.

     Xu H, Uysal KT, Becherer JD, Arner P, Hotamisligil GS. Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity. Diabetes. 2002;51:1876-1883.

     Not in our library10.2337/diabetes.51.6.1876

220. 220.

     Xu H, Barnes GT, Yang Q, Tna G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 2003;112:1821-1830.

     Not in our library10.1172/jci19451

221. 221.

     Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007;445:656-660.

     Not in our library10.1038/nature05529

222. 222.

     Yamamoto Y, Gesta S, Lee KY, Tran TT, Saadatirad P, Kahn CR. Adipose depots possess unique developmental gene signatures. Obesity (Silver Spring). 2010;18:872-878.

     Not in our library10.1038/oby.2009.512

223. 223.

     Yeh WC, Cao M, Classon M, McKnight SL. Cascade regulation of terminal adipocyte differentiation by three members of the C/EBP family of leucine zipper proteins. Genes Dev. 1995;9:168-181.

     Not in our library10.1101/gad.9.2.168

224. 224.

     Yki-Jarvinen H, Kiviluoto T, Nikkila EA. Insulin binding and action in adipocytes in vitro in relation to insulin action in vivo in young and middle-aged subjects. Acta Endocrinol. 1986;113:88-92.

     Not in our library10.1530/acta.0.1130088

225. 225.

     Yu BP, Masoro EJ, Murata I, Bertrand HA, Lynd FT. Lifespan study of SPF Fischer 344 male rats fed ad libitum or restricted diets: longevity, growth lean body mass and disease. J. Gerontol. 1982;37:130-141.

     Not in our library10.1093/geronj/37.2.130

226. 226.

     Zhang Y, Herbert BS, Rajashekhar G, Ingram DA, Yoder MC, Clauss M, Rehman J. Premature senescence of highly proliferative endothelial progenitor cells is induced by tumor necrosis factor-alpha via the p38 mitogen-activated protein kinase pathway. FASEB J. 2009;23:1358-1365.

     Not in our library10.1096/fj.08-110296

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