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Androgen supplementation improves some but not all aspects of immune senescence in aged male macaques

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Abstract

Aging leads to a progressive decline in immune function commonly referred to as immune senescence, which results in increased incidence and severity of infection. In addition, older males experience a significant disruption in their levels of circulating androgens, notably testosterone and dehydroepiandrosterone (DHEA), which has been linked to sarcopenia, osteoporosis, cardiovascular disease, and diabetes. Since sex steroid levels modulate immune function, it is possible that the age-related decline in androgen levels can also affect immune senescence. Therefore, in this study, we evaluated the pleiotropic effects of physiological androgen supplementation in aged male rhesus macaques (n = 7/group) on immune cell subset frequency and response to vaccination. As expected, frequency of naïve CD4 and CD8 T cells declined in aged non-treated macaques, while that of memory T cells increased. In contrast, frequency of naïve and memory T cells remained stable in androgen-supplemented males. In addition, levels of inflammatory cytokines increased less steeply in supplemented aged males compared to the aged controls. Despite these changes, androgen-supplemented animals only showed modest improvement in antibody responses following vaccination compared to age non-treated controls. These data indicate that short-term physiological androgen supplementation can improve some but not all aspects of immune senescence.

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References

  • Asquith M, Haberthur K, Brown M, Engelmann F, Murphy A, Al-Mahdi Z and Messaoudi I (2012) “Age-dependent changes in innate immune phenotype and function in rhesus macaques (Macaca mulatta).” Pathobiol Aging Age Relat Dis 2

  • Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, LeBrasseur N, Fiore LD, Bhasin S (2010) Adverse events associated with testosterone administration. N Engl J Med 363(2):109–122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bremner WJ, Vitiello MV, Prinz PN (1983) Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab 56(6):1278–1281

    Article  CAS  PubMed  Google Scholar 

  • Carroll TD, Matzinger SR, Barry PA, McChesney MB, Fairman J, Miller CJ (2014) Efficacy of influenza vaccination of elderly rhesus macaques is dramatically improved by addition of a cationic lipid/DNA adjuvant. J Infect Dis 209(1):24–33

    Article  CAS  PubMed  Google Scholar 

  • Cherrier MM, Matsumoto AM, Amory JK, Ahmed S, Bremner W, Peskind ER, Raskind MA, Johnson M, Craft S (2005a) The role of aromatization in testosterone supplementation: effects on cognition in older men. Neurology 64(2):290–296

    Article  CAS  PubMed  Google Scholar 

  • Cherrier MM, Matsumoto AM, Amory JK, Asthana S, Bremner W, Peskind ER, Raskind MA, Craft S (2005b) Testosterone improves spatial memory in men with Alzheimer disease and mild cognitive impairment. Neurology 64(12):2063–2068

    Article  CAS  PubMed  Google Scholar 

  • Cicin-Sain L, Smyk-Pearson S, Currier N, Byrd L, Koudelka C, Robinson T, Swarbrick G, Tackitt S, Legasse A, Fischer M, Nikolich-Zugich D, Park B, Hobbs T, Doane CJ, Mori M, Axthelm MK, Lewinsohn DA, Nikolich-Zugich J (2010) Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates. J Immunol 184(12):6739–6745

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cunningham GR, Stephens-Shields AJ, Rosen RC, Wang C, Bhasin S, Matsumoto AM, Parsons JK, Gill TM, Molitch ME, Farrar JT, Cella D, Barrett-Connor E, Cauley JA, Cifelli D, Crandall JP, Ensrud KE, Gallagher L, Zeldow B, Lewis CE, Pahor M, Swerdloff RS, Hou X, Anton S, Basaria S, Diem SJ, Tabatabaie V, Ellenberg SS, Snyder PJ (2016) Testosterone treatment and sexual function in older men with low testosterone levels. J Clin Endocrinol Metab 101(8):3096–3104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM and Goronzy JJ (2008) T cell subset-specific susceptibility to aging. Clin Immunol

  • De Martinis M, Franceschi C, Monti D, Ginaldi L (2005) Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity. FEBS Lett 579(10):2035–2039

    Article  CAS  PubMed  Google Scholar 

  • Ellis TM, Moser MT, Le PT, Flanigan RC, Kwon ED (2001) Alterations in peripheral B cells and B cell progenitors following androgen ablation in mice. Int Immunol 13(4):553–558

    Article  CAS  PubMed  Google Scholar 

  • Engelmann F, Barron A, Urbanski H, Neuringer M, Kohama SG, Park B, Messaoudi I (2011) Accelerated immune senescence and reduced response to vaccination in ovariectomized female rhesus macaques. Age (Dordr) 33(3):275–289

    Article  CAS  Google Scholar 

  • Fagnoni FF, Vescovini R, Passeri G, Bologna G, Pedrazzoni M, Lavagetto G, Casti A, Franceschi C, Passeri M, Sansoni P (2000) Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging. Blood 95(9):2860–2868

    CAS  PubMed  Google Scholar 

  • Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, Fraumeni JF Jr, Hoover RN (2014) Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 9(1):e85805

    Article  PubMed  PubMed Central  Google Scholar 

  • Fulop T, McElhaney J, Pawelec G, Cohen AA, Morais JA, Dupuis G, Baehl S, Camous X, Witkowski JM, Larbi A (2015) Frailty, inflammation and immunosenescence. Interdiscip Top Gerontol Geriatr 41:26–40

    PubMed  Google Scholar 

  • Goodwin K, Viboud C, Simonsen L (2006) Antibody response to influenza vaccination in the elderly: a quantitative review. Vaccine 24(8):1159–1169

    Article  CAS  PubMed  Google Scholar 

  • Haberthur K, Engelman F, Barron A, Messaoudi I (2010) Immune senescence in aged nonhuman primates. Exp Gerontol 45(9):655–661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR, Baltimore Longitudinal Study of Aging (2001) Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore longitudinal study of aging. J Clin Endocrinol Metab 86(2):724–731

    Article  CAS  PubMed  Google Scholar 

  • High KP (2004) Infection as a cause of age-related morbidity and mortality. Ageing Res Rev 3(1):1–14

    Article  PubMed  Google Scholar 

  • Holmang S, Marin P, Lindstedt G, Hedelin H (1993) Effect of long-term oral testosterone undecanoate treatment on prostate volume and serum prostate-specific antigen concentration in eugonadal middle-aged men. Prostate 23(2):99–106

    Article  CAS  PubMed  Google Scholar 

  • Janowsky JS, Oviatt SK, Orwoll ES (1994) Testosterone influences spatial cognition in older men. Behav Neurosci 108(2):325–332

    Article  CAS  PubMed  Google Scholar 

  • Josset L, Engelmann F, Haberthur K, Kelly S, Park B, Kawoaka Y, Garcia-Sastre A, Katze MG, Messaoudi I (2012) Increased viral loads and exacerbated innate host responses in aged macaques infected with the 2009 pandemic H1N1 influenza a virus. J Virol 86(20):11115–11127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Larbi A, Franceschi C, Mazzatti D, Solana R, Wikby A, Pawelec G (2008) Aging of the immune system as a prognostic factor for human longevity. Physiology (Bethesda) 23:64–74

    Article  CAS  Google Scholar 

  • Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH (2004a) The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 89(7):3313–3318

    Article  CAS  PubMed  Google Scholar 

  • Malkin CJ, Pugh PJ, Morris PD, Kerry KE, Jones RD, Jones TH, Channer KS (2004b) Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart 90(8):871–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Müller L, Hamprecht K, Pawelec G (2017) The role of CMV in immunosenescence. The Ageing Immune System and Health. V. Bueno. J. M. Lord and T. A. Jackson. Cham, Springer International Publishing: 53–68

  • Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174(11):7446–7452

    Article  CAS  PubMed  Google Scholar 

  • Olsen NJ, Kovacs WJ (2001) Effects of androgens on T and B lymphocyte development. Immunol Res 23(2–3):281–288

    Article  CAS  PubMed  Google Scholar 

  • Page ST, Amory JK, Bowman FD, Anawalt BD, Matsumoto AM, Bremner WJ, Tenover JL (2005) Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T. J Clin Endocrinol Metab 90(3):1502–1510

    Article  CAS  PubMed  Google Scholar 

  • Page ST, Plymate SR, Bremner WJ, Matsumoto AM, Hess DL, Lin DW, Amory JK, Nelson PS, Wu JD (2006) Effect of medical castration on CD4+ CD25+ T cells, CD8+ T cell IFN-gamma expression, and NK cells: a physiological role for testosterone and/or its metabolites. Am J Physiol Endocrinol Metab 290(5):E856–E863

    Article  CAS  PubMed  Google Scholar 

  • Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Cifelli D, Dougar D, Fluharty L, Resnick SM, Storer TW, Anton S, Basaria S, Diem SJ, Hou X, Mohler ER 3rd, Parsons JK, Wenger NK, Zeldow B, Landis JR, Ellenberg SS, I. Testosterone Trials (2016a) Effects of testosterone treatment in older men. N Engl J Med 374(7):611–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Snyder PJ, Ellenberg SS, Farrar JT (2016b) Testosterone treatment in older men. N Engl J Med 375(1):90

    Article  PubMed  Google Scholar 

  • Stanworth RD, Jones TH (2008) Testosterone for the aging male; current evidence and recommended practice. Clin Interv Aging 3(1):25–44

    CAS  PubMed  PubMed Central  Google Scholar 

  • Strindhall J, Ernerudh J, Mörner A, Waalen K, Löfgren S, Matussek A, Bengner M (2016) Humoral response to influenza vaccination in relation to pre-vaccination antibody titres, vaccination history, cytomegalovirus serostatus and CD4/CD8 ratio. Infectious Diseases 48(6):436–442

    Article  CAS  PubMed  Google Scholar 

  • Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, Blazar BR, Millar JL, Malin MA, Chidgey AP, Boyd RL (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175(4):2741–2753

    Article  CAS  PubMed  Google Scholar 

  • Swerdloff R, Wang C (2011) Testosterone treatment of older men—why are controversies created? J Clin Endocrinol Metab 96(1):62–65

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tan RS, Pu SJ (2003) A pilot study on the effects of testosterone in hypogonadal aging male patients with Alzheimer’s disease. Aging Male 6(1):13–17

    Article  CAS  PubMed  Google Scholar 

  • Tivesten A, Moverare-Skrtic S, Chagin A, Venken K, Salmon P, Vanderschueren D, Savendahl L, Holmang A, Ohlsson C (2004) Additive protective effects of estrogen and androgen treatment on trabecular bone in ovariectomized rats. J Bone Miner Res 19(11):1833–1839

    Article  CAS  PubMed  Google Scholar 

  • Urbanski HF, Sorwell KG (2012) Age-related changes in neuroendocrine rhythmic function in the rhesus macaque. Age (Dordr) 34(5):1111–1121

    Article  CAS  Google Scholar 

  • Urbanski HF, Sorwell KG, Garyfallou VT, Garten J, Weiss A, Renner L, Neuringer M, Kohama SG (2014) Androgen supplementation during aging: development of a physiologically appropriate protocol. Rejuvenation Res 17(2):150–153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C (2004) Androgens and bone. Endocr Rev 25(3):389–425

    Article  CAS  PubMed  Google Scholar 

  • Vasto S, Candore G, Balistreri CR, Caruso M, Colonna-Romano G, Grimaldi MP, Listi F, Nuzzo D, Lio D, Caruso C (2007) Inflammatory networks in ageing, age-related diseases and longevity. Mech Ageing Dev 128(1):83–91

    Article  CAS  PubMed  Google Scholar 

  • Viallard JF, Marit G, Mercie P, Leng B, Reiffers J, Pellegrin JL (2000) Polycythaemia as a complication of transdermal testosterone therapy. Br J Haematol 110(1):237–238

    Article  CAS  PubMed  Google Scholar 

  • Vigen R, O’Donnell CI, Baron AE, Grunwald GK, Maddox TM, Bradley SM, Barqawi A, Woning G, Wierman ME, Plomondon ME, Rumsfeld JS, Ho PM (2013) Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 310(17):1829–1836

    Article  CAS  PubMed  Google Scholar 

  • Wang C, Cunningham G, Dobs A, Iranmanesh A, Matsumoto AM, Snyder PJ, Weber T, Berman N, Hull L, Swerdloff RS (2004) Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J Clin Endocrinol Metab 89(5):2085–2098

    Article  CAS  PubMed  Google Scholar 

  • Webb CM, Adamson DL, de Zeigler D, Collins P (1999a) Effect of acute testosterone on myocardial ischemia in men with coronary artery disease. Am J Cardiol 83(3):437–439 A439

    Article  CAS  PubMed  Google Scholar 

  • Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P (1999b) Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 100(16):1690–1696

    Article  CAS  PubMed  Google Scholar 

  • Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B (2008a) Biology of immune responses to vaccines in elderly persons. Clin Infect Dis 46(7):1078–1084

    Article  PubMed  Google Scholar 

  • Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B (2008b) Vaccines: biology of immune responses to vaccines in elderly persons. Clin Infect Dis 46(7):1078–1084

    Article  PubMed  Google Scholar 

  • Wikby A, Nilsson BO, Forsey R, Thompson J, Strindhall J, Lofgren S, Ernerudh J, Pawelec G, Ferguson F, Johansson B (2006) The immune risk phenotype is associated with IL-6 in the terminal decline stage: findings from the Swedish NONA immune longitudinal study of very late life functioning. Mech Ageing Dev 127(8):695–704

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank the veterinarians and the husbandry staff at the Oregon National Primate Research Center for sample collection and expert care of the animals. We also thank Norma Mendoza for her help in performing ELISA to measure IgG titers. This work was supported by R21AG-043896, NIH R01AG-036670, OD-010426, and OD-011092.

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Authors and Affiliations

  1. Graduate program in Biomedical Sciences, School of Medicine, University of California, Riverside, CA, USA

    Maham Rais & Ilhem Messaoudi

  2. Graduate program in Cell, Molecular, and Developmental Biology, University of California, Riverside, CA, USA

    Randall M. Wilson & Ilhem Messaoudi

  3. Division of Neuroscience and Division of Reproductive and Developmental Sciences, Oregon National Primate Research Center, Beaverton, OR, USA

    Henryk F. Urbanski

  4. Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, USA

    Henryk F. Urbanski

  5. Molecular Biology and Biochemistry, School of Biological Sciences, University of California Irvine, 2400 Biological Sciences III, Irvine, CA, 92697, USA

    Ilhem Messaoudi

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  1. Maham Rais
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  2. Randall M. Wilson
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  4. Ilhem Messaoudi
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Contributions

Designed and directed the project: IM and HU; performed experiments: MR, IM, and RW; analyzed data and the prepared figures: MR and IM; wrote the manuscript: MR, IM, and HU.

Corresponding author

Correspondence to Ilhem Messaoudi.

Ethics declarations

This study was carried out in strict accordance with the recommendations described in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health, the Office of Animal Welfare, and the US Department of Agriculture. All animal work was approved by the Oregon National Primate Research Center Institutional Animal Care and Use Committee.

All procedures were carried out under ketamine anesthesia in the presence of veterinary staff, and all efforts were made to minimize animal suffering. White blood cell counts were obtained using a complete blood count machine (Hemavet; Drew Scientific Group, Waterbury, CT).

Electronic supplementary material

Supplemental Fig. 1

Gating strategy of rhesus macaque PBMC. (A) Flow cytometric gating strategy to delineate T and B cell populations. (B) Flow cytometric gating strategy to delineate innate cell populations. (C) Flow cytometric analysis of T cell cytokine response to stimulation with MVA and H1N1 antigens (example show is following stimulation with PMA/ionomycin). (PDF 1337 kb)

Supplemental Fig. 2

Frequency of circulating naïve and memory B cell populations. The frequencies (mean ± SEM) of (A) total B cells; (B) naïve (IgD+ CD27-); (C) marginal zone (MZ)-like (IgD+ CD27+); (D) class-switched memory (IgD− CD27+); (E) and double-negative (Other; IgD− CD27−) B cells were measured in PBMC samples by flow cytometry. (PDF 273 kb)

Supplemental Fig. 3

Frequencies of circulating monocytes, dendritic cells, and natural killer cells. The frequencies (means ± SEM) of (A) dendritic cells (DCs; CD3− CD20- CD14− HLA-DR+); (B) monocytes (CD3− CD20- CD14+ HLA-DR−); (C) natural killer cells (NK cells; CD3− CD20- CD8α +); (D) myeloid DCs (mDCs; CD123− CD11c+); and (E) plasmacytoid DCs (pDCs; CD123+ CD11c−) in PBMC were measured by flow cytometry (*, P < 0.05 supplemented macaques compared to aged controls). (PDF 278 kb)

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Rais, M., Wilson, R.M., Urbanski, H.F. et al. Androgen supplementation improves some but not all aspects of immune senescence in aged male macaques. GeroScience 39, 373–384 (2017). https://doi.org/10.1007/s11357-017-9979-5

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