Abstract
Irisin might play an important role in reducing the risk of obesity, insulin resistance, or several related diseases, and high irisin levels may contribute to successful aging. Thus, the irisin precursor (FNDC5) gene is a candidate to influence exceptional longevity (EL), i.e., being a centenarian. It has been recently shown that two single-nucleotide polymorphisms (SNPs) in the FNDC5 gene, rs16835198 and rs726344, are associated with in vivo insulin sensitivity in adults. We determined luciferase gene reporter activity in the two above-mentioned SNPs and studied genotype distributions among centenarians (n = 175, 144 women) and healthy controls (n = 347, 142 women) from Spain. We also studied an Italian [79 healthy centenarians (40 women) and 316 healthy controls (156 women)] and a Japanese cohort [742 centenarians (623 women) and 499 healthy controls (356 women)]. The rs726344 SNP had functional significance, as shown by differences in luciferase activity between the constructs of this SNP (all P ≤ 0.05), with the variant A-allele having higher luciferase activity compared with the G-allele (P = 0.04). For the rs16835198 SNP, the variant T-allele tended to show higher luciferase activity compared with the G-allele (P = 0.07). However, we found no differences between genotype/allele frequencies of the two SNPs in centenarians versus controls in any cohort, and no significant association (using logistic regression adjusted by sex) between the two SNPs and EL. Further research is needed with different cohorts as well as with additional variants in the FNDC5 gene or in other genes involved in irisin signaling.
Similar content being viewed by others
References
Barbieri M, Gambardella A, Paolisso G, Varricchio M (2008) Metabolic aspects of the extreme longevity. Exp Gerontol 43:74–78
Bostrom P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, Rasbach KA, Bostrom EA, Choi JH, Long JZ, Kajimura S, Zingaretti MC, Vind BF, Tu H, Cinti S, Hojlund K, Gygi SP, Spiegelman BM (2012) A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481:463–468
Bostrom PA, Fernandez-Real JM (2014) Metabolism: Irisin, the metabolic syndrome and follistatin in humans. Nat Rev Endocrinol 10:11–12
Bostrom PA, Graham EL, Georgiadi A, Ma X (2013) Impact of exercise on muscle and nonmuscle organs. IUBMB Life 65:845–850
Brunet A (2012) Aging and the control of the insulin-FOXO signaling pathway. Med Sci (Paris) 28:316–320
Choi HY, Kim S, Park JW, Lee NS, Hwang SY, Huh JY, Hong HC, Yoo HJ, Baik SH, Youn BS, Mantzoros CS, Choi KM (2014). Implication of Circulating Irisin Levels with Brown Adipose Tissue and Sarcopenia in Humans. J Clin Endocrinol Metab, jc20141195.
Choi YK, Kim MK, Bae KH, Seo HA, Jeong JY, Lee WK, Kim JG, Lee IK, Park KG (2013) Serum irisin levels in new-onset type 2 diabetes. Diabetes Res Clin Pract 100:96–101
Duzova H (2012) Skeletal Muscle. Myokines and Health Med Sci 1:211–231
Eckardt K, Gorgens SW, Raschke S, Eckel J (2014). Myokines in insulin resistance and type 2 diabetes. Diabetologia.
Elbelt U, Hofmann T, Stengel A (2013) Irisin: what promise does it hold? Curr Opin Clin Nutr Metab Care 16:541–547
Emanuele E, Fontana JM, Minoretti P, Geroldi D (2010) Preliminary evidence of a genetic association between chromosome 9p21.3 and human longevity. Rejuvenation Res 13:23–26
Emanuele E, Minoretti P, Pareja-Galeano H, Sanchis-Gomar F, Garatachea N, Lucia A (2014) Serum irisin levels, precocious myocardial infarction, and healthy exceptional longevity. J Med, Am
Erickson HP (2013) Irisin and FNDC5 in retrospect: An exercise hormone or a transmembrane receptor? Adipocyte 2:289–293
Febbraio MA, Pedersen BK (2005) Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 33:114–119
Fiuza-Luces C, Garatachea N, Berger NA, Lucia A (2013) Exercise is the real polypill. Physiology (Bethesda) 28:330–358
Flachsbart F, Caliebe A, Kleindorp R, Blanche H, von Eller-Eberstein H, Nikolaus S, Schreiber S, Nebel A (2009) Association of FOXO3A variation with human longevity confirmed in German centenarians. Proc Natl Acad Sci U S A 106:2700–2705
Garatachea N, Fuku N, He ZH, Tian Y, Arai Y, Abe Y, Murakami H, Miyachi M, Yvert T, Venturini L, Santiago C, Santos-Lozano A, Rodriguez-Romo G, Ricevuti G, Pareja-Galiano H, Sanchis-Gomar F, Emanuele E, Hirose N, Lucia A (2014). PTK2 rs7460 and rs7843014 polymorphisms and exceptional longevity: a functional replication study. Rejuvenation Res
Garatachea N, Pinos T, Camara Y, Rodriguez-Romo G, Emanuele E, Ricevuti G, Venturini L, Santos-Lozano A, Santiago-Dorrego C, Fiuza-Luces C, Yvert T, Andreu AL, Lucia A (2013) Association of the K153R polymorphism in the myostatin gene and extreme longevity. Age (Dordr) 35:2445–2454
Gondo Y, Hirose N, Arai Y, Inagaki H, Masui Y, Yamamura K, Shimizu K, Takayama M, Ebihara Y, Nakazawa S, Kitagawa K (2006) Functional status of centenarians in Tokyo Japan: developing better phenotypes of exceptional longevity. J Gerontol A Biol Sci Med Sci 61:305–310
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng CW, Hwang D, Martin-Montalvo A, Saavedra J, Ingles S, de Cabo R, Cohen P, Longo VD (2011). Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 3, 70ra13.
Hashemi MS, Ghaedi K, Salamian A, Karbalaie K, Emadi-Baygi M, Tanhaei S, Nasr-Esfahani MH, Baharvand H (2013) Fndc5 knockdown significantly decreased neural differentiation rate of mouse embryonic stem cells. Neuroscience 231:296–304
He ZH, Hu Y, Li YC, Yvert T, Santiago C, Gomez-Gallego F, Ruiz JR, Lucia A (2011) Are calcineurin genes associated with athletic status? A function, replication study. Med Sci Sports Exerc 43:1433–1440
Hojlund K, Bostrom P (2013) Irisin in obesity and type 2 diabetes. J Diabetes Complicate 27:303–304
Huh JY, Panagiotou G, Mougios V, Brinkoetter M, Vamvini MT, Schneider BE, Mantzoros CS (2012) FNDC5 and irisin in humans: I Predictors of circulating concentrations in serum and plasma and II mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism 61:1725–1738
Knight JC (2005) Regulatory polymorphisms underlying complex disease traits. J Mol Med (Berl) 83:97–109
Lecker SH, Zavin A, Cao P, Arena R, Allsup K, Daniels KM, Joseph J, Schulze PC, Forman DE (2012) Expression of the irisin precursor FNDC5 in skeletal muscle correlates with aerobic exercise performance in patients with heart failure. Circ Heart Fail 5:812–818
Liu JJ, Wong MD, Toy WC, Tan CS, Liu S, Ng XW, Tavintharan S, Sum CF, Lim SC (2013) Lower circulating irisin is associated with type 2 diabetes mellitus. J Diabetes Complica 27:365–369
Lopez-Legarrea P, de la Iglesia R, Crujeiras AB, Pardo M, Casanueva FF, Zulet MA, Martinez JA (2014) Higher baseline irisin concentrations are associated with greater reductions in glycemia and insulinemia after weight loss in obese subjects. Nutr Diabetes 4:e110
Mango SE (2011) Ageing: generations of longevity. Nature 479:302–303
Mercado PA, Ayala YM, Romano M, Buratti E, Baralle FE (2005) Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene. Nucleic Acids Res 33:6000–6010
Moreno-Navarrete JM, Ortega F, Serrano M, Guerra E, Pardo G, Tinahones F, Ricart W, Manuel-Fernandez-Real J (2013) Irisin Is Expressed and Produced by Human Muscle and Adipose Tissue in Association With Obesity and Insulin Resistance. J Clin Endocrinol Metab 98:E769–778
Park KH, Zaichenko L, Brinkoetter M, Thakkar B, Sahin-Efe A, Joung KE, Tsoukas M, Geladari EV, Young Huh J, Dincer F, Davis CR, Crowell JA, Mantzoros CS (2013). Circulating Irisin in Relation to Insulin Resistance and the Metabolic Syndrome. J Clin Endocrinol Metab.
Pekkala S, Wiklund P, Hulmi JJ, Ahtiainen JP, Horttanainen M, Pollanen E, Makela KA, Kainulainen H, Hakkinen K, Nyman K, Alen M, Herzig KH, Cheng S (2013) Are Skeletal Muscle FNDC5 Gene Expression and Irisin Release Regulated by Exercise and Related to Health? J Physiol 591:5393–5400
Polyzos SA, Kountouras J, Shields K, Mantzoros CS (2013). Irisin: A renaissance in metabolism? Metabolism.
Rana KS, Arif M, Hill EJ, Aldred S, Nagel DA, Nevill A, Randeva HS, Bailey CJ, Bellary S, Brown JE (2014) Plasma irisin levels predict telomere length in healthy adults. Age (Dordr) 36:995–1001
Raschke S, Elsen M, Gassenhuber H, Sommerfeld M, Schwahn U, Brockmann B, Jung R, Wisloff U, Tjonna AE, Raastad T, Hallen J, Norheim F, Drevon CA, Romacho T, Eckardt K, Eckel J (2013) Evidence against a Beneficial Effect of Irisin in Humans. PLoS One 8:e73680
Rozing MP, Westendorp RG, de Craen AJ, Frolich M, de Goeij MC, Heijmans BT, Beekman M, Wijsman CA, Mooijaart SP, Blauw GJ, Slagboom PE, van Heemst D (2010) Favorable glucose tolerance and lower prevalence of metabolic syndrome in offspring without diabetes mellitus of nonagenarian siblings: the Leiden longevity study. J Am Geriatr Soc 58:564–569
Sanchis-Gomar F (2013) The skeletal muscle-metabolism axis in prostate-cancer therapy. N Engl J Med 367:2257–2258
Sanchis-Gomar F, Alis R, Pareja-Galeano H, Romagnoli M, Perez-Quilis C (2014a) Inconsistency in circulating Irisin levels: What is really happening? Horm Metab Res 46:1–6
Sanchis-Gomar F, Alis R, Pareja-Galeano H, Sola E, Victor VM, Rocha M, Hernandez-Mijares A, Romagnoli M (2014b). Circulating irisin levels are not correlated with BMI, age, and other biological parameters in obese and diabetic patients. Endocrine.
Sanchis-Gomar F, Lippi G, Mayero S, Perez-Quilis C, Garcia-Gimenez JL (2012) Irisin: a new potential hormonal target for the treatment of obesity and type 2 diabetes. J Diabetes 4:196
Sanchis-Gomar F, Perez-Quilis C (2013) Irisinemia: A Novel Concept to Coin in Clinical Medicine? Ann Nutr Metab 63:60–61
Sanchis-Gomar F, Perez-Quilis C (2014) The p38-PGC-1alpha-irisin-betatrophin axis: Exploring new pathways in insulin resistance. Adipocyte 3:67–68
Sasabe T, Furukawa A, Matsusita S, Higuchi S, Ishiura S (2007) Association analysis of the dopamine receptor D2 (DRD2) SNP rs1076560 in alcoholic patients. Neurosci Lett 412:139–142
Sole X, Guino E, Valls J, Iniesta R, Moreno V (2006) SNPStats: a web tool for the analysis of association studies. Bioinformatics 22:1928–1929
Spiegelman BM (2013) Banting lecture 2012: regulation of adipogenesis: toward new therapeutics for metabolic disease. Diabetes 62:1774–1782
Staiger H, Bohm A, Scheler M, Berti L, Machann J, Schick F, Machicao F, Fritsche A, Stefan N, Weigert C, Krook A, Haring HU, de Angelis MH (2013) Common genetic variation in the human FNDC5 locus, encoding the novel muscle-derived ‘browning’ factor irisin, determines insulin sensitivity. PLoS One 8:e61903
Stengel A, Hofmann T, Goebel-Stengel M, Elbelt U, Kobelt P, Klapp BF (2013) Circulating levels of irisin in patients with anorexia nervosa and different stages of obesity - Correlation with body mass index. Peptides 39:125–130
Tabor HK, Risch NJ, Myers RM (2002) Candidate-gene approaches for studying complex genetic traits: practical considerations. Nat Rev Genet 3:391–397
Takayama M, Hirose N, Arai Y, Gondo Y, Shimizu K, Ebihara Y, Yamamura K, Nakazawa S, Inagaki H, Masui Y, Kitagawa K (2007) Morbidity of Tokyo-area centenarians and its relationship to functional status. J Gerontol A Biol Sci Med Sci 62:774–782
Tanisawa K, Taniguchi H, Sun X, Ito T, Cao ZB, Sakamoto S, Higuchi M (2014) Common single nucleotide polymorphisms in the FNDC5 gene are associated with glucose metabolism but do not affect serum irisin levels in Japanese men with low fitness levels. Metabolism 63:574–583
Timmons JA, Baar K, Davidsen PK, Atherton PJ (2012). Is irisin a human exercise gene? Nature. 488, E9-10; discussion E10-11.
Vamvini MT, Aronis KN, Panagiotou G, Huh JY, Chamberland JP, Brinkoetter MT, Petrou M, Christophi CA, Kales SN, Christiani DC, Mantzoros CS (2013) Irisin mRNA and circulating levels in relation to other myokines in healthy and morbidly obese humans. Eur J Endocrinol 169:829–834
Villarroya F (2013) Irisin, turning up the heat. Cell Metab 15:277–278
Willcox BJ, Donlon TA, He Q, Chen R, Grove JS, Yano K, Masaki KH, Willcox DC, Rodriguez B, Curb JD (2008) FOXO3A genotype is strongly associated with human longevity. Proc Natl Acad Sci U S A 105:13987–13992
Willcox DC, Willcox BJ, Hsueh WC, Suzuki M (2006) Genetic determinants of exceptional human longevity: insights from the Okinawa Centenarian Study. Age (Dordr) 28:313–332
Wolffe AP, Matzke MA (1999) Epigenetics: regulation through repression. Science 286:481–486
Acknowledgments
This study was funded by the Fondo de Investigaciones Sanitarias (FIS, ref. # PI12/00914).
Conflicts of interests
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Additional information
Fabian Sanchis-Gomar and Nuria Garatachea contributed equally to this paper
About this article
Cite this article
Sanchis-Gomar, F., Garatachea, N., He, Zh. et al. FNDC5 (irisin) gene and exceptional longevity: a functional replication study with rs16835198 and rs726344 SNPs. AGE 36, 9733 (2014). https://doi.org/10.1007/s11357-014-9733-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11357-014-9733-1