Research Article
No access
Published Online: 24 August 2010

Environmental Enrichment Improves Age-Related Immune System Impairment: Long-Term Exposure Since Adulthood Increases Life Span in Mice

Publication: Rejuvenation Research
Volume 13, Issue Number 4

Abstract

Age-related changes in immunity have been shown to highly influence morbidity and mortality. The aim of the present work was to study the effects of environmental enrichment (EE) (8–16 weeks) on several functions and oxidative stress parameters of peritoneal leukocytes, previously described as health and longevity markers, in mice at different ages, namely adult (44 ± 4 weeks), old (69 ± 4 weeks), and very old (92 ± 4 weeks). Mortality rates were monitored in control and enriched animals, and effects on survival of long-term exposure to EE until natural death were determined. The results showed that exposure to EE was efficient in improving the function (i.e., macrophage chemotaxis and phagocytosis, lymphocyte chemotaxis and proliferation, natural killer cell activity, interleukin-2 and tumor necrosis factor-α levels) and decreasing the oxidative–inflammatory stress (i.e., lowered oxidized glutathione content, xanthine oxidase activity, expression of Toll-like receptors 2 and 4 on CD4 and CD8 cells, and increased reduced glutathione and glutathione peroxidase and catalase activities) of immune cells. These positive effects of EE were especially remarkable in animals at older ages. Importantly, long-term exposure to EE from adult age and until natural death stands out as a useful strategy to extend longevity. Thus, the present work confirms the importance of maintaining active mental and/or physical activity aiming to improve quality of life in terms of immunity, and demonstrates that this active life must be initiated at early stages of the aging process and preserved until death to improve life span.

Get full access to this article

View all available purchase options and get full access to this article.

References

1.
Mattson MPDuan WLee JGuo Z. Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanismsMech Ageing Dev2001122757-778. 1. Mattson MP, Duan W, Lee J, Guo Z. Suppression of brain aging and neurodegenerative disorders by dietary restriction and environmental enrichment: molecular mechanisms. Mech Ageing Dev 2001;122:757–778.
2.
Segovia GYagüe AGGarcía-Verdugo JMMora F. Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged ratsBrain Res Bull2006708-14. 2. Segovia G, Yagüe AG, García-Verdugo JM, Mora F. Environmental enrichment promotes neurogenesis and changes the extracellular concentrations of glutamate and GABA in the hippocampus of aged rats. Brain Res Bull 2006;70:8–14.
3.
Segovia GArco ADMora F. Environmental enrichment, prefrontal cortex, stress, and aging of the brainJ Neural Transm20091161007-1016. 3. Segovia G, Arco AD, Mora F. Environmental enrichment, prefrontal cortex, stress, and aging of the brain. J Neural Transm 2009;116:1007–1016.
4.
Fernández CICollazo JBauza YCastellanos MRLópez O. Environmental enrichment-behavior-oxidative stress interactions in the aged rat: Issues for a therapeutic approach in human agingAnn NY Acad Sci2004101953-57. 4. Fernández CI, Collazo J, Bauza Y, Castellanos MR, López O. Environmental enrichment-behavior-oxidative stress interactions in the aged rat: Issues for a therapeutic approach in human aging. Ann NY Acad Sci 2004;1019:53–57.
5.
Wayne SJRhyne RLGarry PJGoodwin JS. Cell-mediated immunity as a predictor of morbidity and mortality in subjects over 60J Gerontol199045M45-M48. 5. Wayne SJ, Rhyne RL, Garry PJ, Goodwin JS. Cell-mediated immunity as a predictor of morbidity and mortality in subjects over 60. J Gerontol 1990;45:M45–M48.
6.
Wikby AFerguson FForsey RThompson JStrindhall JLofgren SNilsson BOErnerudh JPawelec GJohansson B. An immune risk phenotype, cognitive impairment, and survival in very late life: Impact of allostatic load in Swedish octogenarian and nonagenarian humansJ Gerontol A Biol Sci Med Sci200560556-565. 6. Wikby A, Ferguson F, Forsey R, Thompson J, Strindhall J, Lofgren S, Nilsson BO, Ernerudh J, Pawelec G, Johansson B. An immune risk phenotype, cognitive impairment, and survival in very late life: Impact of allostatic load in Swedish octogenarian and nonagenarian humans. J Gerontol A Biol Sci Med Sci 2005;60:556–565.
7.
De la Rosa OPawelec GPeralbo EWikby AMariani EMocchegiani ETarazona RSolana R. Immunological biomarkers of ageing in man: Changes in both innate and adaptive immunity are associated with health and longevityBiogerontology20067471-481. 7. De la Rosa O, Pawelec G, Peralbo E, Wikby A, Mariani E, Mocchegiani E, Tarazona R, Solana R. Immunological biomarkers of ageing in man: Changes in both innate and adaptive immunity are associated with health and longevity. Biogerontology 2006;7:471–481.
8.
De la Fuente MMiquel J. An update of the oxidation-inflammation theory of aging: The involvement of the immune system in oxi-inflamm-agingCurr Pharm Des2009153003-3026. 8. De la Fuente M, Miquel J. An update of the oxidation-inflammation theory of aging: The involvement of the immune system in oxi-inflamm-aging. Curr Pharm Des 2009;15:3003–3026.
9.
Guayerbas NDe la Fuente M. An impairment of phagocytic function is linked to a shorter life span in two strains of prematurely aging miceDev Comp Immunol200327339-350. 9. Guayerbas N, De la Fuente M. An impairment of phagocytic function is linked to a shorter life span in two strains of prematurely aging mice. Dev Comp Immunol 2003;27:339–350.
10.
Besedovsky HDel Rey A. Immune-neuro-endocrine interactions: Facts and hypothesesEndocrin Rev19961764-102. 10. Besedovsky H, Del Rey A. Immune-neuro-endocrine interactions: Facts and hypotheses. Endocrin Rev 1996;17:64–102.
11.
Guayerbas NCatalán MVíctor VMMiquel JDe la Fuente M. Relation of behaviour and macrophage function to life span in a murine model of premature immunosenescenceBehav Brain Res200213441-48. 11. Guayerbas N, Catalán M, Víctor VM, Miquel J, De la Fuente M. Relation of behaviour and macrophage function to life span in a murine model of premature immunosenescence. Behav Brain Res 2002;134:41–48.
12.
Guayerbas NPuerto MVíctor VMMiquel JDe la Fuente M. Leukocyte function and life span in a murine model of premature immunosenescenceExp Gerontol200237249-256. 12. Guayerbas N, Puerto M, Víctor VM, Miquel J, De la Fuente M. Leukocyte function and life span in a murine model of premature immunosenescence. Exp Gerontol 2002;37:249–256.
13.
Viveros MPArranz LHernanz AMiquel JDe la Fuente M. A model of premature aging in mice based on altered stress-related behavioral response and immunosenescenceNeuroimmunomodulation200714157-162. 13. Viveros MP, Arranz L, Hernanz A, Miquel J, De la Fuente M. A model of premature aging in mice based on altered stress-related behavioral response and immunosenescence. Neuroimmunomodulation 2007;14:157–162.
14.
Benaroya-Milshtein NHollander NApter AKukulansky TRaz NWilf AYaniv IPick CG. Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activityEur J Neurosci2004201341-1347. 14. Benaroya-Milshtein N, Hollander N, Apter A, Kukulansky T, Raz N, Wilf A, Yaniv I, Pick CG. Environmental enrichment in mice decreases anxiety, attenuates stress responses and enhances natural killer cell activity. Eur J Neurosci 2004;20:1341–1347.
15.
Zambrana ZMarco EMArranz LDe Castro NMViveros MPDe la Fuente M. Influence of aging and enriched environment on motor activity and emotional responses in miceAnn NY Acad Sci20071100543-552. 15. Zambrana Z, Marco EM, Arranz L, De Castro NM, Viveros MP, De la Fuente M. Influence of aging and enriched environment on motor activity and emotional responses in mice. Ann NY Acad Sci 2007;1100:543–552.
16.
Boyden SV. The chemotaxis effect of mixtures of antibody and antigen on polymorphonuclear leukocytesJ Exp Med1962115453-456. 16. Boyden SV. The chemotaxis effect of mixtures of antibody and antigen on polymorphonuclear leukocytes. J Exp Med 1962;115:453–456.
17.
Puerto MGuayerbas GVíctor VMDe la Fuente M. Effects of N-acetylcysteine on macrophage and lymphocyte functions in a mouse model of premature ageingPharmacol Biochem Behav200273797-804. 17. Puerto M, Guayerbas G, Víctor VM, De la Fuente M. Effects of N-acetylcysteine on macrophage and lymphocyte functions in a mouse model of premature ageing. Pharmacol Biochem Behav 2002;73:797–804.
18.
Alvarado CÁlvarez PPuerto MGausserès NJiménez LDe la Fuente M. Dietary supplementation with antioxidants improves functions and decreases oxidative stress of leukocytes from prematurely aging miceNutrition200622767-777. 18. Alvarado C, Álvarez P, Puerto M, Gausserès N, Jiménez L, De la Fuente M. Dietary supplementation with antioxidants improves functions and decreases oxidative stress of leukocytes from prematurely aging mice. Nutrition 2006;22:767–777.
19.
Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized gluthationeAnal Biochem196917502-522. 19. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized gluthatione. Anal Biochem 1969;17:502–522.
20.
Alvarado CÁlvarez PJiménez LDe la Fuente M. Oxidative stress in leukocytes from young prematurely aging mice is reversed by supplementation with biscuits rich in antioxidantsDev Comp Immunol2006301168-1180. 20. Alvarado C, Álvarez P, Jiménez L, De la Fuente M. Oxidative stress in leukocytes from young prematurely aging mice is reversed by supplementation with biscuits rich in antioxidants. Dev Comp Immunol 2006;30:1168–1180.
21.
Lawrence RABurk RF. Glutathione peroxidase activity in selenium-deficient rat liverBiochem Biophys Res Commun197671952-958. 21. Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 1976;71:952–958.
22.
Beers RFSizer IW. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalaseJ Biol Chem1952195133-140. 22. Beers RF, Sizer IW. A spectrophotometric method for measuring the breakdown of hydrogen peroxide by catalase. J Biol Chem 1952;195:133–140.
23.
Gerondakis SGrumont RJBanerjee A. Regulating B-cell activation and survival in response to TLR signalsImmunol Cell Biol200785471-475. 23. Gerondakis S, Grumont RJ, Banerjee A. Regulating B-cell activation and survival in response to TLR signals. Immunol Cell Biol 2007;85:471–475.
24.
Fassbender KWalter SKühl SLandmann RIshii KBertsch TStalder AKMuehlhauser FLiu YUlmer AJRivest SLentschat AGulbins EJucker MStaufenbiel MBrechtel KWalter JMulthaup GPenke BAdachi YHartmann TBeyreuther K. The LPS receptor (CD14) links innate immunity with Alzheimer's diseaseFASEB J200418203-205. 24. Fassbender K, Walter S, Kühl S, Landmann R, Ishii K, Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, Hartmann T, Beyreuther K. The LPS receptor (CD14) links innate immunity with Alzheimer's disease. FASEB J 2004;18:203–205.
25.
Mullick AETobias PSCurtiss LK. Toll-like receptors and atherosclerosis: Key contributors in disease and health?Immunol Res200634193-209. 25. Mullick AE, Tobias PS, Curtiss LK. Toll-like receptors and atherosclerosis: Key contributors in disease and health? Immunol Res 2006;34:193–209.
26.
Okun EGriffioen KJLathia JDTang SCMattson MPArumugam TV. Toll-like receptors in neurodegenerationBrain Res Rev200959278-292. 26. Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV. Toll-like receptors in neurodegeneration. Brain Res Rev 2009;59:278–292.
27.
Niwa YKasama TMiyachi YKanoh T. Neutrophil chemotaxis, phagocytosis and parameters of reactive oxygen species in human aging: Cross-sectional and longitudinal studiesLife Sci1989441655-1664. 27. Niwa Y, Kasama T, Miyachi Y, Kanoh T. Neutrophil chemotaxis, phagocytosis and parameters of reactive oxygen species in human aging: Cross-sectional and longitudinal studies. Life Sci 1989;44:1655–1664.
28.
Ginaldi LDe Martinis MD'Ostilio AMarini LLoreto MFQuaglino D. The immune system in the elderly III. Innate immunityImmunol Res199920117-126. 28. Ginaldi L, De Martinis M, D'Ostilio A, Marini L, Loreto MF, Quaglino D. The immune system in the elderly III. Innate immunity. Immunol Res 1999;20:117–126.
29.
Lord JMButcher SKillampali VLascelles DSalmon M. Neutrophil ageing and immunosenescenceMech Ageing Dev20011221521-1535. 29. Lord JM, Butcher S, Killampali V, Lascelles D, Salmon M. Neutrophil ageing and immunosenescence. Mech Ageing Dev 2001;122:1521–1535.
30.
Renshaw WRockwell JEngleman CGewirtz AKatz JSambhara S. Cutting edge: Impaired Toll-like receptor expression and function in agingJ Immunol20021694697-4701. 30. Renshaw W, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S. Cutting edge: Impaired Toll-like receptor expression and function in aging. J Immunol 2002;169:4697–4701.
31.
van den Biggelaar AHHuizinga TWde Craen AJGussekloo JHeijmans BTFrölich MWestendorp RG. Impaired innate immunity predicts frailty in old age. The Leiden 85-plus studyExp Gerontol2004391407-1414. 31. van den Biggelaar AH, Huizinga TW, de Craen AJ, Gussekloo J, Heijmans BT, Frölich M, Westendorp RG. Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study. Exp Gerontol 2004;39:1407–1414.
32.
Víctor VMDe la Fuente M. Immune cells redox state from mice with endotoxin-induced oxidative stress. Involvement of NF-kappaBFree Radic Res20033719-27. 32. Víctor VM, De la Fuente M. Immune cells redox state from mice with endotoxin-induced oxidative stress. Involvement of NF-kappaB. Free Radic Res 2003;37:19–27.
33.
Pawelec GBarnett YForsey RFrasca DGloberson AMcLeod JCaruso CFranceschi CFülop TGupta SMariani EMocchegiani ESolana R. T-cells and agingFront Biosci20027d1056-d1183. 33. Pawelec G, Barnett Y, Forsey R, Frasca D, Globerson A, McLeod J, Caruso C, Franceschi C, Fülop T, Gupta S, Mariani E, Mocchegiani E, Solana R. T-cells and aging. Front Biosci 2002;7:d1056–d1183.
34.
Marashi VBarnekow AOssendorf ESachser N. Effects of different forms of environmental enrichment on behavioral, endocrinological, and immunological parameters in male miceHorm Behav200343281-292. 34. Marashi V, Barnekow A, Ossendorf E, Sachser N. Effects of different forms of environmental enrichment on behavioral, endocrinological, and immunological parameters in male mice. Horm Behav 2003;43:281–292.
35.
Marashi VBarnekow ASachser N. Effects of environmental enrichment on males of a docile inbred strain of micePhysiol Behav200482765-776. 35. Marashi V, Barnekow A, Sachser N. Effects of environmental enrichment on males of a docile inbred strain of mice. Physiol Behav 2004;82:765–776.
36.
Simons RJReynolds HY. Altered immune status in the elderlySemin Respir Infect19905251-259. 36. Simons RJ, Reynolds HY. Altered immune status in the elderly. Semin Respir Infect 1990;5:251–259.
37.
Puerto MGuayerbas GÁlvarez PDe la Fuente M. Modulation of neuropeptide Y and norepinephrine on several leucocyte functions in adult, old and very old miceJ Neuroimmunol200516533-40. 37. Puerto M, Guayerbas G, Álvarez P, De la Fuente M. Modulation of neuropeptide Y and norepinephrine on several leucocyte functions in adult, old and very old mice. J Neuroimmunol 2005;165:33–40.
38.
Fiserová AStarec MKuldová MKováru HPáv MVannucci LPospísil M. Effects of D2-dopamine and α-adrenoceptor antagonists in stress induced changes on immune responsiveness of miceJ Neuroimmunol200213055-65. 38. Fiserová A, Starec M, Kuldová M, Kováru H, Páv M, Vannucci L, Pospísil M. Effects of D2-dopamine and α-adrenoceptor antagonists in stress induced changes on immune responsiveness of mice. J Neuroimmunol 2002;130:55–65.
39.
Mocchegiani EMalavolta M. NK and NKT cell functions in immunosenescenceAging Cell20043177-184. 39. Mocchegiani E, Malavolta M. NK and NKT cell functions in immunosenescence. Aging Cell 2004;3:177–184.
40.
Castle SC. Clinical relevance of age-related immune dysfunctionClin Infect Dis200031578-585. 40. Castle SC. Clinical relevance of age-related immune dysfunction. Clin Infect Dis 2000;31:578–585.
41.
Arumugam TVGranger DNMattson MP. Stroke and T-cellsNeuromolecular Med20057229-242. 41. Arumugam TV, Granger DN, Mattson MP. Stroke and T-cells. Neuromolecular Med 2005;7:229–242.
42.
Cohen Tervaert JW. Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitisClin Exp Immunol2009156377-385. 42. Cohen Tervaert JW. Translational Mini-Review Series on Immunology of Vascular Disease: Accelerated atherosclerosis in vasculitis. Clin Exp Immunol 2009;156:377–385.
43.
Hernanz AFernández-Vivancos EMontiel CVázquez JJArnalich F. Changes in the intracellular homocysteine and glutathione content associated with agingLife Sci2000671317-1324. 43. Hernanz A, Fernández-Vivancos E, Montiel C, Vázquez JJ, Arnalich F. Changes in the intracellular homocysteine and glutathione content associated with aging. Life Sci 2000;67:1317–1324.
44.
Dröge W. Oxidative stress and ageing: Is ageing a cysteine deficiency syndrome?Phil Trans R Soc B20053602355-2372. 44. Dröge W. Oxidative stress and ageing: Is ageing a cysteine deficiency syndrome? Phil Trans R Soc B 2005;360:2355–2372.
45.
Alonso-Fernández PPuerto MMaté IRibera JMDe la Fuente M. Neutrophils of centenarians show function levels similar to those of young adultsJ Am Geriatr Soc2008562244-2251. 45. Alonso-Fernández P, Puerto M, Maté I, Ribera JM, De la Fuente M. Neutrophils of centenarians show function levels similar to those of young adults. J Am Geriatr Soc 2008;56:2244–2251.
46.
Dröge WSchulze-Osthoff KMihm SGalter DSchenk HEck HPRoth SGmünder H. Function of glutathione and glutathione disulfide in immunology and immunopathologyFASEB J199481131-1138. 46. Dröge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S, Gmünder H. Function of glutathione and glutathione disulfide in immunology and immunopathology. FASEB J 1994;8:1131–1138.
47.
Aranda RDoménech ERus ADReal JTSastre JViña JPallardó FV. Age-related increase in xanthine oxidase activity in human plasma and rat tissuesFree Radic Res2007411195-1200. 47. Aranda R, Doménech E, Rus AD, Real JT, Sastre J, Viña J, Pallardó FV. Age-related increase in xanthine oxidase activity in human plasma and rat tissues. Free Radic Res 2007;41:1195–1200.
48.
Belz EEKennell JSCzambel RKRubin RTRhodes ME. Environmental enrichment lowers stress-responsive hormones in singly housed male and female ratsPharmacol Biochem Behav200376481-486. 48. Belz EE, Kennell JS, Czambel RK, Rubin RT, Rhodes ME. Environmental enrichment lowers stress-responsive hormones in singly housed male and female rats. Pharmacol Biochem Behav 2003;76:481–486.
49.
Hawkley LCCacioppo JT. Stress and the aging immune systemBrain Behav Immun200418114-119. 49. Hawkley LC, Cacioppo JT. Stress and the aging immune system. Brain Behav Immun 2004;18:114–119.

Information & Authors

Information

Published In

cover image Rejuvenation Research
Rejuvenation Research
Volume 13Issue Number 4August 2010
Pages: 415 - 428
PubMed: 20707722

History

Published online: 24 August 2010
Published ahead of print: 14 August 2010
Published in print: August 2010
Accepted: 5 January 2010
Received: 29 October 2009

Permissions

Request permissions for this article.

Topics

Authors

Affiliations

Lorena Arranz
Department of Physiology (Animal Physiology II), Faculty of Biological Sciences, Madrid Complutense University, Madrid, Spain.
Nuria M. De Castro
Department of Physiology (Animal Physiology II), Faculty of Biological Sciences, Madrid Complutense University, Madrid, Spain.
Isabel Baeza
Department of Physiology (Animal Physiology II), Faculty of Biological Sciences, Madrid Complutense University, Madrid, Spain.
Ianire Maté
Department of Physiology (Animal Physiology II), Faculty of Biological Sciences, Madrid Complutense University, Madrid, Spain.
Maria Paz Viveros
Department of Physiology (Animal Physiology II), Faculty of Biological Sciences, Madrid Complutense University, Madrid, Spain.
Mónica De la Fuente
Department of Physiology (Animal Physiology II), Faculty of Biological Sciences, Madrid Complutense University, Madrid, Spain.

Notes

Address correspondence to:Mónica De la FuenteDepartamento de Fisiología (Fisiología Animal II)Facultad de Ciencias BiológicasUniversidad Complutense28040 Madrid,Spain
E-mail: [email protected]

Author Disclosure Statement

No competing financial interests exist.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Get Access

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/ePub

Full Text

View Full Text

Media

Figures

Other

Tables

Share

Share

Copy the content Link

Share on social media

Back to Top