Aging is a time-related process of functional decline at organelle, cellular, tissue, and organismal level that ultimately limits life. Cellular senescence is a state of permanent growth arrest in response to stress and one of the major drivers of aging and age-related disorders. Senescent cells accumulate with age, and removal of these cells delays age-related disorders in different tissues and prolongs healthy lifespan. One of the most studied aging mechanisms is the accumulation of reactive oxygen species damage in cells, organs, and organisms over time. Elevated oxidative stress is also found in metabolic diseases such as obesity, metabolic syndrome and associated disorders. Moreover, dysregulation of the energy homeostasis is also associated with aging, and many age-related genes also control energy metabolism, with the adipose organ, comprising white, brite, and brown adipocytes, as an important metabolic player in the regulation of whole-body energy homeostasis. This review summarizes transformations in the adipose organ upon aging and cellular senescence and sheds light on the reallocation of fat mass between adipose depots, on the metabolism of white and brown adipose tissue, on the regenerative potential and adipogenic differentiation capacity of preadipocytes, and on alterations in mitochondria and bioenergetics. In conclusion, the aging process is a lifelong, creeping process with gradual decline in (pre-)adipocyte function over time. Thus, slowing down the accumulation of (pre-)adipocyte damage and dysfunction, removal of senescent preadipocytes as well as blocking deleterious compounds of the senescent secretome are protective measures to maintain a lasting state of health at old age.

1.
Rodier F, Campisi J: Four faces of cellular senescence. J Cell Biol 2011;192:547-556.
2.
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, et al: Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 2016;530:184-189.
3.
Schriner SE, Linford NJ, Martin GM, Treuting P, Ogburn CE, Emond M, et al: Extension of murine life span by overexpression of catalase targeted to mitochondria. Science 2005;308:1909-1911.
4.
Bonomini F, Rodella LF, Rezzani R: Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis 2015;6:109-120.
5.
Ahima RS: Connecting obesity, aging and diabetes. Nat Med 2009;15:996-997.
6.
Blüher M, Kahn BB, Kahn CR: Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 2003;299:572-574.
7.
Muzumdar R, Allison DB, Huffman DM, Ma X, Atzmon G, Einstein FH, et al: Visceral adipose tissue modulates mammalian longevity. Aging Cell 2008;7:438-440.
8.
Minamino T, Orimo M, Shimizu I, Kunieda T, Yokoyama M, Ito T, et al: A crucial role for adipose tissue p53 in the regulation of insulin resistance. Nat Med 2009;15:1082-1087.
9.
Curtis R, Geesaman BJ, DiStefano PS: Ageing and metabolism: drug discovery opportunities. Nat Rev Drug Discov 2005;4:569-580.
10.
Cinti S: The adipose organ at a glance. Dis Model Mech 2012;5:588-594.
11.
Schwartz RS, Shuman WP, Bradbury VL, Cain KC, Fellingham GW, Beard JC, et al: Body fat distribution in healthy young and older men. J Gerontol 1990;45:M181-M185.
12.
Shimokata H, Tobin JD, Muller DC, Elahi D, Coon PJ, Andres R: Studies in the distribution of body fat. I. Effects of age, sex, and obesity. J Gerontol 1989;44:M66-M73.
13.
Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC: Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquir Immune Defic Syndr 2000;25:312-321.
14.
Gavi S, Feiner JJ, Melendez MM, Mynarcik DC, Gelato MC, McNurlan MA: Limb fat to trunk fat ratio in elderly persons is a strong determinant of insulin resistance and adiponectin levels. J Gerontol A Biol Sci Med Sci 2007;62:997-1001.
15.
The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 1999;22:623-634.
16.
Haffner SM: Pre-diabetes, insulin resistance, inflammation and CVD risk. Diabetes Res Clin Pract 2003;61(suppl 1):S9-S18.
17.
Armani A, Berry A, Cirulli F, Caprio M: Molecular mechanisms underlying metabolic syndrome: the expanding role of the adipocyte. FASEB J DOI: 10.1096/fj.201601125RRR.
18.
Lettieri Barbato D, Aquilano K: Feast and famine: adipose tissue adaptations for healthy aging. Ageing Res Rev 2016;28:85-93.
19.
Gong H, Pang J, Han Y, Dai Y, Dai D, Cai J, et al: Age-dependent tissue expression patterns of Sirt1 in senescence-accelerated mice. Mol Med Rep 2014;10:3296-3302.
20.
Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, et al: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 2009;460:392-395.
21.
Zoncu R, Efeyan A, Sabatini DM: mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 2011;12:21-35.
22.
Schulz TJ, Graja A, Huang TL, Xue R, An D, Poehle-Kronawitter S, et al: Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance. Diabetologia 2016;59:1769-1777.
23.
Yoneshiro T, Aita S, Matsushita M, Kayahara T, Kameya T, Kawai Y, et al: Recruited brown adipose tissue as an antiobesity agent in humans. J Clin Invest 2013;123:3404-3408.
24.
Scheideler M: MicroRNAs in adipocyte formation and obesity. Best Pract Res Clin Endocrinol Metab 2016;30:653-664.
25.
Beranger GE, Karbiener M, Barquissau V, Pisani DF, Scheideler M, Langin D, et al: In vitro brown and “brite”/“beige” adipogenesis: human cellular models and molecular aspects. Biochim Biophys Acta DOI: 10.1016/j.bbalip.2012.11.001.
26.
Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, et al: Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009;360:1509-1517.
27.
Shin W, Okamatsu-Ogura Y, Machida K, Tsubota A, Nio-Kobayashi J, Kimura K: Impaired adrenergic agonist-dependent beige adipocyte induction in aged mice. Obesity (Silver Spring) 2017;25:417-423.
28.
Ma X, Xu L, Gavrilova O, Mueller E: Role of forkhead box protein A3 in age-associated metabolic decline. Proc Natl Acad Sci USA 2014;111:14289-14294.
29.
Qi T, Chen Y, Li H, Pei Y, Woo S-L, Guo X, et al: A role for PFKFB3/iPFK2 in metformin suppression of adipocyte inflammatory responses. J Mol Endocrinol 2017;59:49-59.
30.
Kim EK, Lee SH, Jhun JY, Byun JK, Jeong JH, Lee S-Y, et al: Metformin prevents fatty liver and improves balance of white/brown adipose in an obesity mouse model by inducing FGF21. Mediators Inflamm 2016;2016:5813030.
31.
Marycz K, Tomaszewski KA, Kornicka K, Henry BM, Wroński S, Tarasiuk J, et al: Metformin decreases reactive oxygen species, enhances osteogenic properties of adipose-derived multipotent mesenchymal stem cells in vitro, and increases bone density in vivo. Oxid Med Cell Longev 2016;2016:9785890.
32.
Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA: Metformin as a tool to target aging. Cell Metab 2016;23:1060-1065.
33.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:854-865.
34.
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.
35.
Zhu M, Kohan E, Bradley J, Hedrick M, Benhaim P, Zuk P: The effect of age on osteogenic, adipogenic and proliferative potential of female adipose-derived stem cells. J Tissue Eng Regen Med 2009;3:290-301.
36.
Madonna R, Renna FV, Cellini C, Cotellese R, Picardi N, Francomano F, et al: Age-dependent impairment of number and angiogenic potential of adipose tissue-derived progenitor cells. Eur J Clin Invest 2011;41:126-133.
37.
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.
38.
Duteil D, Tosic M, Willmann D, Georgiadi A, Kanouni T, Schüle R: Lsd1 prevents age-programed loss of beige adipocytes. Proc Natl Acad Sci USA 2017;114:5265-5270.
39.
Berry DC, Jiang Y, Arpke RW, Close EL, Uchida A, Reading D, et al: Cellular aging contributes to failure of cold-induced beige adipocyte formation in old mice and humans. Cell Metab 2017;25:481.
40.
Florez-Duquet M, Horwitz BA, McDonald RB: Cellular proliferation and UCP content in brown adipose tissue of cold-exposed aging Fischer 344 rats. Am J Physiol 1998;274:R196-R203.
41.
Park J-S, Kim H-Y, Kim H-W, Chae G-N, Oh H-T, Park J-Y, et al: Increased caveolin-1, a cause for the declined adipogenic potential of senescent human mesenchymal stem cells. Mech Ageing Dev 2005;126:551-559.
42.
Coppé J-P, Patil CK, Rodier F, Sun Y, Muñoz DP, Goldstein J, et al: Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol 2008;6:2853-2868.
43.
Mitterberger MC, Lechner S, Mattesich M, Zwerschke W: Adipogenic differentiation is impaired in replicative senescent human subcutaneous adipose-derived stromal/progenitor cells. J Gerontol A Biol Sci Med Sci 2014;69:13-24.
44.
Xu M, Palmer AK, Ding H, Weivoda MM, Pirtskhalava T, White TA, et al: Targeting senescent cells enhances adipogenesis and metabolic function in old age. Elife 2015;4:e12997.
45.
Zhu Y, Tchkonia T, Pirtskhalava T, Gower AC, Ding H, Giorgadze N, et al: The Achilles' heel of senescent cells: from transcriptome to senolytic drugs. Aging Cell 2015;14:644-658.
46.
Mori S, Murano S, Yokote K, Takemoto M, Asaumi S, Take A, et al: Enhanced intra-abdominal visceral fat accumulation in patients with Werner's syndrome. Int J Obes Relat Metab Disord 2001;25:292-295.
47.
Martin GM, Oshima J: Lessons from human progeroid syndromes. Nature 2000;408:263-266.
48.
Dellago H, Khan A, Nussbacher M, Gstraunthaler A, Lämmermann I, Schosserer M, et al: ATM-dependent phosphorylation of SNEVhPrp19/hPso4 is involved in extending cellular life span and suppression of apoptosis. Aging (Albany) 2012;4:290-304.
49.
Garschall K, Dellago H, Gáliková M, Schosserer M, Flatt T, Grillari J: Ubiquitous overexpression of the DNA repair factor dPrp19 reduces DNA damage and extends Drosophila life span. Aging Mech Dis 2017;3:5.
50.
Khan A, Dellago H, Terlecki-Zaniewicz L, Karbiener M, Weilner S, Hildner F, et al: SNEV(hPrp19/hPso4) regulates adipogenesis of human adipose stromal cells. Stem Cell Rep 2017;8:21-29.
51.
Lee J, Lee J, Jung E, Kim Y-S, Roh K, Jung K-H, et al: Ultraviolet A regulates adipogenic differentiation of human adipose tissue-derived mesenchymal stem cells via up-regulation of Kruppel-like factor 2. J Biol Chem 2010;285:32647-32656.
52.
Lee J, Jung E, Hyun J-W, Park D: Ultraviolet A regulates the stemness of human adipose tissue-derived mesenchymal stem cells through downregulation of the HIF-1α via activation of PGE(2)-cAMP signaling. J Cell Biochem 2012;113:3681-3691.
53.
Kruglikov IL, Scherer PE: Skin aging: are adipocytes the next target? Aging (Albany) 2016;8:1457-1469.
54.
De Pauw A, Tejerina S, Raes M, Keijer J, Arnould T: Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations. Am J Pathol 2009;175:927-939.
55.
Tormos KV, Anso E, Hamanaka RB, Eisenbart J, Joseph J, Kalyanaraman B, et al: Mitochondrial complex III ROS regulate adipocyte differentiation. Cell Metab 2011;14:537-544.
56.
Koh EH, Park J-Y, Park H-S, Jeon MJ, Ryu JW, Kim M, et al: Essential role of mitochondrial function in adiponectin synthesis in adipocytes. Diabetes 2007;56:2973-2981.
57.
Mennes E, Dungan CM, Frendo-Cumbo S, Williamson DL, Wright DC: Aging-associated reductions in lipolytic and mitochondrial proteins in mouse adipose tissue are not rescued by metformin treatment. J Gerontol A Biol Sci Med Sci 2014;69:1060-1068.
58.
Hallgren P, Sjöström L, Hedlund H, Lundell L, Olbe L: Influence of age, fat cell weight, and obesity on O2 consumption of human adipose tissue. Am J Physiol 1989;256:E467-E474.
59.
Graier WF, Malli R, Kostner GM: Mitochondrial protein phosphorylation: instigator or target of lipotoxicity? Trends Endocrinol Metab 2009;20:186-193.
60.
Wilson-Fritch L, Nicoloro S, Chouinard M, Lazar MA, Chui PC, Leszyk J, et al: Mitochondrial remodeling in adipose tissue associated with obesity and treatment with rosiglitazone. J Clin Invest 2004;114:1281-1289.
61.
Fabbiano S, Suárez-Zamorano N, Rigo D, Veyrat-Durebex C, Stevanovic Dokic A, Colin DJ, et al: Caloric restriction leads to browning of white adipose tissue through type 2 immune signaling. Cell Metab 2016;24:434-446.
62.
Belaj KJ, Eller P: The fate of fat. Gerontology 2012;58:120-122; discussion 123-125.
63.
Saely CH, Geiger K, Drexel H: Brown versus white adipose tissue: a mini-review. Gerontology 2012;58:15-23.
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