Abstract
Lung function is an independent predictor of mortality and serves as an aging marker in never smokers. The protein sirtuin-1 of gene SIRT1 has profound anti-inflammatory effects and regulates metabolic pathways. Its suggested longevity effects on lower organisms remain poorly studied in humans. In 1132 never smokers of the population-based SAPALDIA cohort, we investigated associations between single nucleotide polymorphisms (SNPs; rs730821, rs10997868, rs10823116) of SIRT1 and aging-related lung function decline over 11 years in terms of change in forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), FEV1/FVC ratio, and forced expiratory flow between 25 and 75 % of FVC (FEF25–75) using multiple linear regression models. Interactions between the SIRT1 SNPs and adiposity parameters (body mass index (BMI), its change and weight gain) were tested by including multiplicative interaction terms into the models. SIRT1 polymorphisms exhibited no main effects, but modified the association between obesity measures and FEV1/FVC and FEF25–75 decline (p = 0.009–0.046). Per risk allele, FEV1/FVC decline was accelerated up to −0.5 % (95 % CI −1.0 to 0 %) and −0.7 % (−1.3 to −0.2 %) over interquartile range increases in BMI (2.4 kg/m2) or weight (6.5 kg), respectively. For FEF25–75 decline, corresponding estimates were −57 mL/s (−117 to 4 mL/s) and −76 mL/s (−1429 to −9 mL/s). Interactions were not present in participants with genetically lowered C-reactive protein concentrations. Genetic variation in SIRT1 might therefore affect lung function and human longevity by modifying subclinical inflammation arising from abdominal adipose tissue.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ackermann-Liebrich U et al. (2005) Follow-up of the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults (SAPALDIA 2) 1991–2003: methods and characterization of participants. Soz Praventivmed 50:245–263
Ahmadi-Abhari S, Kaptoge S, Luben RN, Wareham NJ, Khaw KT (2014) Longitudinal association of C-reactive protein and lung function over 13 years: The EPIC-Norfolk study. Am J Epidemiol 179:48–56. doi:10.1093/aje/kwt208
Albrecht E et al. (2014) Telomere length in circulating leukocytes is associated with lung function and disease. Eur Respir J 43:983–992. doi:10.1183/09031936.00046213
American Thoracic Society (1987) Standardization of spirometry—1987 update. Statement of the American Thoracic Society. Am Rev Respir Dis 136:1285–1298
Berg AH, Scherer PE (2005) Adipose tissue, inflammation, and cardiovascular disease. Circ Res 96:939–949. doi:10.1161/01.RES.0000163635.62927.34
Bigaard J, Frederiksen K, Tjonneland A, Thomsen BL, Overvad K, Heitmann BL, TI Sorensen (2005) Waist circumference and body composition in relation to all-cause mortality in middle-aged men and women. Int J Obes 29:778–784 doi:10.1038/sj.ijo.0802976.
Brandli O et al. (2000) Re-estimated equations for 5th percentiles of lung function variables. Thorax 55:173–174
Burgel PR et al. (2011) Update on the roles of distal airways in COPD. Eur Respir Rev 20:7–22. doi:10.1183/09059180.10010610
Burnett C et al. (2011) Absence of effects of Sir2 overexpression on lifespan in C. elegans and Drosophila. Nature 477:482–485. doi:10.1038/nature10296
Burney PG, Hooper R (2011) Forced vital capacity, airway obstruction and survival in a general population sample from the USA. Thorax 66:49–54. doi:10.1136/thx.2010.147041
Calabro P et al. (2009) Adipose tissue-mediated inflammation: the missing link between obesity and cardiovascular disease? Intern Emerg Med 4:25–34. doi:10.1007/s11739-008-0207-2
Chong ZZ, Shang YC, Wang S, Maiese K (2012) SIRT1: new avenues of discovery for disorders of oxidative stress. Expert Opin Ther Targets 16:167–178. doi:10.1517/14728222.2012.648926
Figarska SM, Vonk JM, Boezen HM (2013) SIRT1 polymorphism, long-term survival and glucose tolerance in the general population. PLoS One 8:e58636. doi:10.1371/journal.pone.0058636
Flachsbart F, Croucher PJ, Nikolaus S, Hampe J, Cordes C, Schreiber S, Nebel A (2006) Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Exp Gerontol 41:98–102. doi:10.1016/j.exger.2005.09.008
Franceschi C, Bonafe M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254
Goyal A, Nimmakayala KR, Zonszein J (2014) Is there a paradox in obesity? Cardiol Rev 22:163–170. doi:10.1097/CRD.0000000000000004
GTEx Consortium, Ardlie KGDD, Segrè AV, Sullivan TJ, Young TR, Gelfand ET, et al. (2015) Human genomics. The Genotype-Tissue Expression (GTEx) pilot analysis: multitissue gene regulation in humans. Science 348:648–660. doi:10.1126/science.1262110
Guarente L (2011) Franklin H. Epstein lecture: sirtuins, aging, and medicine. N Engl J Med 364:2235–2244. doi:10.1056/NEJMra1100831
Hamid Q (2012) Pathogenesis of small airways in asthma. Respiration 84:4–11. doi:10.1159/000339550
Herranz D, Munoz-Martin M, Canamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, Serrano M (2010) Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 1:3. doi:10.1038/ncomms1001
Herranz D, Serrano M (2010) SIRT1: recent lessons from mouse models. Nat Rev Cancer 10:819–823. doi:10.1038/nrc2962
Hwang JW, Chung S, Sundar IK, Yao H, Arunachalam G, McBurney MW, Rahman I (2010) Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD. Arch Biochem Biophys 500:203–209. doi:10.1016/j.abb.2010.05.013
Imboden M et al. (2012) Genome-wide association study of lung function decline in adults with and without asthma. J Allergy Clinical Immunol 129:1218–1228. doi:10.1016/j.jaci.2012.01.074
International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320. doi:10.1038/nature04226
Kedenko L et al. (2014) Genetic polymorphisms at SIRT1 and FOXO1 are associated with carotid atherosclerosis in the SAPHIR cohort. BMC Med Genet 15:112. doi:10.1186/s12881-014-0112-7
Kennedy BK et al. (1997) Redistribution of silencing proteins from telomeres to the nucleolus is associated with extension of life span in S. cerevisiae. Cell 89:381–391
Kettunen T et al. (2011) Polymorphism in the C-reactive protein (CRP) gene affects CRP levels in plasma and one early marker of atherosclerosis in men: The Health 2000 Survey. Scand J Clin Lab Invest 71:353–361. doi:10.3109/00,365,513.2011.568123
Knuiman MW, James AL, Divitini ML, Ryan G, Bartholomew HC, Musk AW (1999) Lung function, respiratory symptoms, and mortality: results from the Busselton Health Study. Ann Epidemiol 9:297–306
Kuningas M, Putters M, Westendorp RG, Slagboom PE, van Heemst D (2007) SIRT1 gene, age-related diseases, and mortality: the Leiden 85-plus study. J Gerontol A Biol Sci Med Sci 62:960–965
Leone N et al. (2009) Lung function impairment and metabolic syndrome: the critical role of abdominal obesity. Am J Respir Crit Care Med 179:509–516. doi:10.1164/rccm.200807-1195OC
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. doi:10.1016/j.cell.2013.05.039
Mannino DM, Reichert MM, Davis KJ (2006) Lung function decline and outcomes in an adult population. Am J Respir Crit Care Med 173:985–990. doi:10.1164/rccm.200508-1344OC
Moffatt MF et al. (2010) A large-scale, consortium-based genomewide association study of asthma. N Engl J Med 363:1211–1221. doi:10.1056/NEJMoa0906312
Ochs-Balcom HM et al. (2006) Pulmonary function and abdominal adiposity in the general population. Chest 129:853–862. doi:10.1378/chest.129.4.853
Picard F, Guarente L (2005) Molecular links between aging and adipose tissue. Int J Obes 29(Suppl 1):S36–S39. doi:10.1038/sj.ijo.0802912
Quanjer PH et al. (2012) Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 40:1324–1343. doi:10.1183/09,031,936.00080312
Radak Z et al. (2013) Redox-regulating sirtuins in aging, caloric restriction, and exercise. Free Radic Biol Med 58:87–97. doi:10.1016/j.freeradbiomed.2013.01.004
Reis JP, Macera CA, Araneta MR, Lindsay SP, Marshall SJ, Wingard DL (2009) Comparison of overall obesity and body fat distribution in predicting risk of mortality. Obesity 17:1232–1239. doi:10.1038/oby.2008.664
Rizki G et al. (2011) The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO. PLoS Genet 7:e1002235. doi:10.1371/journal.pgen.1002235
Ryan G, Knuiman MW, Divitini ML, James A, Musk AW, Bartholomew HC (1999) Decline in lung function and mortality: the Busselton Health Study. J Epidemiol Community Health 53:230–234
Sabia S, Shipley M, Elbaz A, Marmot M, Kivimaki M, Kauffmann F, Singh-Manoux A (2010) Why does lung function predict mortality? Results from the Whitehall II Cohort Study. Am J Epidemiol 172:1415–1423. doi:10.1093/aje/kwq294
Schunemann HJ, Dorn J, Grant BJ, W Winkelstein. Jr., Trevisan M (2000) Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest 118:656–664.
Shaaban R et al. (2006) Change in C-reactive protein levels and FEV1 decline: a longitudinal population-based study. Respir Med 100:2112–2120. doi:10.1016/j.rmed.2006.03.027
Siedlinski M, Boer JM, Smit HA, Postma DS, Boezen HM (2012) Dietary factors and lung function in the general population: wine and resveratrol intake. Eur Respir J 39:385–391. doi:10.1183/09031936.00184110
Tockman MS et al. (1995) Rapid decline in FEV1. A new risk factor for coronary heart disease mortality. Am J Respir Crit Care Med 151:390–398. doi:10.1164/ajrccm.151.2.7842197
Viswanathan M, Guarente L (2011) Regulation of Caenorhabditis elegans lifespan by sir-2.1 transgenes. Nature 477:E1–E2. doi:10.1038/nature10440
Ward LD, Kellis M (2012) HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40:D930–D934. doi:10.1093/nar/gkr917
Wehrmeister FC, Menezes AM, Muniz LC, Martinez-Mesa J, Domingues MR, Horta BL (2012) Waist circumference and pulmonary function: a systematic review and meta-analysis. Syst Rev 1:55. doi:10.1186/2046-4053-1-55
Yao H et al. (2013) SIRT1 redresses the imbalance of tissue inhibitor of matrix metalloproteinase-1 and matrix metalloproteinase-9 in the development of mouse emphysema and human COPD. Am J Phys Lung Cell Mol Phys 305:L615–L624. doi:10.1152/ajplung.00249.2012
Yao H et al. (2014) SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism. Am J Phys Lung Cell Mol Phys 306:L816–L828. doi:10.1152/ajplung.00323.2013
Zhang C, Rexrode KM, van Dam RM, Li TY, Hu FB (2008) Abdominal obesity and the risk of all-cause, cardiovascular, and cancer mortality: sixteen years of follow-up in US women. Circulation 117:1658–1667. doi:10.1161/CIRCULATIONAHA.107.739714
Zillikens MC et al. (2009a) SIRT1 genetic variation is related to BMI and risk of obesity. Diabetes 58:2828–2834. doi:10.2337/db09-0536
Zillikens MC et al. (2009b) SIRT1 genetic variation and mortality in type 2 diabetes: interaction with smoking and dietary niacin. Free Radic Biol Med 46:836–841. doi:10.1016/j.freeradbiomed.2008.12.022
Acknowledgments
The authors acknowledge the work of the whole SAPALDIA team: Study directorate: NM Probst-Hensch (PI; e/g); T Rochat (p), C Schindler (s), N Künzli (e/exp), JM Gaspoz (c); the scientific team: JC Barthélémy (c), W Berger (g), R Bettschart (p), A Bircher (a), C Brombach (n), PO Bridevaux (p), L Burdet (p), Felber Dietrich D (e), M Frey (p), U Frey (pd), MW Gerbase (p), D Gold (e), E de Groot (c), W Karrer (p), F Kronenberg (g), B Martin (pa), A Mehta (e), D Miedinger (o), M Pons (p), F Roche (c), T Rothe (p), P Schmid-Grendelmeyer (a), D Stolz (p), A Schmidt-Trucksäss (pa), J Schwartz (e), A Turk (p), A von Eckardstein (cc), E Zemp Stutz (e); and the scientific team at coordinating centers: M Adam (e), I Aguilera (exp), S Brunner (s), D Carballo (c), S Caviezel (pa), I Curjuric (e), A Di Pascale (s), J Dratva (e), R Ducret (s), E Dupuis Lozeron (s), M Eeftens (exp), I Eze (e), E Fischer (g), M Foraster (e), M Germond (s), L Grize (s), S Hansen (e), A Hensel (s), M Imboden (g), A Ineichen (exp), A Jeong (g), D Keidel (s), A Kumar (g), N Maire (s), A Mehta (e), R Meier (exp), E Schaffner (s), T Schikowski (e), M Tsai (exp).
The study could not have been done without the help of the study participants, technical and administrative support, and the medical teams and field workers at the local study sites. Local fieldworkers: Aarau: S Brun, G Giger, M Sperisen, M Stahel, Basel: C Bürli, C Dahler, N Oertli, I Harreh, F Karrer, G Novicic, N Wyttenbacher, Davos: A Saner, P Senn, R Winzeler, Geneva: F Bonfils, B Blicharz, C Landolt, J Rochat, Lugano: S Boccia, E Gehrig, MT Mandia, G Solari, B Viscardi, Montana: AP Bieri, C Darioly, M Maire, Payerne: F Ding, P Danieli A Vonnez, Wald: D Bodmer, E Hochstrasser, R Kunz, C Meier, J Rakic, U Schafroth, and A Walder; administrative staff: N Bauer Ott, C Gabriel, and R Gutknecht.
(a) corresponds to allergology, (c) cardiology, (cc) clinical chemistry, (e) epidemiology, (exp) exposure, (g) genetic and molecular biology, (m) meteorology, (n) nutrition, (o) occupational health, (p) pneumology, (pa) physical activity, (pd) pediatrics, (s) statistics.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
All study participants gave written informed consent, and the study was approved by the Swiss Academy of Medical Sciences as well as the respective regional ethics committees.
Funding
This work was supported by the Swiss National Science Foundation (grant nos. 33CS30-148470/1, 33CSCO-134276/1, 33CSCO-108796, 324730_135673, 3247BO-104283, 3247BO-104288, 3247BO-104284, 3247-065896, 3100-059302, 3200-052720, 3200-042532, 4026-028099, PMPDP3_129021/1, PMPDP3_141671/1); the Federal Office for the Environment; the Federal Office of Public Health; the Federal Office of Roads and Transport; the canton’s government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, Valais, and Zürich; the Swiss Lung League; the canton’s Lung League of Basel Stadt/ Basel Landschaft, Geneva, Ticino, Valais, Graubünden, and Zurich; Stiftung ehemals Bündner Heilstätten; SUVA; Freiwillige Akademische Gesellschaft; UBS Wealth Foundation; Talecris Biotherapeutics GmbH; Abbott Diagnostics; European Commission 018996 (GABRIEL), and Wellcome Trust WT 084703MA.
About this article
Cite this article
Curjuric, I., Imboden, M., Bridevaux, PO. et al. Common SIRT1 variants modify the effect of abdominal adipose tissue on aging-related lung function decline. AGE 38, 52 (2016). https://doi.org/10.1007/s11357-016-9917-y
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11357-016-9917-y