Skip to main content

Advertisement

Log in

Plasma biomarkers of mouse aging

  • Published:
AGE Aims and scope Submit manuscript

Abstract

Normal aging is accompanied by a series of physiological changes such as gray hair, cataracts, reduced immunity, and increased susceptibility to disease. To identify novel biomarkers of normal aging, we analyzed plasma proteins of male mice longitudinally from 2 to 19 months of age. Plasma proteins were analyzed by two-dimensional gel electrophoresis and identified using mass spectrometry (MS), MS/MS and liquid chromatography MS/MS. We found that many plasma proteins exist as multiple isoforms with different masses and/or charges. Thirty-nine protein spots (corresponding to six distinct proteins) have been identified, 13 of which exhibited significant changes with age. For example, several proteins increased significantly during aging including one isoform of transthyretin, two isoforms of haptoglobin, and three isoforms of immunoglobulin kappa chain. Conversely, several proteins decreased significantly during aging including peroxiredoxin-2, serum amyloid protein A-1, and five isoforms of albumin. Identification of these proteins provides new biomarkers of normal aging in mice. If validated in humans, these biomarkers may facilitate therapeutic interventions to identify premature aging, delay aging, and/or improve healthspan of the elderly.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  • Anderson NL, Anderson NG (2002) The human plasma proteome: history, character, and diagnostic prospects. Mol Cell Proteomics 1:845–867

    Article  PubMed  CAS  Google Scholar 

  • Asleh R, Levy AP (2005) In vivo and in vitro studies establishing haptoglobin as a major susceptibility gene for diabetic vascular disease. Vasc Health Risk Manag 1:19–28

    Article  PubMed  CAS  Google Scholar 

  • Atzmon G, Gabriely I, Greiner W, Davidson D, Schechter C, Barzilai N (2002) Plasma HDL levels highly correlate with cognitive function in exceptional longevity. J Gerontol A Biol Sci Med Sci 57:M712–M715

    Article  PubMed  Google Scholar 

  • Ballesteros M, Fredriksson A, Henriksson J, Nystrom T (2001) Bacterial senescence: protein oxidation in non-proliferating cells is dictated by the accuracy of the ribosomes. EMBO J 20:5280–5289

    Article  PubMed  CAS  Google Scholar 

  • Barber BJ, Babbitt RA, Parameswaran S, Dutta S (1995) Age-related changes in rat interstitial matrix hydration and serum proteins. J Gerontol A Biol Sci Med Sci 50A:B282–B287

    Article  CAS  Google Scholar 

  • Berryman DE et al (2009) Two-year body composition analyses of long-lived GHR null mice. J Gerontol A Biol Sci Med Sci:glp175

  • Bessa SS, Hamdy SM, Ali EMM (2007) Haptoglobin gene polymorphism in type 2 diabetic patients with and without nephropathy: an Egyptian study. Eur J Intern Med 18:489–495

    Article  PubMed  CAS  Google Scholar 

  • Bijon C, Jürgen B (2009) A 2-DE MALDI-TOF study to identify disease regulated serum proteins in lung cancer of c-myc transgenic mice. Proteomics 9:1044–1056

    Article  Google Scholar 

  • Bittner V (2003) Non-high-density lipoprotein cholesterol and cardiovascular disease. Curr Opin Lipidol 14:367–371

    Article  PubMed  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein–dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Chen CC et al (2009) Levels of retinol-binding protein 4 and uric acid in patients with type 2 diabetes mellitus. Metabolism 58(12):1812–1816

    Article  PubMed  CAS  Google Scholar 

  • Colman RJ et al (2009) Caloric restriction delays disease onset and mortality in rhesus monkeys. Science 325:201–204

    Article  PubMed  CAS  Google Scholar 

  • Coschigano KT, Holland AN, Riders ME, List EO, Flyvbjerg A, Kopchick JJ (2003) Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144:3799–3810. doi:10.1210/en.2003-0374

    Article  PubMed  CAS  Google Scholar 

  • Dobryszycka W (1997) Biological functions of haptoglobin—new pieces to an old puzzle. Eur J Clin Chem Clin Biochem 35:647–654

    PubMed  CAS  Google Scholar 

  • Dowling DK, Simmons LW (2009) Reactive oxygen species as universal constraints in life-history evolution. Proc Biol Sci 276:1737–1745

    Article  PubMed  CAS  Google Scholar 

  • Duan X, Yarmush DM, Berthiaume F, Jayaraman A, Yarmush ML (2004) A mouse serum two-dimensional gel map: application to profiling burn injury and infection. Electrophoresis 25:3055–3065

    Article  PubMed  CAS  Google Scholar 

  • Fanciulli G, Delitala A, Delitala G (2009) Growth hormone, menopause and ageing: no definite evidence for ‘rejuvenation’ with growth hormone. Hum Reprod Update 15:341–358

    Article  PubMed  CAS  Google Scholar 

  • Ferrucci L et al (2005) The origins of age-related proinflammatory state. Blood 105:2294–2299

    Article  PubMed  CAS  Google Scholar 

  • Gazzana G, Jr B (2008) Mapping of the serum proteome of hepatocellular carcinoma induced by targeted overexpression of epidermal growth factor to liver cells of transgenic mice. J Proteome Res 7:928–937

    Article  PubMed  CAS  Google Scholar 

  • Gillum RF (2000) Assessment of serum albumin concentration as a risk factor for stroke and coronary disease in African Americans and whites. J Natl Med Assoc 92:3–9

    PubMed  CAS  Google Scholar 

  • Gom I et al (2007) Relationship between serum albumin level and aging in community-dwelling self-supported elderly population. J Nutr Sci Vitaminol (Tokyo) 53:37–42

    Article  Google Scholar 

  • Gonzalez-Quintela A et al (2008) Serum levels of immunoglobulins (IgG, IgA, IgM) in a general adult population and their relationship with alcohol consumption, smoking and common metabolic abnormalities. Clin Exp Immunol 151:42–50

    Article  PubMed  CAS  Google Scholar 

  • Granger J, Siddiqui J, Copeland S, Remick D (2005) Albumin depletion of human plasma also removes low abundance proteins including the cytokines. Proteomics 5:4713–4718

    Article  PubMed  CAS  Google Scholar 

  • Gromov P, Skovgaard GL, Palsdottir H, Gromova I, Ostergaard M, Celis JE (2003) Protein profiling of the human epidermis from the elderly reveals up-regulation of a signature of interferon-{gamma}-induced polypeptides that includes manganese-superoxide dismutase and the p85{beta} subunit of phosphatidylinositol 3-kinase. Mol Cell Proteomics 2:70–84

    Article  PubMed  CAS  Google Scholar 

  • Guipaud O et al (2007) Time-course analysis of mouse serum proteome changes following exposure of the skin to ionizing radiation. Proteomics 7:3992–4002

    Article  PubMed  CAS  Google Scholar 

  • Han Y-H, Kwon J-H, Yu D-Y, Moon E-Y (2006) Inhibitory effect of peroxiredoxin ii (prx ii) on Ras-Erk-NFkb pathway in mouse embryonic fibroblast (MEF) senescence. Free Radic Res 40:1182–1189

    Article  PubMed  CAS  Google Scholar 

  • Harper JM, Wolf N, Galecki AT, Pinkosky SL, Miller RA (2003) Hormone levels and cataract scores as sex-specific, mid-life predictors of longevity in genetically heterogeneous mice. Mech Ageing Dev 124:801–810

    Article  PubMed  CAS  Google Scholar 

  • Holloszy JO, Fontana L (2007) Caloric restriction in humans. Exp Gerontol 42:709–712

    Article  PubMed  CAS  Google Scholar 

  • Ingram DK (2000) Age-related decline in physical activity: generalization to nonhumans. Med Sci Sports Exerc 32:1623–1629

    Article  PubMed  CAS  Google Scholar 

  • James MH, Adam BS, Scott FL, Andrzej TG, Richard AM (2007) Skin-derived fibroblasts from long-lived species are resistant to some, but not all, lethal stresses and to the mitochondrial inhibitor rotenone. Aging Cell 6:1–13

    Article  Google Scholar 

  • Katz PR, Karuza J, Gutman SI, Bartholomew W, Richman G (1990) A comparison between erythrocyte sedimentation rate (esr) and selected acute-phase proteins in the elderly. Am J Clin Pathol 94:637–640

    PubMed  CAS  Google Scholar 

  • Klein BEK, Klein R, Lee KE (2002) Incidence of age-related cataract over a 10-year interval: the beaver dam eye study. Ophthalmology 109:2052–2057

    Article  PubMed  Google Scholar 

  • Kowalska I et al (2008) Serum retinol binding protein 4 is related to insulin resistance and nonoxidative glucose metabolism in lean and obese women with normal glucose tolerance. J Clin Endocrinol Metab 93:2786–2789

    Article  PubMed  CAS  Google Scholar 

  • Kronmal RA, Cain KC, Ye Z, Omenn GS (1993) Total serum cholesterol levels and mortality risk as a function of age. A report based on the Framingham data. Arch Intern Med 153:1065–1073

    Article  PubMed  CAS  Google Scholar 

  • Leslie M (2008) Aging: searching for the secrets of the super old. Science 321:1764–1765

    Article  PubMed  CAS  Google Scholar 

  • List EO et al (2007a) Application of bioinformatics and scalable computing to perform proteomic analysis of stomach tissue from diabetic mice. Scalable Comput Pract Exp 8:173–183

    Google Scholar 

  • List EO et al (2007b) Analysis of mouse skin reveals proteins that are altered in a diet-induced diabetic state: a new method for detection of type 2 diabetes. Proteomics 7:1140–1149

    Article  PubMed  CAS  Google Scholar 

  • List EO, Palmer AJ, Berryman DE, Bower B, Kelder B, Kopchick JJ (2009) Growth hormone improves body composition, fasting blood glucose, glucose tolerance and liver triacylglycerol in a mouse model of diet-induced obesity and type 2 diabetes. Diabetologia 52(8):1647–1655

    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 

  • Malone JP, Radabaugh MR, Leimgruber RM, Gerstenecker GS (2001) Practical aspects of fluorescent staining for proteomic applications. Electrophoresis 22:919–932

    Article  PubMed  CAS  Google Scholar 

  • McMillan DE (1989) Increased levels of acute-phase serum proteins in diabetes. Metabolism 38:1042–1046

    Article  PubMed  CAS  Google Scholar 

  • Merlini G, Bellotti V (2003) Molecular mechanisms of amyloidosis. N Engl J Med 349:583–596

    Article  PubMed  CAS  Google Scholar 

  • Miller RA (1996) The aging immune system: primer and prospectus. Science 273:70–74

    Article  PubMed  CAS  Google Scholar 

  • Miller RA, Nadon NL (2000) Principles of animal use for gerontological research. J Gerontol A Biol Sci Med Sci 55:B117–B123

    Article  PubMed  CAS  Google Scholar 

  • Miura Y et al (2007) Proteomic study on x-irradiation-responsive proteins and ageing: search for responsible proteins for radiation adaptive response. J Biochem 142:145–155

    Article  PubMed  CAS  Google Scholar 

  • Muhlhausler B, Smith SR (2009) Early life origins of metabolic dysfunction: role of the adipocyte. Trends Endocrinol Metab 20:51–57

    Article  PubMed  CAS  Google Scholar 

  • Nakamura E, Miyao K (2007) A method for identifying biomarkers of aging and constructing an index of biological age in humans. J Gerontol A Biol Sci Med Sci 62:1096–1105

    PubMed  Google Scholar 

  • Nakhoul FM, Miller-Lotan R, Awaad H, Asleh R, Levy AP (2007) Hypothesis—haptoglobin genotype and diabetic nephropathy. Nat Clin Pract Nephrol 3:339–344

    Article  PubMed  CAS  Google Scholar 

  • Nass R, Johannsson G, Christiansen JS, Kopchick JJ, Thorner MO (2009) The aging population—is there a role for endocrine interventions? Growth Horm IGF Res 19:89–100

    Article  PubMed  CAS  Google Scholar 

  • Nir B, Ilan G, Magda G, Nancy I, John DS (2001) Offspring of centenarians have a favorable lipid profile. J Am Geriatr Soc 49:76–79

    Article  Google Scholar 

  • Okada S, List E, Sankaran S, Kopchick J (2010) Plasma protein biomarkers correlated with the development of diet-induced type 2 diabetes in mice. Clinical Proteomics 6(1–2):6–17. doi:10.1007/s12014-009-9040-5

    Article  PubMed  CAS  Google Scholar 

  • OlÃhovà M et al (2008) A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance. Proc Natl Acad Sci USA 105:19839–19844

    Article  PubMed  Google Scholar 

  • Orentreich N, Brind JL, Vogelman JH, Andres R, Baldwin H (1992) Long-term longitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 75:1002–1004

    Article  PubMed  CAS  Google Scholar 

  • Palmer AJ et al (2009) Age-related changes in body composition of bovine growth hormone transgenic mice. Endocrinology 150:1353–1360

    Article  PubMed  CAS  Google Scholar 

  • PlantÃ-Bordeneuve V, Said G (2000) Transthyretin related familial amyloid polyneuropathy. Curr Opin Neurol 13:569–573

    Article  Google Scholar 

  • Qiu L, List EO, Kopchick JJ (2005) Differentially expressed proteins in the pancreas of diet-induced diabetic mice. Mol Cell Proteomics 4:1311–1318

    Article  PubMed  CAS  Google Scholar 

  • Raila J, Henze A, Spranger J, Mohlig M, Pfeiffer AF, Schweigert FJ (2007) Microalbuminuria is a major determinant of elevated plasma retinol-binding protein 4 in type 2 diabetic patients. Kidney Int 72:505–511

    Article  PubMed  CAS  Google Scholar 

  • Richard AM et al (2005) T cells in aging mice: genetic, developmental, and biochemical analyses. Immunol Rev 205:94–103

    Article  Google Scholar 

  • Robert FR, Glenn EP, Louis MN, Olga N (1999) Reference distributions for the negative acute-phase proteins, albumin, transferrin, and transthyretin: a comparison of a large cohort to the world's literature. J Clin Lab Anal 13:280–286

    Article  Google Scholar 

  • Roberto G et al (2008) Proteomic analysis of the pathophysiological process involved in the antisnake venom effect of mucuna pruriens extract. Proteomics 8:402–412

    Article  Google Scholar 

  • Rothemund DL, Locke VL, Liew A, Thomas TM, Wasinger V, Rylatt DB (2003) Depletion of the highly abundant protein albumin from human plasma using the gradiflow. Proteomics 3:279–287

    Article  PubMed  CAS  Google Scholar 

  • Sackmann-Sala L, Ding J, Frohman LA, Kopchick JJ (2009) Activation of the GH/IGF-1 axis by cjc-1295, a long-acting ghrh analog, results in serum protein profile changes in normal adult subjects. Growth Horm IGF Res 19:471–477

    Article  PubMed  CAS  Google Scholar 

  • Sato Y et al (2006) Identification and characterization of an increased glycoprotein in aging: age-associated translocation of cathepsin d. Mech Ageing Dev 127:771–778

    Article  PubMed  CAS  Google Scholar 

  • Simell B, Lahdenkari M, Reunanen A, Kayhty H, Vakevainen M (2008) Effects of ageing and gender on naturally acquired antibodies to pneumococcal capsular polysaccharides and virulence-associated proteins. Clin Vaccine Immunol 15:1391–1397

    Article  PubMed  CAS  Google Scholar 

  • Song J, Stastny J, Fosslien E, Robertson AL Jr (1985) Effect of aging on human aortic protein composition. II. Two-dimensional polyacrylamide gel electrophoretic analysis. Exp Mol Pathol 43:297–304

    Article  PubMed  CAS  Google Scholar 

  • Suhr OB et al (1999) Impact of age and amyloidosis on thiol conjugation of transthyretin in hereditary transthyretin amyloidosis. Amyloid 6:187–191

    Article  PubMed  CAS  Google Scholar 

  • Teunissen CE et al (2003) Inflammation markers in relation to cognition in a healthy aging population. J Neuroimmunol 134:142–150

    Article  PubMed  CAS  Google Scholar 

  • Thadikkaran L, Siegenthaler MA, Crettaz D, Queloz PA, Schneider P, Tissot JD (2005) Recent advances in blood-related proteomics. Proteomics 5:3019–3014

    Article  PubMed  CAS  Google Scholar 

  • van der Hilst JCH, Yamada T, Op den Camp HJM, van der Meer JWM, Drenth JPH, Simon A (2008) Increased susceptibility of serum amyloid a 1.1 to degradation by mmp-1: potential explanation for higher risk of type aa amyloidosis. Rheumatology (Oxford) 47:1651–1654

    Article  Google Scholar 

  • Westermark P, Sletten K, Johansson B, Cornwell GG 3rd (1990) Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci USA 87:2843–2845

    Article  PubMed  CAS  Google Scholar 

  • Wilson PW, Anderson KM, Harris T, Kannel WB, Castelli WP (1994) Determinants of change in total cholesterol and HDL-c with age: the Framingham study. J Gerontol 49:M252–M257

    PubMed  CAS  Google Scholar 

  • Yuan RPB (2008) Aging study: lifespan and survival curves. In: http://phenome.jax.org/phenome/protodocs/yuan2/cut_200804/yuan2.xls

Download references

Acknowledgment

This work was supported by World Anti-Doping Agency (WADA), Diabetes Research Initiative and by the State of Ohio’s Eminent Scholars Program that includes a gift by Milton and Lawrence Goll. JJK also is supported by the following grants: National Institute of Health (NIH) R15DK075436, NIH R01AG019899, and 1P01AG031736-01A1.

We thank Dr. Edward List for reading and commenting on this manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John J. Kopchick.

Electronic supplementary materials

Below is the link to the electronic supplementary material.

ESM1

(DOC 187 kb)

About this article

Cite this article

Ding, J., Kopchick, J.J. Plasma biomarkers of mouse aging. AGE 33, 291–307 (2011). https://doi.org/10.1007/s11357-010-9179-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-010-9179-z

Keywords

Navigation