Skip to main content
SpringerLink
Log in

Metabolomic approaches to the normal aging process

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Aging is a multifaceted process involving the accumulation of diverse deleterious changes in biological systems over time, so significant alterations in cellular metabolism are detected throughout aging. In the present study, the metabolic processes relevant to the normal aging process were investigated via non-targeted metabolomics using liquid chromatography–mass spectrometry. To exclude physiological and environmental differences, the metabolic profiles and the relevant metabolic pathways were analyzed in plasma from two separate study groups comprising two distinctly aged cohorts of healthy individuals, the elderly and the younger. The first group was recruited from an urban hospital, and the second group was recruited from a rural community. Alterations in fatty acid beta-oxidation, glycerophospholipid metabolism, and sphingolipid metabolism were identified as significant metabolic pathways relevant to normal aging. It was also found that sphingosine in sphingolipid metabolism, long-chain acylcarnitines in beta-oxidation, and lysophosphatidylcholines (LysoPCs) in glycerophospholipid metabolism could be critical candidate metabolites in the aging process. These results suggest that the metabolic profile of the healthiest individuals could be associated with the normal function of mitochondria, the primary organelle of redox homeostasis, as indicated by their low acylcarnitine to l-carnitine ratio and low levels of LysoPCs and sphingosine in plasma. The present study provides a critical contribution to the entire picture of the aging process.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Beekman, M., Blanche, H., Perola, M., Hervonen, A., Bezrukov, V., Sikora, E., et al. (2013). Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study. Aging Cell, 12(2), 184–193. doi:10.1111/acel.12039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bruunsgaard, H., Pedersen, M., & Pedersen, B. K. (2001). Aging and proinflammatory cytokines. Current Opinion in Hematology, 8(3), 131–136.

    Article  CAS  PubMed  Google Scholar 

  • Bylesjo, M., Eriksson, D., Sjodin, A., Jansson, S., Moritz, T., & Trygg, J. (2007). Orthogonal projections to latent structures as a strategy for microarray data normalization. BMC Bioinformatics, 8, 207. doi:10.1186/1471-2105-8-207.

    Article  PubMed  PubMed Central  Google Scholar 

  • Chalmers, R. A., Roe, C. R., Stacey, T. E., & Hoppel, C. L. (1984). Urinary excretion of l-carnitine and acylcarnitines by patients with disorders of organic acid metabolism: Evidence for secondary insufficiency of l-carnitine. Pediatric Research, 18(12), 1325–1328.

    Article  CAS  PubMed  Google Scholar 

  • Choe, M., Jackson, C., & Yu, B. P. (1995). Lipid peroxidation contributes to age-related membrane rigidity. Free Radical Biology and Medicine, 18(6), 977–984.

    Article  CAS  PubMed  Google Scholar 

  • Chung, H. Y., Cesari, M., Anton, S., Marzetti, E., Giovannini, S., Seo, A. Y., et al. (2009). Molecular inflammation: Underpinnings of aging and age-related diseases. Ageing Research Reviews, 8(1), 18–30. doi:10.1016/j.arr.2008.07.002.

    Article  CAS  PubMed  Google Scholar 

  • Cooper, R. A. (1978). Influence of increased membrane cholesterol on membrane fluidity and cell function in human red blood cells. Journal of Supramolecular Structure, 8(4), 413–430. doi:10.1002/jss.400080404.

    Article  CAS  PubMed  Google Scholar 

  • D’Adamo, P., Ulivi, S., Beneduci, A., Pontoni, G., Capasso, G., Lanzara, C., et al. (2010). Metabonomics and population studies: Age-related amino acids excretion and inferring networks through the study of urine samples in two Italian isolated populations. Amino Acids, 38(1), 65–73. doi:10.1007/s00726-008-0205-8.

    Article  PubMed  Google Scholar 

  • Dunn, W. B., Broadhurst, D., Begley, P., Zelena, E., Francis-McIntyre, S., Anderson, N., et al. (2011). Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nature Protocols, 6(7), 1060–1083. doi:10.1038/nprot.2011.335.

    Article  CAS  PubMed  Google Scholar 

  • Edsall, L. C., Van Brocklyn, J. R., Cuvillier, O., Kleuser, B., & Spiegel, S. (1998). N,N-dimethylsphingosine is a potent competitive inhibitor of sphingosine kinase but not of protein kinase C: Modulation of cellular levels of sphingosine 1-phosphate and ceramide. Biochemistry, 37(37), 12892–12898. doi:10.1021/bi980744d.

    Article  CAS  PubMed  Google Scholar 

  • Findeisen, H. M., Pearson, K. J., Gizard, F., Zhao, Y., Qing, H., Jones, K. L., et al. (2011). Oxidative stress accumulates in adipose tissue during aging and inhibits adipogenesis. PLoS ONE, 6(4), e18532. doi:10.1371/journal.pone.0018532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fouque, D., Holt, S., Guebre-Egziabher, F., Nakamura, K., Vianey-Saban, C., Hadj-Aissa, A., et al. (2006). Relationship between serum carnitine, acylcarnitines, and renal function in patients with chronic renal disease. Journal of Renal Nutrition, 16(2), 125–131. doi:10.1053/j.jrn.2006.01.004.

    Article  PubMed  Google Scholar 

  • Gelinas, D. S., & McLaurin, J. (2005). PPAR-alpha expression inversely correlates with inflammatory cytokines IL-1beta and TNF-alpha in aging rats. Neurochemical Research, 30(11), 1369–1375. doi:10.1007/s11064-005-8341-y.

    Article  CAS  PubMed  Google Scholar 

  • Gika, H. G., Macpherson, E., Theodoridis, G. A., & Wilson, I. D. (2008a). Evaluation of the repeatability of ultra-performance liquid chromatography–TOF-MS for global metabolic profiling of human urine samples. Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences, 871(2), 299–305. doi:10.1016/j.jchromb.2008.05.048.

    Article  CAS  PubMed  Google Scholar 

  • Gika, H. G., Theodoridis, G. A., Earll, M., & Wilson, I. D. (2012). A QC approach to the determination of day-to-day reproducibility and robustness of LC–MS methods for global metabolite profiling in metabonomics/metabolomics. Bioanalysis, 4(18), 2239–2247. doi:10.4155/bio.12.212.

    Article  CAS  PubMed  Google Scholar 

  • Gika, H. G., Theodoridis, G. A., & Wilson, I. D. (2008b). Liquid chromatography and ultra-performance liquid chromatography–mass spectrometry fingerprinting of human urine: Sample stability under different handling and storage conditions for metabonomics studies. Journal of Chromatography A, 1189(1–2), 314–322. doi:10.1016/j.chroma.2007.10.066.

    Article  CAS  PubMed  Google Scholar 

  • Gika, H. G., Theodoridis, G. A., Wingate, J. E., & Wilson, I. D. (2007). Within-day reproducibility of an HPLC–MS-based method for metabonomic analysis: Application to human urine. Journal of Proteome Research, 6(8), 3291–3303. doi:10.1021/pr070183p.

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez-Covarrubias, V., Beekman, M., Uh, H. W., Dane, A., Troost, J., Paliukhovich, I., et al. (2013). Lipidomics of familial longevity. Aging Cell, 12(3), 426–434. doi:10.1111/acel.12064.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gregersen, N. (1985). The acyl-CoA dehydrogenation deficiencies. Recent advances in the enzymic characterization and understanding of the metabolic and pathophysiological disturbances in patients with acyl-CoA dehydrogenation deficiencies. Scandinavian Journal of Clinical and Laboratory Investigation. Supplementum, 174, 1–60.

    CAS  PubMed  Google Scholar 

  • Grolleau-Julius, A., Ray, D., & Yung, R. L. (2010). The role of epigenetics in aging and autoimmunity. Clinical Reviews in Allergy and Immunology, 39(1), 42–50. doi:10.1007/s12016-009-8169-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Harman, D. (1956). Aging: A theory based on free radical and radiation chemistry. The Journal of Gerontology, 11(3), 298–300.

    Article  CAS  PubMed  Google Scholar 

  • Hiona, A., & Leeuwenburgh, C. (2008). The role of mitochondrial DNA mutations in aging and sarcopenia: Implications for the mitochondrial vicious cycle theory of aging. Experimental Gerontology, 43(1), 24–33. doi:10.1016/j.exger.2007.10.001.

    Article  CAS  PubMed  Google Scholar 

  • Hong, S. E., Heo, H. S., Kim, D. H., Kim, M. S., Kim, C. H., Lee, J., et al. (2010). Revealing system-level correlations between aging and calorie restriction using a mouse transcriptome. Age, 32(1), 15–30. doi:10.1007/s11357-009-9106-3.

    Article  CAS  PubMed  Google Scholar 

  • Knight, J. A. (2000). The biochemistry of aging. Advances in Clinical Chemistry, 35, 1–62.

    Article  CAS  PubMed  Google Scholar 

  • Kregel, K. C., & Zhang, H. J. (2007). An integrated view of oxidative stress in aging: Basic mechanisms, functional effects, and pathological considerations. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 292(1), R18–R36. doi:10.1152/ajpregu.00327.2006.

    Article  CAS  PubMed  Google Scholar 

  • Kristal, B. S., & Shurubor, Y. I. (2005). Metabolomics: Opening another window into aging. Science of Aging Knowledge Environment, 2005(26), pe19. doi:10.1126/sageke.2005.26.pe19.

    Article  PubMed  Google Scholar 

  • Lai, L., Michopoulos, F., Gika, H., Theodoridis, G., Wilkinson, R. W., Odedra, R., et al. (2010). Methodological considerations in the development of HPLC–MS methods for the analysis of rodent plasma for metabonomic studies. Molecular Biosystems, 6(1), 108–120. doi:10.1039/b910482h.

    Article  CAS  PubMed  Google Scholar 

  • Lawton, K. A., Berger, A., Mitchell, M., Milgram, K. E., Evans, A. M., Guo, L., et al. (2008). Analysis of the adult human plasma metabolome. Pharmacogenomics, 9(4), 383–397. doi:10.2217/14622416.9.4.383.

    Article  CAS  PubMed  Google Scholar 

  • Lehmann, R., Zhao, X., Weigert, C., Simon, P., Fehrenbach, E., Fritsche, J., et al. (2010). Medium chain acylcarnitines dominate the metabolite pattern in humans under moderate intensity exercise and support lipid oxidation. PLoS ONE, 5(7), e11519. doi:10.1371/journal.pone.0011519.

    Article  PubMed  PubMed Central  Google Scholar 

  • Leslie, C. C. (1997). Properties and regulation of cytosolic phospholipase A2. The Journal of Biological Chemistry, 272(27), 16709–16712.

    Article  CAS  PubMed  Google Scholar 

  • Moyes, K. M., Drackley, J. K., Morin, D. E., Bionaz, M., Rodriguez-Zas, S. L., Everts, R. E., et al. (2009). Gene network and pathway analysis of bovine mammary tissue challenged with Streptococcus uberis reveals induction of cell proliferation and inhibition of PPARgamma signaling as potential mechanism for the negative relationships between immune response and lipid metabolism. BMC Genomics, 10, 542. doi:10.1186/1471-2164-10-542.

    Article  PubMed  PubMed Central  Google Scholar 

  • Pearson, K. (1909). Determination of the coefficient of correlation. Science, 30(757), 23–25. doi:10.1126/science.30.757.23.

    Article  CAS  PubMed  Google Scholar 

  • Pellkofer, R., & Sandhoff, K. (1980). Halothane increases membrane fluidity and stimulates sphingomyelin degradation by membrane-bound neutral sphingomyelinase of synaptosomal plasma membranes from calf brain already at clinical concentrations. Journal of Neurochemistry, 34(4), 988–992.

    Article  CAS  PubMed  Google Scholar 

  • Pohjantahti-Maaroos, H., Palomaki, A., Kankkunen, P., Laitinen, R., Husgafvel, S., & Oksanen, K. (2010). Circulating oxidized low-density lipoproteins and arterial elasticity: Comparison between men with metabolic syndrome and physically active counterparts. Cardiovascular Diabetology, 9, 41. doi:10.1186/1475-2840-9-41.

    Article  PubMed  PubMed Central  Google Scholar 

  • Psihogios, N. G., Gazi, I. F., Elisaf, M. S., Seferiadis, K. I., & Bairaktari, E. T. (2008). Gender-related and age-related urinalysis of healthy subjects by NMR-based metabonomics. NMR in Biomedicine, 21(3), 195–207. doi:10.1002/nbm.1176.

    Article  CAS  PubMed  Google Scholar 

  • Qin, Z. X., Zhu, H. Y., & Hu, Y. H. (2009). Effects of lysophosphatidylcholine on beta-amyloid-induced neuronal apoptosis. Acta Pharmacologica Sinica, 30(4), 388–395. doi:10.1038/aps.2009.25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rebouche, C. J., & Seim, H. (1998). Carnitine metabolism and its regulation in microorganisms and mammals. Annual Review of Nutrition, 18, 39–61. doi:10.1146/annurev.nutr.18.1.39.

    Article  CAS  PubMed  Google Scholar 

  • Sacket, S. J., Chung, H. Y., Okajima, F., & Im, D. S. (2009). Increase in sphingolipid catabolic enzyme activity during aging. Acta Pharmacologica Sinica, 30(10), 1454–1461. doi:10.1038/aps.2009.136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sangster, T., Major, H., Plumb, R., Wilson, A. J., & Wilson, I. D. (2006). A pragmatic and readily implemented quality control strategy for HPLC–MS and GC–MS-based metabonomic analysis. The Analyst, 131(10), 1075–1078. doi:10.1039/b604498k.

    Article  CAS  PubMed  Google Scholar 

  • Sheikh, A. M., & Nagai, A. (2011). Lysophosphatidylcholine modulates fibril formation of amyloid beta peptide. The FEBS Journal, 278(4), 634–642. doi:10.1111/j.1742-4658.2010.07984.x.

    Article  CAS  PubMed  Google Scholar 

  • Slupsky, C. M., Rankin, K. N., Wagner, J., Fu, H., Chang, D., Weljie, A. M., et al. (2007). Investigations of the effects of gender, diurnal variation, and age in human urinary metabolomic profiles. Analytical Chemistry, 79(18), 6995–7004. doi:10.1021/ac0708588.

    Article  CAS  PubMed  Google Scholar 

  • Steinbrecher, U. P., Parthasarathy, S., Leake, D. S., Witztum, J. L., & Steinberg, D. (1984). Modification of low density lipoprotein by endothelial cells involves lipid peroxidation and degradation of low density lipoprotein phospholipids. Proceedings of the National Academy of Sciences of the United States of America, 81(12), 3883–3887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Suhre, K., & Gieger, C. (2012). Genetic variation in metabolic phenotypes: Study designs and applications. Nature Reviews Genetics, 13(11), 759–769. doi:10.1038/nrg3314.

    Article  CAS  PubMed  Google Scholar 

  • Sung, B., Park, S., Yu, B. P., & Chung, H. Y. (2006). Amelioration of age-related inflammation and oxidative stress by PPARgamma activator: Suppression of NF-kappaB by 2,4-thiazolidinedione. Experimental Gerontology, 41(6), 590–599. doi:10.1016/j.exger.2006.04.005.

    Article  CAS  PubMed  Google Scholar 

  • Wick, G., & Grubeck-Loebenstein, B. (1997). Primary and secondary alterations of immune reactivity in the elderly: Impact of dietary factors and disease. Immunological Reviews, 160, 171–184.

    Article  CAS  PubMed  Google Scholar 

  • Wick, G., Huber, L. A., Xu, Q. B., Jarosch, E., Schonitzer, D., & Jurgens, G. (1991). The decline of the immune response during aging: The role of an altered lipid metabolism. Annals of the New York Academy of Sciences, 621, 277–290.

    Article  CAS  PubMed  Google Scholar 

  • Won, J. S., & Singh, I. (2006). Sphingolipid signaling and redox regulation. Free Radical Biology and Medicine, 40(11), 1875–1888. doi:10.1016/j.freeradbiomed.2006.01.035.

    Article  CAS  PubMed  Google Scholar 

  • Woodward, M., Rumley, A., Lowe, G. D., & Tunstall-Pedoe, H. (2003). C-reactive protein: Associations with haematological variables, cardiovascular risk factors and prevalent cardiovascular disease. British Journal of Haematology, 122(1), 135–141.

    Article  CAS  PubMed  Google Scholar 

  • Wu, D., Ren, Z., Pae, M., Guo, W., Cui, X., Merrill, A. H., et al. (2007). Aging up-regulates expression of inflammatory mediators in mouse adipose tissue. Journal of Immunology, 179(7), 4829–4839.

    Article  CAS  Google Scholar 

  • Xia, J., Mandal, R., Sinelnikov, I. V., Broadhurst, D., & Wishart, D. S. (2012). MetaboAnalyst 2.0—A comprehensive server for metabolomic data analysis. Nucleic Acids Research, 40(Web Server issue), W127–W133. doi:10.1093/nar/gks374.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Xing, J., Chen, X., Sun, Y., Luan, Y., & Zhong, D. (2005). Interaction of baicalin and baicalein with antibiotics in the gastrointestinal tract. The Journal of Pharmacy and Pharmacology, 57(6), 743–750. doi:10.1211/0022357056244.

    Article  CAS  PubMed  Google Scholar 

  • Yu, B. P., Suescun, E. A., & Yang, S. Y. (1992). Effect of age-related lipid peroxidation on membrane fluidity and phospholipase A2: Modulation by dietary restriction. Mechanisms of Ageing and Development, 65(1), 17–33.

    Article  CAS  PubMed  Google Scholar 

  • Yu, Z., Zhai, G., Singmann, P., He, Y., Xu, T., Prehn, C., et al. (2012). Human serum metabolic profiles are age dependent. Aging Cell, 11(6), 960–967. doi:10.1111/j.1474-9726.2012.00865.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zou, Y., Kim, D. H., Jung, K. J., Heo, H. S., Kim, C. H., Baik, H. S., et al. (2009). Lysophosphatidylcholine enhances oxidative stress via the 5-lipoxygenase pathway in rat aorta during aging. Rejuvenation Research, 12(1), 15–24. doi:10.1089/rej.2008.0807.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by the Creative Fusion Research Program through the Creative Allied Project funded by the Korea Research Council of Fundamental Science and Technology (CAP-12-1), the Bio-Synergy Research Project (NRF-2013M3A9C4078145) of the Ministry of Science, ICT and Future Planning through the National Research Foundation and the Korea Institute of Science and Technology (KIST). We would like to especially thank Prof. Hyun Ok Kim (Department of Laboratory Medicine, Yonsei University College of Medicine, Seoul, Korea) for her help with the serum biochemical analyses.

Author information

Authors and Affiliations

  1. Department of Medical Records and Health Information Management, College of Nursing and Health, Kongju National University, 56 Kongjudaehakro, Kongju, Chungnam, 314-701, Republic of Korea

    Soo Hyun Lee

  2. Division of Cardiology, Yonsei Cardiovascular Center, Yonsei University College of Medicine, Seoul, Republic of Korea

    Sungha Park

  3. Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Taejon, Republic of Korea

    Sungha Park

  4. Department of Laboratory Medicine and Cell Therapy Center, Yonsei University College of Medicine, Seoul, 120-752, Republic of Korea

    Sungha Park & Han-Soo Kim

  5. Molecular Recognition Research Center, Korea Institute of Science and Technology, Hwarangro 14-gil 5, Seongbuk-gu, Seoul, 136-791, Republic of Korea

    Byung Hwa Jung

  6. University of Science and Technology, 113 Gwahangno, Yuseong-gu, Taejon, 305-333, Republic of Korea

    Byung Hwa Jung

Authors
  1. Soo Hyun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sungha Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Han-Soo Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Byung Hwa Jung
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Byung Hwa Jung.

Additional information

Both Soo Hyun Lee and Sungha Park contributed equally to this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 2084 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, S.H., Park, S., Kim, HS. et al. Metabolomic approaches to the normal aging process. Metabolomics 10, 1268–1292 (2014). https://doi.org/10.1007/s11306-014-0663-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11306-014-0663-9

Keywords

Search

Navigation