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Caloric restriction attenuates the age-associated increase of adipose-derived stem cells but further reduces their proliferative capacity

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Abstract

White adipose tissue is a promising source of mesenchymal stem cells. Currently, little is known about the effect of age and caloric restriction (CR) on adipose-derived stem cells (ASC). This is important for three reasons: firstly, age and CR cause extensive remodeling of WAT; it is currently unknown how this remodeling affects the resident stem cell population. Secondly, stem cell senescence has been theorized as one of the causes of aging and could reduce the utility of a stem cell as a reagent. Thirdly, the mechanism by which CR extends lifespan is currently not known, one theory postulates that CR maintains the resident stem cell population in youthful “fit” state. For the purpose of this study, we define ASC as lineage negative (lin−)/CD34+(low)/CD31−. We show that aging increases the abundance of ASC and the expression of Cdkn2a 9.8-fold and Isl1 60.6-fold. This would suggest that aging causes an accumulation of non-replicative ASC. CR reduced the percentage of ASC in the lin− SVF while also reducing colony forming ability. Therefore, CR appears to have anti-proliferative effects on ASC that may be advantageous from the perspective of cancer, but our data raises the possibility that it may be disadvantageous for regenerative medicine applications.

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References

  • Alison MR, Islam S (2009) Attributes of adult stem cells. J Pathol 217:144–160

    Article  PubMed  CAS  Google Scholar 

  • Alison MR, Brittan M, Lovell MJ, Wright NA (2006) Markers of adult tissue-based stem cells. Handb Exp Pharmacol 174:185–227

    Article  PubMed  CAS  Google Scholar 

  • Anderson RM, Shanmuganayagam D, Weindruch R (2009) Caloric restriction and aging: studies in mice and monkeys. Toxicol Pathol 37:47–51

    Article  PubMed  Google Scholar 

  • Beitnes JO, Hopp E, Lunde K, Solheim S, Arnesen H, Brinchmann JE, Forfang K, Aakhus S (2009) Long-term results after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: the ASTAMI randomised, controlled study. Heart 95:1983–1989

    Article  PubMed  CAS  Google Scholar 

  • Blagosklonny MV, Pardee AB (2002) The restriction point of the cell cycle. Cell Cycle 1:103–110

    PubMed  CAS  Google Scholar 

  • Boquest AC, Shahdadfar A, Fronsdal K, Sigurjonsson O, Tunheim SH, Collas P, Brinchmann JE (2005) Isolation and transcription profiling of purified uncultured human stromal stem cells: alteration of gene expression after in vitro cell culture. Mol Biol Cell 16:1131–1141

    Article  PubMed  CAS  Google Scholar 

  • Bu L, Jiang X, Martin-Puig S, Caron L, Zhu S, Shao Y, Roberts DJ, Huang PL, Domian IJ, Chien KR (2009) Human ISL1 heart progenitors generate diverse multipotent cardiovascular cell lineages. Nature 460:113–117

    Article  PubMed  CAS  Google Scholar 

  • Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110

    Article  PubMed  CAS  Google Scholar 

  • Cartwright MJ, Schlauch K, Lenburg ME, Tchkonia T, Pirtskhalava T, Cartwright A, Thomou T, Kirkland JL (2010) Aging, depot origin, and preadipocyte gene expression. J Gerontol A Biol Sci Med Sci 65A:242–251

    Article  CAS  Google Scholar 

  • Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, Colussi C, Di Meglio F, Nadal-Ginard B, Frustaci A, Leri A et al (2003) Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res 93:604–613

    Article  PubMed  CAS  Google Scholar 

  • de Girolamo L, Lopa S, Arrigoni E, Sartori MF, Baruffaldi Preis FW, Brini AT (2009) Human adipose-derived stem cells isolated from young and elderly women: their differentiation potential and scaffold interaction during in vitro osteoblastic differentiation. Cytotherapy 11:793–803

    Article  PubMed  Google Scholar 

  • Dill T, Schachinger V, Rolf A, Mollmann S, Thiele H, Tillmanns H, Assmus B, Dimmeler S, Zeiher AM, Hamm C (2009) Intracoronary administration of bone marrow-derived progenitor cells improves left ventricular function in patients at risk for adverse remodeling after acute ST-segment elevation myocardial infarction: results of the Reinfusion of Enriched Progenitor cells And Infarct Remodeling in Acute Myocardial Infarction study (REPAIR-AMI) cardiac magnetic resonance imaging substudy. Am Heart J 157:541–547

    Article  PubMed  Google Scholar 

  • Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O et al (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA 92:9363–9367

    Article  PubMed  CAS  Google Scholar 

  • Djian P, Roncari AK, Hollenberg CH (1983) Influence of anatomic site and age on the replication and differentiation of rat adipocyte precursors in culture. J Clin Invest 72:1200–1208

    Article  PubMed  CAS  Google Scholar 

  • Eberhardt M, Salmon P, von Mach MA, Hengstler JG, Brulport M, Linscheid P, Seboek D, Oberholzer J, Barbero A, Martin I et al (2006) Multipotential nestin and Isl-1 positive mesenchymal stem cells isolated from human pancreatic islets. Biochem Biophys Res Commun 345:1167–1176

    Article  PubMed  CAS  Google Scholar 

  • Gimble JM, Katz AJ, Bunnell BA (2007) Adipose-derived stem cells for regenerative medicine. Circ Res 100:1249–1260

    Article  PubMed  CAS  Google Scholar 

  • Gronthos S, Franklin DM, Leddy HA, Robey PG, Storms RW, Gimble JM (2001) Surface protein characterization of human adipose tissue-derived stromal cells. J Cell Physiol 189:54–63

    Article  PubMed  CAS  Google Scholar 

  • Hagege AA, Carrion C, Menasche P, Vilquin JT, Duboc D, Marolleau JP, Desnos M, Bruneval P (2003) Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy. Lancet 361:491–492

    Article  PubMed  Google Scholar 

  • Hsieh EA, Chai CM, Hellerstein MK (2005) Effects of caloric restriction on cell proliferation in several tissues in mice: role of intermittent feeding. Am J Physiol Endocrinol Metab 288:E965–E972

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Krishnamurthy J, Ramsey MR, Ligon KL, Torrice C, Koh A, Bonner-Weir S, Sharpless NE (2006) p16INK4a induces an age-dependent decline in islet regenerative potential. Nature 443:453–457

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Lin L, Bu L, Cai CL, Zhang X, Evans S (2006) Isl1 is upstream of sonic hedgehog in a pathway required for cardiac morphogenesis. Dev Biol 295:756–763

    Article  PubMed  CAS  Google Scholar 

  • Madonna R, Geng YJ, De Caterina R (2009) Adipose tissue-derived stem cells: characterization and potential for cardiovascular repair. Arterioscler Thromb Vasc Biol 29:1723–1729

    Article  PubMed  CAS  Google Scholar 

  • Mair W, Dillin A (2008) Aging and survival: the genetics of life span extension by dietary restriction. Annu Rev Biochem 77:727–754

    Article  PubMed  CAS  Google Scholar 

  • Martinez-Estrada OM, Munoz-Santos Y, Julve J, Reina M, Vilaro S (2005) Human adipose tissue as a source of Flk-1+ cells: new method of differentiation and expansion. Cardiovasc Res 65:328–333

    Article  PubMed  CAS  Google Scholar 

  • McIntosh K, Zvonic S, Garrett S, Mitchell JB, Floyd ZE, Hammill L, Kloster A, Di Halvorsen Y, Ting JP, Storms RW et al (2006) The immunogenicity of human adipose-derived cells: temporal changes in vitro. Stem Cells 24:1246–1253

    Article  PubMed  CAS  Google Scholar 

  • Menasche P, Hagege AA, Scorsin M, Pouzet B, Desnos M, Duboc D, Schwartz K, Vilquin JT, Marolleau JP (2001) Myoblast transplantation for heart failure. Lancet 357:279–280

    Article  PubMed  CAS  Google Scholar 

  • Miranville A, Heeschen C, Sengenes C, Curat CA, Busse R, Bouloumie A (2004) Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 110:349–355

    Article  PubMed  CAS  Google Scholar 

  • Nakagami H, Morishita R, Maeda K, Kikuchi Y, Ogihara T, Kaneda Y (2006) Adipose tissue-derived stromal cells as a novel option for regenerative cell therapy. J Atheroscler Thromb 13:77–81

    PubMed  Google Scholar 

  • Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902

    Article  PubMed  CAS  Google Scholar 

  • Planat-Benard V, Silvestre JS, Cousin B, Andre M, Nibbelink M, Tamarat R, Clergue M, Manneville C, Saillan-Barreau C, Duriez M et al (2004) Plasticity of human adipose lineage cells toward endothelial cells: physiological and therapeutic perspectives. Circulation 109:656–663

    Article  PubMed  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414:105–111

    Article  PubMed  CAS  Google Scholar 

  • Rodeheffer MS, Birsoy K, Friedman JM (2008) Identification of white adipocyte progenitor cells in vivo. Cell 135:240–249

    Article  PubMed  CAS  Google Scholar 

  • Rota M, LeCapitaine N, Hosoda T, Boni A, De Angelis A, Padin-Iruegas ME, Esposito G, Vitale S, Urbanek K, Casarsa C et al (2006) Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene. Circ Res 99:42–52

    Article  PubMed  CAS  Google Scholar 

  • Sengenes C, Lolmede K, Zakaroff-Girard A, Busse R, Bouloumie A (2005) Preadipocytes in the human subcutaneous adipose tissue display distinct features from the adult mesenchymal and hematopoietic stem cells. J Cell Physiol 205:114–122

    Article  PubMed  CAS  Google Scholar 

  • Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602

    Article  PubMed  CAS  Google Scholar 

  • Sharpless NE, DePinho RA (2007) How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8:703–713

    Article  PubMed  CAS  Google Scholar 

  • Timper K, Seboek D, Eberhardt M, Linscheid P, Christ-Crain M, Keller U, Muller B, Zulewski H (2006) Human adipose tissue-derived mesenchymal stem cells differentiate into insulin, somatostatin, and glucagon expressing cells. Biochem Biophys Res Commun 341:1135–1140

    Article  PubMed  CAS  Google Scholar 

  • Torella D, Rota M, Nurzynska D, Musso E, Monsen A, Shiraishi I, Zias E, Walsh K, Rosenzweig A, Sussman MA et al (2004) Cardiac stem cell and myocyte aging, heart failure, and insulin-like growth factor-1 overexpression. Circ Res 94:514–524

    Article  PubMed  CAS  Google Scholar 

  • Trayhurn P, Beattie JH (2001) Physiological role of adipose tissue: white adipose tissue as an endocrine and secretory organ. Proc Nutr Soc 60:329–339

    Article  PubMed  CAS  Google Scholar 

  • van der Loo B, Fenton MJ, Erusalimsky JD (1998) Cytochemical detection of a senescence-associated beta-galactosidase in endothelial and smooth muscle cells from human and rabbit blood vessels. Exp Cell Res 241:309–315

    Article  PubMed  Google Scholar 

  • Weindruch R (1996) The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol 24:742–745

    Article  PubMed  CAS  Google Scholar 

  • Weindruch R, Walford RL, Fligiel S, Guthrie D (1986) The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr 116:641–654

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Yoshimura K, Shigeura T, Matsumoto D, Sato T, Takaki Y, Aiba-Kojima E, Sato K, Inoue K, Nagase T, Koshima I, Gonda K (2006) Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates. J Cell Physiol 208:64–76

    Article  PubMed  CAS  Google Scholar 

  • Zhu M, Lee GD, Ding L, Hu J, Qiu G, de Cabo R, Bernier M, Ingram DK, Zou S (2007) Adipogenic signaling in rat white adipose tissue: modulation by aging and calorie restriction. Exp Gerontol 42:733–744

    Article  PubMed  CAS  Google Scholar 

  • Zhu M, Kohan E, Bradley J, Hedrick M, Benhaim P, Zuk P (2009) The effect of age on osteogenic, adipogenic and proliferative potential of female adipose-derived stem cells. J Tissue Eng Regen Med 3:290–301

    Article  PubMed  CAS  Google Scholar 

  • Zuk PA, Zhu M, Ashjian P, De Ugarte DA, Huang JI, Mizuno H, Alfonso ZC, Fraser JK, Benhaim P, Hedrick MH (2002) Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 13:4279–4295

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This study was supported by the National Heart, Lung, and Blood Institute grant number 1R21HL092477 and the National Institutes of Health, under Ruth L. Kirschstein National Research Service Award T32 HL 07936 from the National Heart Lung and Blood Institute to the University of Wisconsin-Madison Cardiovascular Research Center.

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Authors and Affiliations

  1. Department of Physiology, University of Wisconsin, Madison, WI, 53706, USA

    Eric G. Schmuck

  2. Department of Medicine, University of Wisconsin, Madison, WI, 53706, USA

    Jacob D. Mulligan

  3. Department of Medicine, University of Wisconsin, 1300 University Ave, Madison, WI, 53706, USA

    Kurt W. Saupe

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  1. Eric G. Schmuck
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  2. Jacob D. Mulligan
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Correspondence to Kurt W. Saupe.

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Schmuck, E.G., Mulligan, J.D. & Saupe, K.W. Caloric restriction attenuates the age-associated increase of adipose-derived stem cells but further reduces their proliferative capacity. AGE 33, 107–118 (2011). https://doi.org/10.1007/s11357-010-9166-4

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  • DOI: https://doi.org/10.1007/s11357-010-9166-4

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