Aging and adipose tissue: potential interventions for diabetes and regenerative medicine

Experimental Gerontology

Volumn 86, Issue , 2016, Pages 97-105

  Palmer, Allyson K ^a   Kirkland, James L ^a  

^a MAYO CLINIC   (United States)

Author keywords

Adipose Tissue; Aging; Cellular Senescence; Insulin Resistance; Preadipocyte; Stem Cell

Indexed keywords

CCAAT ENHANCER BINDING PROTEIN ALPHA; INSULIN; METFORMIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; HORMONE;

ADIPOSE DERIVED STEM CELL; ADIPOSE TISSUE; AGING; BODY FAT; BROWN ADIPOSE TISSUE; CARDIOVASCULAR DISEASE; CELL AGING; DEMENTIA; DISEASE PREDISPOSITION; GENE CONTROL; HUMAN; INFLAMMATION; INSULIN RESISTANCE; INSULIN SENSITIVITY; LIFESPAN; LIPID STORAGE; LONGEVITY; MALIGNANT NEOPLASTIC DISEASE; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PRIORITY JOURNAL; PROADIPOCYTE; PROTEIN EXPRESSION; REGENERATIVE MEDICINE; REVIEW; STEM CELL; STEM CELL TRANSPLANTATION; TISSUE DISTRIBUTION; ADIPOCYTE; ADULT; AGED; BODY FAT DISTRIBUTION; DIABETES MELLITUS, TYPE 2; LIPID METABOLISM; MIDDLE AGED; PATHOPHYSIOLOGY; PHYSIOLOGY; PROCEDURES; REGENERATION;

ADIPOCYTES; ADIPOSE TISSUE; ADULT; AGED; AGING; BODY FAT DISTRIBUTION; CELL AGING; DIABETES MELLITUS, TYPE 2; HORMONES; HUMANS; INFLAMMATION; INSULIN RESISTANCE; LIPID METABOLISM; MIDDLE AGED; OBESITY; REGENERATION; REGENERATIVE MEDICINE; STEM CELLS;

EID: 84959440332     PISSN: 05315565     EISSN: 18736815     Source Type: Journal    
DOI: 10.1016/j.exger.2016.02.013     Document Type: Review

References (138)

1. Allison, D.B., Faith, M.S., Heo, M., Kotler, D.P., Hypothesis concerning the U-shaped relation between body mass index and mortality. Am. J. Epidemiol. 146 (1997), 339–349.
2. Asterholm, I.W., McDonald, J., Blanchard, P.G., Sinha, M., Xiao, Q., Mistry, J., Rutkowski, J.M., Deshaies, Y., Brekken, R.A., Scherer, P.E., Lack of “immunological fitness” during fasting in metabolically challenged animals. J. Lipid Res. 53 (2012), 1254–1267.
3. Atzmon, G., Yang, X.M., Muzumdar, R., Ma, X.H., Gabriely, I., Barzilai, N., Differential gene expression between visceral and subcutaneous fat depots. Horm. Metab. Res. 34 (2002), 622–628.
4. Atzmon, G., Pollin, T.I., Crandall, J., Tanner, K., Schechter, C.B., Scherer, P.E., Rincon, M., Siegel, G., Katz, M., Lipton, R.B., Shuldiner, A.R., Barzilai, N., Adiponectin levels and genotype: a potential regulator of life span in humans. J. Gerontol. Ser. A Biol. Med. Sci. 63 (2008), 447–453.
5. Baker, D.J., Perez-Terzic, C., Jin, F., Pitel, K.S., Niederlander, N.J., Jeganathan, K., Yamada, S., Reyes, S., Rowe, L., Hiddinga, H.J., Eberhardt, N.L., Terzic, A., van Deursen, J.M., Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10 (2008), 825–836.
6. Baker, D.J., Wijshake, T., Tchkonia, T., LeBrasseur, N.K., Childs, B.G., van de Sluis, B., Kirkland, J.L., van Deursen, J.M., Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479 (2011), 232–236.
7. Bannister, C.A., Holden, S.E., Jenkins-Jones, S., Morgan, C.L., Halcox, J.P., Schernthaner, G., Mukherjee, J., Currie, C.J., Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes. Metab., 2014.
8. Blaum, C.S., Xue, Q.L., Michelon, E., Semba, R.D., Fried, L.P., The association between obesity and the frailty syndrome in older women: the Women's Health and Aging Studies. J. Am. Geriatr. Soc. 53 (2005), 927–934.
9. Bluher, M., Kahn, B.B., Kahn, C.R., Extended longevity in mice lacking the insulin receptor in adipose tissue. Science (New York, N.Y.) 299 (2003), 572–574.
10. Bonora, E., Del Prato, S., Bonadonna, R.C., Gulli, G., Solini, A., Shank, M.L., Ghiatas, A.A., Lancaster, J.L., Kilcoyne, R.F., Alyassin, A.M., et al. Total body fat content and fat topography are associated differently with in vivo glucose metabolism in nonobese and obese nondiabetic women. Diabetes 41 (1992), 1151–1159.
11. Calle, E.E., Rodriguez, C., Walker-Thurmond, K., Thun, M.J., Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348 (2003), 1625–1638.
12. Carlson, M.E., Conboy, M.J., Hsu, M., Barchas, L., Jeong, J., Agrawal, A., Mikels, A.J., Agrawal, S., Schaffer, D.V., Conboy, I.M., Relative roles of TGF-beta1 and Wnt in the systemic regulation and aging of satellite cell responses. Aging Cell 8 (2009), 676–689.
13. Cartwright, M.J., Tchkonia, T., Kirkland, J.L., Aging in adipocytes: potential impact of inherent, depot-specific mechanisms. Exp. Gerontol. 42 (2007), 463–471.
14. Caso, G., McNurlan, M.A., Mileva, I., Zemlyak, A., Mynarcik, D.C., Gelato, M.C., Peripheral fat loss and decline in adipogenesis in older humans. Metab. Clin. Exp. 62 (2013), 337–340.
15. Chen, G.Y., Nunez, G., Sterile inflammation: sensing and reacting to damage. Nat. Rev. Immunol. 10 (2010), 826–837.
16. Chen, M., Bergman, R.N., Pacini, G., Porte, D. Jr., Pathogenesis of age-related glucose intolerance in man: insulin resistance and decreased beta-cell function. J. Clin. Endocrinol. Metab. 60 (1985), 13–20.
17. Coleman, S.R., Grover, R., The anatomy of the aging face: volume loss and changes in 3-dimensional topography. Aesthet. Surg. J. 26 (2006), S4–S9.
18. Conboy, I.M., Conboy, M.J., Wagers, A.J., Girma, E.R., Weissman, I.L., Rando, T.A., Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433 (2005), 760–764.
19. Conboy, I.M., Conboy, M.J., Rebo, J., Systemic problems: a perspective on stem cell aging and rejuvenation. Aging 7 (2015), 754–765.
20. Coppe, J.P., Patil, C.K., Rodier, F., Sun, Y., Munoz, D.P., Goldstein, J., Nelson, P.S., Desprez, P.Y., Campisi, J., Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6 (2008), 2853–2868.
21. Cypess, A.M., Lehman, S., Williams, G., Tal, I., Rodman, D., Goldfine, A.B., Kuo, F.C., Palmer, E.L., Tseng, Y.H., Doria, A., Kolodny, G.M., Kahn, C.R., Identification and importance of brown adipose tissue in adult humans. N. Engl. J. Med. 360 (2009), 1509–1517.
22. Danforth, E. Jr., Failure of adipocyte differentiation causes type II diabetes mellitus?. Nat. Genet., 26, 2000, 13.
23. De Pergola, G., Silvestris, F., Obesity as a major risk factor for cancer. J. Obes., 291546, 2013, 2013.
24. Defronzo, R.A., Glucose intolerance and aging: evidence for tissue insensitivity to insulin. Diabetes 28 (1979), 1095–1101.
25. Delmonico, M.J., Harris, T.B., Visser, M., Park, S.W., Conroy, M.B., Velasquez-Mieyer, P., Boudreau, R., Manini, T.M., Nevitt, M., Newman, A.B., Goodpaster, B.H., Health, A., Body. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am. J. Clin. Nutr. 90 (2009), 1579–1585.
26. Demaria, M., Ohtani, N., Youssef, S.A., Rodier, F., Toussaint, W., Mitchell, J.R., Laberge, R.M., Vijg, J., Van Steeg, H., Dolle, M.E., Hoeijmakers, J.H., de Bruin, A., Hara, E., Campisi, J., An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31 (2014), 722–733.
27. Donofrio, L.M., Fat distribution: a morphologic study of the aging face. Dermatol. Surg. 26 (2000), 1107–1112 ([et al]).
28. Fabbrini, E., Tamboli, R.A., Magkos, F., Marks-Shulman, P.A., Eckhauser, A.W., Richards, W.O., Klein, S., Abumrad, N.N., Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. Gastroenterology 139 (2010), 448–455.
29. Fernandez-Real, J.M., Lopez-Bermejo, A., Casamitjana, R., Ricart, W., Novel interactions of adiponectin with the endocrine system and inflammatory parameters. J. Clin. Endocrinol. Metab. 88 (2003), 2714–2718.
30. Folsom, A.R., Kaye, S.A., Sellers, T.A., Hong, C.P., Cerhan, J.R., Potter, J.D., Prineas, R.J., Body fat distribution and 5-year risk of death in older women. J. Am. Med. Assoc. 269 (1993), 483–487.
31. Fonseca, V., Effect of thiazolidinediones on body weight in patients with diabetes mellitus. Am. J. Med. 115:Suppl. 8 A (2003), 42S–48S.
32. Fontana, L., Klein, S., Aging, adiposity, and calorie restriction. J. Am. Med. Assoc. 297 (2007), 986–994.
33. Fox, C.S., Massaro, J.M., Hoffmann, U., Pou, K.M., Maurovich-Horvat, P., Liu, C.Y., Vasan, R.S., Murabito, J.M., Meigs, J.B., Cupples, L.A., D'Agostino, R.B. Sr., O'Donnell, C.J., Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation 116 (2007), 39–48.
34. Fu, Y., Luo, N., Klein, R.L., Garvey, W.T., Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation. J. Lipid Res. 46 (2005), 1369–1379.
35. Furukawa, S., Fujita, T., Shimabukuro, M., Iwaki, M., Yamada, Y., Nakajima, Y., Nakayama, O., Makishima, M., Matsuda, M., Shimomura, I., Increased oxidative stress in obesity and its impact on metabolic syndrome. J. Clin. Invest. 114 (2004), 1752–1761.
36. Gabriely, I., Ma, X.H., Yang, X.M., Rossetti, L., Barzilai, N., Leptin resistance during aging is independent of fat mass. Diabetes 51 (2002), 1016–1021.
37. Garg, S.K., Delaney, C., Shi, H., Yung, R., Changes in adipose tissue macrophages and T cells during aging. Crit. Rev. Immunol. 34 (2014), 1–14.
38. Gavi, S., Feiner, J.J., Melendez, M.M., Mynarcik, D.C., Gelato, M.C., McNurlan, M.A., Limb fat to trunk fat ratio in elderly persons is a strong determinant of insulin resistance and adiponectin levels. J. Gerontol. Ser. A Biol. Med. Sci. 62 (2007), 997–1001.
39. Giannakou, M.E., Goss, M., Junger, M.A., Hafen, E., Leevers, S.J., Partridge, L., Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science (New York, N.Y.), 305, 2004, 361.
40. Gilbert, C.A., Slingerland, J.M., Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annu. Rev. Med. 64 (2013), 45–57.
41. Guo, S.S., Zeller, C., Chumlea, W.C., Siervogel, R.M., Aging, body composition, and lifestyle: the Fels Longitudinal Study. Am. J. Clin. Nutr. 70 (1999), 405–411.
42. Guo, W., Pirtskhalava, T., Tchkonia, T., Xie, W., Thomou, T., Han, J., Wang, T., Wong, S., Cartwright, A., Hegardt, F.G., Corkey, B.E., Kirkland, J.L., Aging results in paradoxical susceptibility of fat cell progenitors to lipotoxicity. Am. J. Physiol. Endocrinol. Metab. 292 (2007), E1041–E1051.
43. Gustafson, B., Hedjazifar, S., Gogg, S., Hammarstedt, A., Smith, U., Insulin resistance and impaired adipogenesis. Trends Endocrinol. Metab. 26 (2015), 193–200.
44. Hamm, J.K., el Jack, A.K., Pilch, P.F., Farmer, S.R., Role of PPAR gamma in regulating adipocyte differentiation and insulin-responsive glucose uptake. Ann. N. Y. Acad. Sci. 892 (1999), 134–145.
45. Harris, M.I., Klein, R., Welborn, T.A., Knuiman, M.W., Onset of NIDDM occurs at least 4–7 yr before clinical diagnosis. Diabetes Care 15 (1992), 815–819.
46. Herrera, M.F., Pantoja, J.P., Velazquez-Fernandez, D., Cabiedes, J., Aguilar-Salinas, C., Garcia-Garcia, E., Rivas, A., Villeda, C., Hernandez-Ramirez, D.F., Davila, A., Zarain, A., Potential additional effect of omentectomy on metabolic syndrome, acute-phase reactants, and inflammatory mediators in grade III obese patients undergoing laparoscopic Roux-en-Y gastric bypass: a randomized trial. Diabetes Care 33 (2010), 1413–1418.
47. Hubbard, R.E., Lang, I.A., Llewellyn, D.J., Rockwood, K., Frailty, body mass index, and abdominal obesity in older people. J. Gerontol. Ser. A Biol. Med. Sci. 65 (2010), 377–381.
48. Huffman, D.M., Barzilai, N., Role of visceral adipose tissue in aging. Biochim. Biophys. Acta 1790 (2009), 1117–1123.
49. Huffman, D.M., Barzilai, N., Contribution of adipose tissue to health span and longevity. Interdiscip. Top. Gerontol. 37 (2010), 1–19.
50. Idoate, F., Cadore, E.L., Casas-Herrero, A., Zambom-Ferraresi, F., Marcellan, T., Ruiz de Gordoa, A., Rodriguez-Manas, L., Bastarrika, G., Marques, M.C., Martinez-Velilla, N., Vicente-Campos, D., Izquierdo, M., Adipose tissue compartments, muscle mass, muscle fat infiltration, and coronary calcium in institutionalized frail nonagenarians. Eur. Radiol. 25 (2015), 2163–2175.
51. Itoh, M., Suganami, T., Hachiya, R., Ogawa, Y., Adipose tissue remodeling as homeostatic inflammation. Int. J. Inflamm., 720926, 2011, 2011.
52. Jensen, M.D., Role of body fat distribution and the metabolic complications of obesity. J. Clin. Endocrinol. Metab. 93 (2008), S57–S63.
53. Jerschow, E., Anwar, S.A., Barzilai, N., Rosenstreich, D., Macrophages accumulation in visceral and subcutaneous adipose tissue correlates with age. J. Allergy Clin. Immunol., 119, 2007, S179.
54. Kanda, H., Tateya, S., Tamori, Y., Kotani, K., Hiasa, K., Kitazawa, R., Kitazawa, S., Miyachi, H., Maeda, S., Egashira, K., Kasuga, M., MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Investig. 116 (2006), 1494–1505.
55. Karagiannides, I., Tchkonia, T., Dobson, D.E., Steppan, C.M., Cummins, P., Chan, G., Salvatori, K., Hadzopoulou-Cladaras, M., Kirkland, J.L., Altered expression of C/EBP family members results in decreased adipogenesis with aging. Am. J. Physiol. Regul. Integr. Comp. Physiol. 280 (2001), R1772–R1780.
56. Karakasilioti, I., Kamileri, I., Chatzinikolaou, G., Kosteas, T., Vergadi, E., Robinson, A.R., Tsamardinos, I., Rozgaja, T.A., Siakouli, S., Tsatsanis, C., Niedernhofer, L.J., Garinis, G.A., DNA damage triggers a chronic autoinflammatory response, leading to fat depletion in NER progeria. Cell Metab. 18 (2013), 403–415.
57. Karakelides, H., Irving, B.A., Short, K.R., O'Brien, P., Nair, K.S., Age, obesity, and sex effects on insulin sensitivity and skeletal muscle mitochondrial function. Diabetes 59 (2010), 89–97.
58. Katic, M., Kennedy, A.R., Leykin, I., Norris, A., McGettrick, A., Gesta, S., Russell, S.J., Bluher, M., Maratos-Flier, E., Kahn, C.R., Mitochondrial gene expression and increased oxidative metabolism: role in increased lifespan of fat-specific insulin receptor knock-out mice. Aging Cell 6 (2007), 827–839.
59. Katsuda, T., Kosaka, N., Takeshita, F., Ochiya, T., The therapeutic potential of mesenchymal stem cell-derived extracellular vesicles. Proteomics 13 (2013), 1637–1653.
60. Kim, S.M., Lun, M., Wang, M., Senyo, S.E., Guillermier, C., Patwari, P., Steinhauser, M.L., Loss of white adipose hyperplastic potential is associated with enhanced susceptibility to insulin resistance. Cell Metab. 20 (2014), 1049–1058.
61. Kirkland, J.L., Dobson, D.E., Preadipocyte function and aging: links between age-related changes in cell dynamics and altered fat tissue function. J. Am. Geriatr. Soc. 45 (1997), 959–967.
62. Kirkland, J.L., Tchkonia, T., Clinical strategies and animal models for developing senolytic agents. Exp. Gerontol. 68 (2015), 19–25.
63. Kirkland, J.L., Tchkonia, T., Pirtskhalava, T., Han, J., Karagiannides, I., Adipogenesis and aging: does aging make fat go MAD?. Exp. Gerontol. 37 (2002), 757–767.
64. Kivipelto, M., Ngandu, T., Fratiglioni, L., Viitanen, M., Kareholt, I., Winblad, B., Helkala, E.L., Tuomilehto, J., Soininen, H., Nissinen, A., Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch. Neurol. 62 (2005), 1556–1560.
65. Klein, S., Fontana, L., Young, V.L., Coggan, A.R., Kilo, C., Patterson, B.W., Mohammed, B.S., Absence of an effect of liposuction on insulin action and risk factors for coronary heart disease. N. Engl. J. Med. 350 (2004), 2549–2557.
66. Koehler, E.M., Schouten, J.N., Hansen, B.E., van Rooij, F.J., Hofman, A., Stricker, B.H., Janssen, H.L., Prevalence and risk factors of non-alcoholic fatty liver disease in the elderly: results from the Rotterdam study. J. Hepatol. 57 (2012), 1305–1311.
67. Krizhanovsky, V., Yon, M., Dickins, R.A., Hearn, S., Simon, J., Miething, C., Yee, H., Zender, L., Lowe, S.W., Senescence of activated stellate cells limits liver fibrosis. Cell 134 (2008), 657–667.
68. Laberge, R.M., Sun, Y., Orjalo, A.V., Patil, C.K., Freund, A., Zhou, L., Curran, S.C., Davalos, A.R., Wilson-Edell, K.A., Liu, S., Limbad, C., Demaria, M., Li, P., Hubbard, G.B., Ikeno, Y., Javors, M., Desprez, P.Y., Benz, C.C., Kapahi, P., Nelson, P.S., Campisi, J., MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat. Cell Biol. 17 (2015), 1049–1061.
69. Lakowa, N., Trieu, N., Flehmig, G., Lohmann, T., Schon, M.R., Dietrich, A., Zeplin, P.H., Langer, S., Stumvoll, M., Bluher, M., Kloting, N., Telomere length differences between subcutaneous and visceral adipose tissue in humans. Biochem. Biophys. Res. Commun. 457 (2015), 426–432.
70. Linford, N.J., Beyer, R.P., Gollahon, K., Krajcik, R.A., Malloy, V.L., Demas, V., Burmer, G.C., Rabinovitch, P.S., Transcriptional response to aging and caloric restriction in heart and adipose tissue. Aging Cell 6 (2007), 673–688.
71. Lottati, M., Kolka, C.M., Stefanovski, D., Kirkman, E.L., Bergman, R.N., Greater omentectomy improves insulin sensitivity in nonobese dogs. Obesity 17 (2009), 674–680.
72. Lumeng, C.N., Bodzin, J.L., Saltiel, A.R., Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J. Clin. Invest. 117 (2007), 175–184.
73. Lumeng, C.N., Liu, J., Geletka, L., Delaney, C., Delproposto, J., Desai, A., Oatmen, K., Martinez-Santibanez, G., Julius, A., Garg, S., Yung, R.L., Aging is associated with an increase in T cells and inflammatory macrophages in visceral adipose tissue. J. Immunol. 187 (2011), 6208–6216.
74. Ma, X.H., Muzumdar, R., Yang, X.M., Gabriely, I., Berger, R., Barzilai, N., Aging is associated with resistance to effects of leptin on fat distribution and insulin action. J. Gerontol. Ser. A Biol. Med. Sci. 57 (2002), B225–B231.
75. Manolopoulos, K.N., Karpe, F., Frayn, K.N., Gluteofemoral body fat as a determinant of metabolic health. Int. J. Obes. 34 (2010), 949–959.
76. Mansilla, E., Diaz Aquino, V., Zambon, D., Marin, G.H., Martire, K., Roque, G., Ichim, T., Riordan, N.H., Patel, A., Sturla, F., Larsen, G., Spretz, R., Nunez, L., Soratti, C., Ibar, R., van Leeuwen, M., Tau, J.M., Drago, H., Maceira, A., Could metabolic syndrome, lipodystrophy, and aging be mesenchymal stem cell exhaustion syndromes?. Stem Cells Int., 943216, 2011, 2011.
77. Marcus, R.L., Addison, O., Kidde, J.P., Dibble, L.E., Lastayo, P.C., Skeletal muscle fat infiltration: impact of age, inactivity, and exercise. J. Nutr. Health Aging 14 (2010), 362–366.
78. Martin-Montalvo, A., Mercken, E.M., Mitchell, S.J., Palacios, H.H., Mote, P.L., Scheibye-Knudsen, M., Gomes, A.P., Ward, T.M., Minor, R.K., Blouin, M.J., Schwab, M., Pollak, M., Zhang, Y., Yu, Y., Becker, K.G., Bohr, V.A., Ingram, D.K., Sinclair, D.A., Wolf, N.S., Spindler, S.R., Bernier, M., de Cabo, R., Metformin improves healthspan and lifespan in mice. Nat. Commun., 4, 2013, 2192.
79. Mattson, M.P., Perspective: does brown fat protect against diseases of aging?. Ageing Res. Rev. 9 (2010), 69–76.
80. Mazereeuw-Hautier, J., Wilson, L.C., Mohammed, S., Smallwood, D., Shackleton, S., Atherton, D.J., Harper, J.I., Hutchinson–Gilford progeria syndrome: clinical findings in three patients carrying the G608G mutation in LMNA and review of the literature. Br. J. Dermatol. 156 (2007), 1308–1314.
81. McLaughlin, T., Allison, G., Abbasi, F., Lamendola, C., Reaven, G., Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals. Metab. Clin. Exp. 53 (2004), 495–499.
82. Menke, A., Casagrande, S., Geiss, L., Cowie, C.C., Prevalence of and trends in diabetes among adults in the United States, 1988–2012. J. Am. Med. Assoc. 314 (2015), 1021–1029.
83. 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. 15 (2009), 1082–1087.
84. Minor, R.K., Lopez, M., Younts, C.M., Jones, B., Pearson, K.J., Anson, R.M., Dieguez, C., de Cabo, R., The arcuate nucleus and neuropeptide Y contribute to the antitumorigenic effect of calorie restriction. Aging Cell 10 (2011), 483–492.
85. Mori, M.A., Raghavan, P., Thomou, T., Boucher, J., Robida-Stubbs, S., Macotela, Y., Russell, S.J., Kirkland, J.L., Blackwell, T.K., Kahn, C.R., Role of microRNA processing in adipose tissue in stress defense and longevity. Cell Metab. 16 (2012), 336–347.
86. Mori, M.A., Thomou, T., Boucher, J., Lee, K.Y., Lallukka, S., Kim, J.K., Torriani, M., Yki-Jarvinen, H., Grinspoon, S.K., Cypess, A.M., Kahn, C.R., Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy. J. Clin. Invest. 124 (2014), 3339–3351.
87. Muzumdar, R., Allison, D.B., Huffman, D.M., Ma, X., Atzmon, G., Einstein, F.H., Fishman, S., Poduval, A.D., McVei, T., Keith, S.W., Barzilai, N., Visceral adipose tissue modulates mammalian longevity. Aging Cell 7 (2008), 438–440.
88. Naveiras, O., Nardi, V., Wenzel, P.L., Hauschka, P.V., Fahey, F., Daley, G.Q., Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460 (2009), 259–263.
89. Okada-Iwabu, M., Yamauchi, T., Iwabu, M., Honma, T., Hamagami, K., Matsuda, K., Yamaguchi, M., Tanabe, H., Kimura-Someya, T., Shirouzu, M., Ogata, H., Tokuyama, K., Ueki, K., Nagano, T., Tanaka, A., Yokoyama, S., Kadowaki, T., A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503 (2013), 493–499.
90. Ortega Martinez de Victoria, E., Xu, X., Koska, J., Francisco, A.M., Scalise, M., Ferrante, A.W. Jr., Krakoff, J., Macrophage content in subcutaneous adipose tissue: associations with adiposity, age, inflammatory markers, and whole-body insulin action in healthy Pima Indians. Diabetes 58 (2009), 385–393.
91. Palmer, A.K., Tchkonia, T., LeBrasseur, N.K., Chini, E.N., Xu, M., Kirkland, J.L., Cellular senescence in type 2 diabetes: a therapeutic opportunity. Diabetes 64 (2015), 2289–2298.
92. Parrinello, S., Coppe, J.P., Krtolica, A., Campisi, J., Stromal–epithelial interactions in aging and cancer: senescent fibroblasts alter epithelial cell differentiation. J. Cell Sci. 118 (2005), 485–496.
93. Picard, F., Guarente, L., Molecular links between aging and adipose tissue. Int. J. Obes. 29:Suppl. 1 (2005), S36–S39.
94. Pincus, Z., Smith-Vikos, T., Slack, F.J., MicroRNA predictors of longevity in Caenorhabditis elegans. PLoS Genet., 7, 2011, e1002306.
95. Preis, S.R., Massaro, J.M., Robins, S.J., Hoffmann, U., Vasan, R.S., Irlbeck, T., Meigs, J.B., Sutherland, P., D'Agostino, R.B. Sr., O'Donnell, C.J., Fox, C.S., Abdominal subcutaneous and visceral adipose tissue and insulin resistance in the Framingham heart study. Obesity 18 (2010), 2191–2198.
96. Raj, A., van Oudenaarden, A., Nature, nurture, or chance: stochastic gene expression and its consequences. Cell 135 (2008), 216–226.
97. Ranganath, S.H., Levy, O., Inamdar, M.S., Karp, J.M., Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease. Cell Stem Cell 10 (2012), 244–258.
98. Rogers, N.H., Landa, A., Park, S., Smith, R.G., Aging leads to a programmed loss of brown adipocytes in murine subcutaneous white adipose tissue. Aging Cell 11 (2012), 1074–1083.
99. Romero-Corral, A., Somers, V.K., Sierra-Johnson, J., Thomas, R.J., Collazo-Clavell, M.L., Korinek, J., Allison, T.G., Batsis, J.A., Sert-Kuniyoshi, F.H., Lopez-Jimenez, F., Accuracy of body mass index in diagnosing obesity in the adult general population. Int. J. Obes. 32 (2008), 959–966.
100. Roos, C.M., Zhang, B., Palmer, A.K., Ogrodnik, M.B., Pirtskhalava, T., Thalji, N.M., Hagler, M., Jurk, D., Smith, L.A., Casaclang-Verzosa, G., Zhu, Y., Schafer, M.J., Tchkonia, T., Kirkland, J.L., Miller, J.D., Chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice. Aging Cell, 2016.
101. Saito, M., Okamatsu-Ogura, Y., Matsushita, M., Watanabe, K., Yoneshiro, T., Nio-Kobayashi, J., Iwanaga, T., Miyagawa, M., Kameya, T., Nakada, K., Kawai, Y., Tsujisaki, M., High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes 58 (2009), 1526–1531.
102. Samanic, C., Gridley, G., Chow, W.H., Lubin, J., Hoover, R.N., Fraumeni, J.F. Jr., Obesity and cancer risk among white and black United States veterans. Cancer Causes Control 15 (2004), 35–43.
103. Schipper, B.M., Marra, K.G., Zhang, W., Donnenberg, A.D., Rubin, J.P., Regional anatomic and age effects on cell function of human adipose-derived stem cells. Ann. Plast. Surg. 60 (2008), 538–544.
104. Sepe, A., Tchkonia, T., Thomou, T., Zamboni, M., Kirkland, J.L., Aging and regional differences in fat cell progenitors - a mini-review. Gerontology 57 (2011), 66–75.
105. Sjostrom, L., Narbro, K., Sjostrom, C.D., Karason, K., Larsson, B., Wedel, H., Lystig, T., Sullivan, M., Bouchard, C., Carlsson, B., Bengtsson, C., Dahlgren, S., Gummesson, A., Jacobson, P., Karlsson, J., Lindroos, A.K., Lonroth, H., Naslund, I., Olbers, T., Stenlof, K., Torgerson, J., Agren, G., Carlsson, L.M., Swedish obese subjects, S. Effects of bariatric surgery on mortality in Swedish obese subjects. N. Engl. J. Med. 357 (2007), 741–752.
106. Snijder, M.B., Dekker, J.M., Visser, M., Yudkin, J.S., Stehouwer, C.D., Bouter, L.M., Heine, R.J., Nijpels, G., Seidell, J.C., Larger thigh and hip circumferences are associated with better glucose tolerance: the Hoorn study. Obes. Res. 11 (2003), 104–111.
107. Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M.C., Di Giacomo, V., Yosef, R., Pilpel, N., Krizhanovsky, V., Sharpe, J., Keyes, W.M., Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell 155 (2013), 1119–1130.
108. Stout, M.B., Tchkonia, T., Pirtskhalava, T., Palmer, A.K., List, E.O., Berryman, D.E., Lubbers, E.R., Escande, C., Spong, A., Masternak, M.M., Oberg, A.L., LeBrasseur, N.K., Miller, R.A., Kopchick, J.J., Bartke, A., Kirkland, J.L., Growth hormone action predicts age-related white adipose tissue dysfunction and senescent cell burden in mice. Aging 6 (2014), 575–586.
109. Stout, M.B., Steyn, F.J., Jurczak, M.J., Camporez, J.G., Zhu, Y., Hawse, J.R., Jurk, D., Palmer, A.K., Xu, M., Pirtskhalava, T., Evans, G.L., de Souza Santos, R., Frank, A.P., White, T.A., Monroe, D.G., Singh, R.J., Casaclang-Verzosa, G., Miller, J.D., Clegg, D.J., LeBrasseur, N.K., von Zglinicki, T., Shulman, G.I., Tchkonia, T., Kirkland, J.L., 17alpha-estradiol alleviates age-related metabolic and inflammatory dysfunction in male mice without inducing feminization. J. Gerontol. Ser. A Biol. Med. Sci., 2016.
110. Strioga, M., Viswanathan, S., Darinskas, A., Slaby, O., Michalek, J., Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev. 21 (2012), 2724–2752.
111. Stumvoll, M., Nurjhan, N., Perriello, G., Dailey, G., Gerich, J.E., Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 333 (1995), 550–554.
112. Tan, C.Y., Virtue, S., Bidault, G., Dale, M., Hagen, R., Griffin, J.L., Vidal-Puig, A., Brown adipose tissue thermogenic capacity is regulated by Elovl6. Cell Rep. 13 (2015), 2039–2047.
113. Tchkonia, T., Corkey, B.E., Kirkland, J.L., Current views of the fat cell as an endocrine cell: lipotoxicity. overweight and the metabolic syndrome: from bench to bedside (Endocrine Updates). 2006.
114. Tchkonia, T., Giorgadze, N., Pirtskhalava, T., Thomou, T., DePonte, M., Koo, A., Forse, R.A., Chinnappan, D., Martin-Ruiz, C., von Zglinicki, T., Kirkland, J.L., Fat depot-specific characteristics are retained in strains derived from single human preadipocytes. Diabetes 55 (2006), 2571–2578.
115. Tchkonia, T., Morbeck, D.E., Von Zglinicki, T., Van Deursen, J., Lustgarten, J., Scrable, H., Khosla, S., Jensen, M.D., Kirkland, J.L., Fat tissue, aging, and cellular senescence. Aging Cell 9 (2010), 667–684.
116. Tchkonia, T., Thomou, T., Zhu, Y., Karagiannides, I., Pothoulakis, C., Jensen, M.D., Kirkland, J.L., Mechanisms and metabolic implications of regional differences among fat depots. Cell Metab. 17 (2013), 644–656.
117. Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J., Kirkland, J.L., Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J. Clin. Invest. 123 (2013), 966–972.
118. Tilg, H., Moschen, A.R., Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat. Rev. Immunol. 6 (2006), 772–783.
119. Timmons, J.A., Pedersen, B.K., The importance of brown adipose tissue. N. Engl. J. Med. 361 (2009), 415–416 (author reply 418-421).
120. Tran, T.T., Yamamoto, Y., Gesta, S., Kahn, C.R., Beneficial effects of subcutaneous fat transplantation on metabolism. Cell Metab. 7 (2008), 410–420.
121. Unger, R.H., Zhou, Y.T., Lipotoxicity of beta-cells in obesity and in other causes of fatty acid spillover. Diabetes 50:Suppl. 1 (2001), S118–S121.
122. Valdes, A.M., Andrew, T., Gardner, J.P., Kimura, M., Oelsner, E., Cherkas, L.F., Aviv, A., Spector, T.D., Obesity, cigarette smoking, and telomere length in women. Lancet 366 (2005), 662–664.
123. Valle, A., Guevara, R., Garcia-Palmer, F.J., Roca, P., Oliver, J., Caloric restriction retards the age-related decline in mitochondrial function of brown adipose tissue. Rejuvenation Res. 11 (2008), 597–604.
124. van Marken Lichtenbelt, W.D., Vanhommerig, J.W., Smulders, N.M., Drossaerts, J.M., Kemerink, G.J., Bouvy, N.D., Schrauwen, P., Teule, G.J., Cold-activated brown adipose tissue in healthy men. N. Engl. J. Med. 360 (2009), 1500–1508.
125. Verstovsek, S., Kantarjian, H., Mesa, R.A., Pardanani, A.D., Cortes-Franco, J., Thomas, D.A., Estrov, Z., Fridman, J.S., Bradley, E.C., Erickson-Viitanen, S., Vaddi, K., Levy, R., Tefferi, A., Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis. N. Engl. J. Med. 363 (2010), 1117–1127.
126. Virtanen, K.A., Lidell, M.E., Orava, J., Heglind, M., Westergren, R., Niemi, T., Taittonen, M., Laine, J., Savisto, N.J., Enerback, S., Nuutila, P., Functional brown adipose tissue in healthy adults. N. Engl. J. Med. 360 (2009), 1518–1525.
127. Wolk, A., Gridley, G., Svensson, M., Nyren, O., McLaughlin, J.K., Fraumeni, J.F., Adam, H.O., A prospective study of obesity and cancer risk (Sweden). Cancer Causes Control 12 (2001), 13–21.
128. Wu, D., Ren, Z., Pae, M., Guo, W., Cui, X., Merrill, A.H., Meydani, S.N., Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. J. Immunol. 179 (2007), 4829–4839.
129. Wu, J., Bostrom, P., Sparks, L.M., Ye, L., Choi, J.H., Giang, A.H., Khandekar, M., Virtanen, K.A., Nuutila, P., Schaart, G., Huang, K., Tu, H., van Marken Lichtenbelt, W.D., Hoeks, J., Enerback, S., Schrauwen, P., Spiegelman, B.M., Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell 150 (2012), 366–376.
130. Wyles, C.C., Houdek, M.T., Crespo-Diaz, R.J., Norambuena, G.A., Stalboerger, P.G., Terzic, A., Behfar, A., Sierra, R.J., Adipose-derived mesenchymal stem cells are phenotypically superior for regeneration in the setting of osteonecrosis of the femoral head. Clin. Orthop. Relat. Res. 473 (2015), 3080–3090.
131. Xu, M., Palmer, A.K., Ding, H., Weivoda, M.M., Pirtskhalava, T., White, T.A., Sepe, A., Johnson, K.O., Stout, M.B., Giorgadze, N., Jensen, M.D., LeBrasseur, N.K., Tchkonia, T., Kirkland, J.L., Targeting senescent cells enhances adipogenesis and metabolic function in old age. eLife, 4, 2015.
132. Xu, M., Tchkonia, T., Ding, H., Ogrodnik, M., Lubbers, E.R., Pirtskhalava, T., White, T.A., Johnson, K.O., Stout, M.B., Mezera, V., Giorgadze, N., Jensen, M.D., LeBrasseur, N.K., Kirkland, J.L., JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age. Proc. Natl. Acad. Sci. U. S. A. 112 (2015), E6301–E6310.
133. Yamashita, H., Sato, Y., Mori, N., Difference in induction of uncoupling protein genes in adipose tissues between young and old rats during cold exposure. FEBS Lett. 458 (1999), 157–161.
134. Yamauchi, T., Kadowaki, T., Adiponectin receptor as a key player in healthy longevity and obesity-related diseases. Cell Metab. 17 (2013), 185–196.
135. Yoneshiro, T., Aita, S., Matsushita, M., Okamatsu-Ogura, Y., Kameya, T., Kawai, Y., Miyagawa, M., Tsujisaki, M., Saito, M., Age-related decrease in cold-activated brown adipose tissue and accumulation of body fat in healthy humans. Obesity 19 (2011), 1755–1760.
136. Zhu, Y., Tchkonia, T., Fuhrmann-Stroissnigg, H., Dai, H.M., Ling, Y.Y., Stout, M.B., Pirtskhalava, T., Giorgadze, N., Johnson, K.O., Giles, C.B., Wren, J.D., Niedernhofer, L.J., Robbins, P.D., Kirkland, J.L., Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell, 2015.
137. Zhu, Y., Tchkonia, T., Pirtskhalava, T., Gower, A.C., Ding, H., Giorgadze, N., Palmer, A.K., Ikeno, Y., Hubbard, G.B., Lenburg, M., O' Hara, S.P., LaRusso, N.F., Miller, J.D., Roos, C.M., Verzosa, G.C., LeBrasseur, N.K., Wren, J.D., Farr, J.N., Khosla, S., Stout, M.B., McGowan, S.J., Fuhrmann-Stroissnigg, H., Gurkar, A.U., Zhao, J., Colangelo, D., Dorronsoro, A., Ling, Y.Y., Barghouthy, A.S., Navarro, D.C., Sano, T., Robbins, P.D., Niedernhofer, L.J., Kirkland, J.L., The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 14 (2015), 644–658.
138. Zuk, P.A., Zhu, M., Ashjian, P., De Ugarte, D.A., Huang, J.I., Mizuno, H., Alfonso, Z.C., Fraser, J.K., Benhaim, P., Hedrick, M.H., Human adipose tissue is a source of multipotent stem cells. Mol. Biol. Cell 13 (2002), 4279–4295.