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The journal of nutrition, health & aging
Published in: The journal of nutrition, health & aging 4/2018

Open Access 01-04-2018

Dietary Restriction Ameliorates Age-Related Increase in DNA Damage, Senescence and Inflammation in Mouse Adipose Tissuey

Authors: A. Ishaq, J. Schröder, N. Edwards, T. von Zglinicki, Gabriele Saretzki

Published in: The journal of nutrition, health & aging | Issue 4/2018

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Abstract

Ageing is associated with redistribution of fat around the body and saturation of visceral adipose depots. Likewise, the presence of excess fat in obesity or during ageing places extra stress on visceral depots, resulting in chronic inflammation and increased senescence. This process can contribute to the establishment of the metabolic syndrome and accelerated ageing. Dietary restriction (DR) is known to alleviate physiological signs of inflammation, ageing and senescence in various tissues including adipose tissue.

Objectives

Our pilot study aimed to analyse senescence and inflammation parameters in mouse visceral fat tissue during ageing and by short term, late-onset dietary restriction as a nutritional intervention.

Design, measurements

In this study we used visceral adipose tissue from mice between 5 and 30 months of age and analysed markers of senescence (adipocyte size, γH2A.X, p16, p21) and inflammation (e.g. IL-6, TNFα, IL-1β, macrophage infiltration) using immuno-staining, as well as qPCR for gene expression analysis. Fat tissues from 3 mice per group were analysed.

Results

We found that the amount of γH2A.X foci as well as the expression of senescence and inflammation markers increased during ageing but decreased with short term DR. In contrast, the increase in amounts of single or aggregated macrophages in fat depots occurred only at higher ages. Surprisingly, we also found that adipocyte size as well as some senescence parameters decreased at very high age (30 months).

Conclusions

Our results demonstrate increased senescence and inflammation during ageing in mouse visceral fat while DR was able to ameliorate several of these parameters as well as increased adipocyte size at 17.5 months of age. This highlights the health benefits of a decreased nutritional intake over a relatively short period of time at middle age.
Literature
1.
Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, et al. Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mechanisms of Ageing and Development 2007;1281:92–105. doi: 10.1016/j.mad.2006.11.016CrossRef
2.
Fontana L, Partridge L. Promoting Health and Longevity through Diet: from Model Organisms to Humans. Cell 2015;1611:106–18. doi: 10.1016/j.cell.2015.02.020CrossRef
3.
Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 2016;5307589:184–9. doi: 10.1038/nature16932CrossRef
4.
Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes 1997;461:3–10. doi: 10.2337/diabetes.46.1.3CrossRef
5.
Tchkonia T, Morbeck DE, von Zglinicki T, van Deursen J, Lustgarten J, Scrable H, et al. Fat tissue, aging, and cellular senescence. Aging Cell 2010;95:667–84. doi:10.1111/j.1474-9726.2010.00608.xCrossRef
6.
Hemmeryckx B, Loeckx D, Dresselaers T, Himmelreich U, Hoylaerts MF, Lijnen HR. Age-associated adaptations in murine adipose tissues. Endocrine journal 2010;5710:925–30. doi: 10.1507/endocrj.K10E-179CrossRef
7.
Barzilai N, Gupta G. Revisiting the role of fat mass in the life extension induced by caloric restriction. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences 1999;543:B89–96; discussion B7-8. doi: 10.1093/gerona/54.3.B89CrossRef
8.
Masoro EJ. Caloric Restriction and Aging: Controversial Issues. The Journals of Gerontology: Series A 2006;611:14–9. doi: 10.1093/gerona/61.1.14CrossRef
9.
Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L. Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. The Journal of Clinical Investigation 1998;1017:1353–61. doi: 10.1172/jci485CrossRef
10.
Sierra Rojas JX, Garcia-San Frutos M, Horrillo D, Lauzurica N, Oliveros E, Carrascosa JM, et al. Differential Development of Inflammation and Insulin Resistance in Different Adipose Tissue Depots Along Aging in Wistar Rats: Effects of Caloric Restriction. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences 2016;713:310–22. doi: 10.1093/gerona/glv117CrossRef
11.
Laforest S, Labrecque J, Michaud A, Cianflone K, Tchernof A. Adipocyte size as a determinant of metabolic disease and adipose tissue dysfunction. Critical Reviews in Clinical Laboratory Sciences 2015;526:301–13. doi: 10.3109/10408363.2015.1041582CrossRef
12.
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. Arteriosclerosis, Thrombosis, and Vascular Biology 2005;2510:2062–8. doi: 10.1161/01.atv.0000183883.72263.13CrossRef
13.
Coppe JP, Patil CK, Rodier F, Sun Y, Munoz DP, Goldstein J, et al. Senescenceassociated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biology 2008;612:2853–68. doi: 10.1371/journal.pbio.0060301
14.
Hu X, Cifarelli V, Sun S, Kuda O, Abumrad NA, Su X. Major role of adipocyte prostaglandin E2 in lipolysis-induced macrophage recruitment. Journal of Lipid Research 2016;574:663–73. doi: 10.1194/jlr.M066530CrossRef
15.
West M. Dead adipocytes and metabolic dysfunction: recent progress. Current Opinion in Endocrinology, Diabetes, and Obesity 2009;162:178–82. doi: 10.1097/MED.0b013e3283292327CrossRef
16.
Murano I, Barbatelli G, Parisani V, Latini C, Muzzonigro G, Castellucci M, et al. Dead adipocytes, detected as crown-like structures, are prevalent in visceral fat depots of genetically obese mice. Journal of Lipid Research 2008;497:1562–8. doi: 10.1194/jlr. M800019-JLR200CrossRef
17.
Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Molecular Systems Biology 2010;6:347-. doi: 10.1038/msb.2010.5
18.
Correia-Melo C, Marques FD, Anderson R, Hewitt G, Hewitt R, Cole J, et al. Mitochondria are required for pro-ageing features of the senescent phenotype. The EMBO Journal 2016;357:724–42. doi: 10.15252/embj.201592862CrossRef
19.
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. Nature Medicine 2009;159:1082–7. doi: 10.1038/nm.2014CrossRef
20.
Schafer MJ, White TA, Evans G, Tonne JM, Verzosa GC, Stout MB, et al. Exercise Prevents Diet-induced Cellular Senescence in Adipose Tissue. Diabetes. 2016;doi: 10.2337/db15-0291
21.
Lam YY, Ghosh S, Civitarese AE, Ravussin E. Six-month Calorie Restriction in Overweight Individuals Elicits Transcriptomic Response in Subcutaneous Adipose Tissue That is Distinct From Effects of Energy Deficit. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences 2016;7110:1258–65. doi: 10.1093/gerona/glv194CrossRef
22.
Wang C, Maddick M, Miwa S, Jurk D, Czapiewski R, Saretzki G, et al. Adult-onset, short-term dietary restriction reduces cell senescence in mice. Aging 2010;29:555–66. doi: 10.18632/aging.100196CrossRef
23.
Speakman JR, Mitchell SE. Caloric restriction. Molecular Aspects of Medicine 2011;323:159–221. doi: 10.1016/j.mam.2011.07.001CrossRef
24.
Salminen A, Hyttinen JM, Kaarniranta K. AMP-activated protein kinase inhibits NF-kappaB signaling and inflammation: impact on healthspan and lifespan. Journal of Molecular Medicine (Berlin, Germany) 2011;897:667–76. doi: 10.1007/s00109-011-0748-0CrossRef
25.
Carling D, Thornton C, Woods A, Sanders MJ. AMP-activated protein kinase: new regulation, new roles? The Biochemical Journal 2012;4451:11–27. doi: 10.1042/bj20120546CrossRef
26.
Daval M, Foufelle F, Ferré P. Functions of AMP-activated protein kinase in adipose tissue. The Journal of Physiology 2006;574Pt 1:55–62. doi: 10.1113/jphysiol.2006.111484
27.
Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nature Reviews Molecular Cell Biology 2012;134:251–62. doi:10.1038/nrm3311CrossRef
28.
Sponarova J, Mustard KJ, Horakova O, Flachs P, Rossmeisl M, Brauner P, et al. Involvement of AMP-activated protein kinase in fat depot-specific metabolic changes during starvation. FEBS letters 2005;57927:6105–10. doi: 10.1016/j.febslet.2005.09.078CrossRef
29.
Cameron KM, Golightly A, Miwa S, Speakman J, Boys R, von Zglinicki T. Gross energy metabolism in mice under late onset, short term caloric restriction. Mechanisms of Ageing and Development 2011;1324:202–9. doi: 10.1016/j.mad.2011.04.004CrossRef
30.
Cameron KM, Miwa S, Walker C, von Zglinicki T. Male mice retain a metabolic memory of improved glucose tolerance induced during adult onset, short-term dietary restriction. Longevity & Healthspan 2012;1:3. doi: 10.1186/2046-2395-1-3CrossRef
31.
Mayer P. Notiz über Hämatein und Hämalaun. Zeitschrift für wissenschaftliche Mikroskopie und für mikroskopische technick 1903;20:409. doi
32.
Arsenijevic T, Grégoire F, Delforge V, Delporte C, Perret J. Murine 3T3-L1 Adipocyte Cell Differentiation Model: Validated Reference Genes for qPCR Gene Expression Analysis. PloS One 2012;75:e37517. doi: 10.1371/journal.pone.0037517CrossRef
33.
Schmittgen TD, Livak KJ. Analyzing real-time PCR data by the comparative C(T) method. Nature Protocols 2008;36:1101–8. doi: doi:10.1038/nprot.2008.73CrossRef
34.
Edwards MG, Anderson RM, Yuan M, Kendziorski CM, Weindruch R, Prolla TA. Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program. BMC Genomics 2007;8:80. doi: 10.1186/1471-2164-8-80CrossRefPubMedPubMedCentral
35.
Scoumanne A, Cho SJ, Zhang J, Chen X. The cyclin-dependent kinase inhibitor p21 is regulated by RNA-binding protein PCBP4 via mRNA stability. Nucleic Acids Research 2011;391:213–24. doi: 10.1093/nar/gkq778CrossRef
36.
Wang T-S, Gao F, Qi Q-R, Qin F-N, Zuo R-J, Li Z-L, et al. Dysregulated LIF-STAT3 pathway is responsible for impaired embryo implantation in a Streptozotocin-induced diabetic mouse model. Biology Open 2015;47:893–902. doi: 10.1242/bio.011890CrossRef
37.
Holl EK, Bond JE, Selim MA, Ehanire T, Sullenger B, Levinson H. The Nucleic Acid Scavenger Dendrimer Polyamidoamine Third-Generation Dendrimer Inhibits Fibroblast Activation and Inhibits Granulation Tissue Contraction. Plastic and reconstructive surgery 2014;1343:420e-33e. doi: 10.1097/PRS.0000000000000471
38.
Spilsbury A, Miwa S, Attems J, Saretzki G. The role of telomerase protein TERT in Alzheimer’s disease and in tau-related pathology in vitro. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 2015;354:1659–74. doi: 10.1523/jneurosci.2925-14.2015CrossRef
39.
Lawless C, Wang C, Jurk D, Merz A, Zglinicki T, Passos JF. Quantitative assessment of markers for cell senescence. Experimental Gerontology 2010;4510:772–8. doi: 10.1016/j.exger.2010.01.018CrossRef
40.
Zamboni M, Rossi AP, Fantin F, Zamboni G, Chirumbolo S, Zoico E, et al. Adipose tissue, diet and aging. Mechanisms of Ageing and Development 2014;136-137:129–37. doi: 10.1016/j.mad.2013.11.008CrossRefPubMed
41.
Garg SK, Delaney C, Shi H, Yung R. Changes in adipose tissue macrophages and T cells during aging. Critical Reviews in Immunology 2014;341:1–14. doiCrossRef
42.
Rossmeisl M, Flachs P, Brauner P, Sponarova J, Matejkova O, Prazak T, et al. Role of energy charge and AMP-activated protein kinase in adipocytes in the control of body fat stores. International Journal of Obesity and Related Metabolic Disorders: Journal of the International Association for the Study of Obesity 2004;28 Suppl 4:S38–44. doi: 10.1038/sj.ijo.0802855CrossRef
43.
Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. The American Journal of Clinical Nutrition 2006;832:461s-5s. doi
44.
Miwa S, Jow H, Baty K, Johnson A, Czapiewski R, Saretzki G, et al. Low abundance of the matrix arm of complex I in mitochondria predicts longevity in mice. Nat Commun 2014;5:3837. doi: 10.1038/ncomms4837CrossRefPubMedPubMedCentral
45.
el Bouazzaoui F, Henneman P, Thijssen P, Visser A, Koning F, Lips MA, et al. Adipocyte telomere length associates negatively with adipocyte size, whereas adipose tissue telomere length associates negatively with the extent of fibrosis in severely obese women. International Journal of Obesity 2014;385:746–9. doi: 10.1038/ijo.2013.175CrossRef
46.
Cartwright MJ, Tchkonia T, Kirkland JL. Aging in adipocytes: potential impact of inherent, depot-specific mechanisms. Experimental Gerontology 2007;426:463–71. doi: 10.1016/j.exger.2007.03.003CrossRef
47.
Ogrodnik M, Miwa S, Tchkonia T, Tiniakos D, Wilson CL, Lahat A, et al. Cellular senescence drives age-dependent hepatic steatosis. Nat Commun 2017;8:15691. doi: 0.1038/ncomms15691CrossRefPubMedPubMedCentral
48.
Hallam D, Wan T, Saretzki G. Dietary restriction mitigates age-related accumulation of DNA damage, but not all changes in mouse corneal epithelium. Experimental Gerontology 2015;67:72–9. doi: 10.1016/j.exger.2015.04.014CrossRefPubMed
49.
Kosteli A, Sugaru E, Haemmerle G, Martin JF, Lei J, Zechner R, et al. Weight loss and lipolysis promote a dynamic immune response in murine adipose tissue. The Journal of Clinical Investigation 2010;12010:3466–79. doi: 10.1172/jci42845CrossRef
50.
Benz V, Bloch M, Wardat S, Böhm C, Maurer L, Mahmoodzadeh S, et al. Sexual Dimorphic Regulation of Body Weight Dynamics and Adipose Tissue Lipolysis. PloS One 2012;75:e37794. doi: 10.1371/journal.pone.0037794CrossRef
51.
Sindhu S, Thomas R, Shihab P, Sriraman D, Behbehani K, Ahmad R. Obesity Is a Positive Modulator of IL-6R and IL-6 Expression in the Subcutaneous Adipose Tissue: Significance for Metabolic Inflammation. PloS One 2015;107:e0133494. doi: 10.1371/journal.pone.0133494CrossRef
52.
Xu XJ, Babo E, Qin F, Croteau D, Colucci WS. Short-term caloric restriction in db/db mice improves myocardial function and increases high molecular weight (HMW) adiponectin. IJC Metabolic & Endocrine 2016;13:28–34. doi: 10.1016/j. ijcme.2016.10.002CrossRef
53.
Luo T, Nocon A, Fry J, Sherban A, Rui X, Jiang B, et al. AMPK Activation by Metformin Suppresses Abnormal Adipose Tissue Extracellular Matrix Remodeling and Ameliorates Insulin Resistance in Obesity. Diabetes 2016.
54.
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 2009;83:311–23. doi: 10.1111/j.1474-9726.2009.00481.xCrossRef
55.
Hewitt G, Jurk D, Marques FDM, Correia-Melo C, Hardy T, Gackowska A, et al. Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. Nature Communications 2012;3:708. doi: 10.1038/ncomms1708CrossRefPubMedPubMedCentral
56.
Jolly SR, Lombardo YB, Lech JJ, Menahan LA. Effect of aging and cellularity on lipolysis in isolated mouse fat cells. Journal of Lipid Research 1980 211:44–52. doi: 10.1111/j.1651-2227.1977.tb07933.x
Metadata
Title
Dietary Restriction Ameliorates Age-Related Increase in DNA Damage, Senescence and Inflammation in Mouse Adipose Tissuey
Authors
A. Ishaq
J. Schröder
N. Edwards
T. von Zglinicki
Gabriele Saretzki
Publication date
01-04-2018
Publisher
Springer Paris
Published in
The journal of nutrition, health & aging / Issue 4/2018
Print ISSN: 1279-7707
Electronic ISSN: 1760-4788
DOI
https://doi.org/10.1007/s12603-017-0968-2

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