Abstract
The rate of telomere-shortening has been widely reported as a marker of risk for age-related conditions and mortality in human population. Genetic, environmental and stochastic factors have been shown to influence telomere attrition. In particular oxidative stress has been reported to play an important role on the process. Uncoupling proteins (UCPs) are among the most important regulators of cellular metabolism and oxidative stress. Several authors investigated the association of UCP genetic variants with leucocyte telomere length (LTL) in both healthy and unhealthy (affected by diabetes) subjects, reporting contrasting results. We tested the influence of four SNPs falling in UCP2–UCP3 genomic region on LTL and glucose metabolism by analyzing these polymorphisms in a cohort of 457 subjects, in an age range 64–105 years. Among subjects younger than 85 years, homozygotes for the minor alleles at two UCP2 variants (rs659366-A and rs660339-T) showed shorter LTL respect to the other genotypes (pmodel = 0.024). In the same samples, AA-rs659366 genotype was found associated with lower haematological levels of Glycosylate Haemoglobyn (p = 0.012 and p = 0.022, respectively). Furthermore, rs659366-AA at UCP2 and rs15673-TT at UCP3 were correlated to diabetes in a small sub-group of patients. Results here presented suggest that UCP variability has different pleiotropic effects, by affecting both telomere length and glucose homeostasis, likely through an influence on energy metabolism and stress response.
Similar content being viewed by others
References
Akushevich I, Kravchenko J, Ukraintseva S, Arbeev K, Yashin AI (2012) Age patterns of incidence of geriatric disease in the U.S. elderly population: medicare-based analysis. J Am Geriatr Soc 60:323–327
Atzmon G, Cho M, Cawthon RM et al (2010) Evolution in health and medicine Sackler colloquium: genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci USA 107:1710–1717
Aubert G, Lansdorp PM (2008) Telomeres and aging. Physiol Rev 88:557–579
Bouchard C, Pérusse L, Chagnon YC, Warden C, Ricquier D (1997) Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans. Hum Mol Genet 6:1887–1889
Cawthon RM (2002) Telomere measurement by quantitative PCR. Nucleic Acids Res 30:e47
Cherkas LF, Hunkin JL, Kato BS, Richards JB, Gardner JP, Surdulescu GL, Kimura M, Lu X, Spector TD, Aviv A (2008) The association between physical activity in leisure time and leukocyte telomere length. Arch Intern Med 168:154–158
Concetti F, Lucarini N, Carpi FM et al (2013) The functional VNTR MNS16A of the TERT gene is associated with human longevity in a population of Central Italy. Exp Gerontol 48:587–592
Crocco P, Montesanto A, Passarino G, Rose G (2011) A common polymorphism in the UCP3 promoter influences hand grip strength in elderly people. Biogerontology 12:265–271
Crocco P, Barale R, Rose G, Rizzato C, Santoro A, De Rango F, Carrai M, Fogar P, Monti D, Biondi F, Bucci L, Ostan R, Tallaro F, Montesanto A, Zambon CF, Franceschi C, Canzian F, Passarino G, Campa D (2015) Population-specific association of genes for telomere-associated proteins with longevity in an Italian population. Biogerontology 16:353–364
Dalgaard LT (2011) Genetic variance in uncoupling protein 2 in relation to obesity, type 2 diabetes, and related metabolic traits: focus on the functional-866G>A promoter variant (rs659366). J Obes. 2011:340241
Dalgaard LT (2012) UCP2 mRNA expression is dependent on glucose metabolism in pancreatic islets. Biochem Biophys Res Commun 417:495–500
Dato S, Soerensen M, Montesanto A, Lagani V, Passarino G, Christensen K, Christiansen L (2012) UCP3 polymorphisms, hand grip performance and survival at old age: association analysis in two Danish middle aged and elderly cohorts. Mech Ageing Dev 133:530–537
Dato S, Soerensen M, Lagani V, Montesanto A, Passarino G, Christensen K, Tan Q, Christiansen L (2014) Contribution of genetic polymorphisms on functional status at very old age: a gene-based analysis of 38 genes (311 SNPs) in the oxidative stress pathway. Exp Gerontol 52C:23–29
de la Monte SM, Wands JR (2006) Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. J Alzheimers Dis 9:167–181
De Rango F, Montesanto A, Berardelli M, Mazzei B, Mari V, Lattanzio F, Corsonello A, Passarino G (2011) To grow old in southern Italy: a comprehensive description of the old and oldest old in Calabria. Gerontology 57:327–334
Deelen J, Beekman M, Codd V, Trompet S, Broer L, Hägg S, Fischer K, Thijssen PE, Suchiman HE, Postmus I, Uitterlinden AG, Hofman A, de Craen AJ, Metspalu A, Pedersen NL, van Duijn CM, Jukema JW, Houwing-Duistermaat JJ, Samani NJ, Slagboom PE (2014) Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers. Int J Epidemiol 43:878–886
Echtay KS (2007) Mitochondrial uncoupling proteins–what is their physiological role? Free Radic Biol Med 43:1351–1371
Elks CE, Scott RA (2014) The long and short of telomeres. Length diabetes. Diabetes 63:65–67
Esterbauer H, Schneitler C, Oberkofler H, Ebenbichler C, Paulweber B, Sandhofer F, Ladurner G, Hell E, Strosberg AD, Patsch JR, Krempler F, Patsch W (2001) A common polymorphism in the promoter of UCP2 is associated with decreased risk of obesity in middle-aged humans. Nature Genet 28:178–183
Evert J, Lawler E, Bogan H, Perls T (2003) Morbidity profiles of centenarians: survivors, delayers, and escapers. J Gerontol A Biol Sci Med Sci 58:232–237
Fleury C, Neverova M, Collins S, Raimbault S, Champigny O, Levi-Meyrueis C, Bouillaud F, Seldin MF, Surwit RS, Ricquier D, Warden CH (1997) Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet 15:269–272
Franceschi C, Valensin S, Bonafè M, Paolisso G, Yashin AI, Monti D, De Benedictis G (2000) The network and the remodeling theories of aging: historical background and new perspectives. Exp Gerontol 35:879–896
Gardner JP, Li S, Srinivasan SR, Chen W, Kimura M, Lu X, Berenson GS, Aviv A (2005) Rise in insulin resistance is associated with escalated telomere attrition. Circulation 111:2171–2177
Gavrilova NS, Gavrilov LA (2015) Biodemography of old-age mortality in humans and rodents. J Gerontol 70:1–9
Hjelmborg JB, Dalgaard C, Möller S, Steenstrup T, Kimura M, Christensen K, Kyvik KO, Aviv A (2015) The heritability of leucocyte telomere length dynamics. J Med Genet 52:297–302
Jia JJ, Zhang X, Ge CR, Jois M (2009) The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes. Obes Rev 10:519–526
Kuhlow D, Florian S, von Figura G et al (2010) Telomerase deficiency impairs glucose metabolism and insulin secretion. Aging 2:650–658
Lee JH, Cheng R, Honig LS et al (2014) Genome wide association and linkage analyses identified three loci-4q25, 17q23.2, and 10q11.21-associated with variation in leukocyte telomere length: the long life family study. Front Genet 4:310
Müezzinler A, Zaineddin AK, Brenner H (2013) A systematic review of leukocyte telomere length and age in adults. Ageing Res Rev 12:509–519
Noma T, Nishiyama A, Mizushige K, Murakami K, Tsuji T, Kohno M, Rahman M, Fukui T, Abe Y, Kimura S (2001) Possible role of uncoupling protein in regulation of myocardial energy metabolism in aortic regurgitation model rats. FASEB J 15:1206–1208
Oktavianthi S, Trimarsanto H, Febinia CA, Suastika K, Saraswati MR, Dwipayana P, Arindrarto W, Sudoyo H, Malik SG (2012) Uncoupling protein 2 gene polymorphisms are associated with obesity. Cardiovasc Diabetol 11:41
Pheiffer C, Jacobs C, Patel O, Ghoor S, Muller C, Louw J (2016) Expression of UCP2 in Wistar rats varies according to age and the severity of obesity. J Physiol Biochem 72:25–32
Robbins D, Zhao Y (2011) New aspects of mitochondrial uncoupling proteins (UCPs) and their roles in tumorigenesis. Int J Mol Sci 12:5285–5293
Rose G, Crocco P, De Rango F, Montesanto A, Passarino G (2011) Further support to the uncoupling-to-survive theory: the genetic variation of human UCP genes is associated with longevity. PLoS ONE 6:e29650
Saleh MC, Wheeler MB, Chan CB (2002) Uncoupling protein-2: evidence for its function as a metabolic regulator. Diabetologia 45:174–187
Salopuro T, Pulkkinen L, Lindström J et al (2009) Variation in the UCP2 and UCP3 genes associates with abdominal obesity and serum lipids: the finnish diabetes prevention study. BMC Med Genet 10:94
Salpea KD, Talmud PJ, Cooper JA et al (2010) Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. Atherosclerosis 209:42–50
Sanders JL, Newman AB (2013) Telomere length in epidemiology: a biomarker of aging, age-related disease, both, or neither? Epidemiol Rev 35:112–131
So HC (2011) Sham PC Robust association tests under different genetic models, allowing for binary or quantitative traits and covariates. Behav Genet 41:768–775
Soerensen M, Thinggaard M, Nygaard M et al (2012) Genetic variation in TERT and TERC and human leukocyte telomere length and longevity: a cross-sectional and longitudinal analysis. Aging Cell 11:223–227
Souza BM, Assmann TS, Kliemann LM, Gross JL, Canani LH, Crispim D (2011) The role of uncoupling protein 2 (UCP2) on the development of type 2 diabetes mellitus and its chronic complications. Arq Bras Endocrinol Metabol 55:239–248
Testa R, Olivieri F, Sirolla C et al (2011) Leukocyte telomere length is associated with complications of type 2 diabetes mellitus. Diabet Med 28:1388–1394
Tzanetakou IP, Katsilambros NL, Benetos A, Mikhailidis DP, Perrea DN (2012) “Is obesity linked to aging?”: adipose tissue and the role of telomeres. Ageing Res Rev 11:220–229
von Zglinicki T (2002) Oxidative stress shortens telomeres. Trends Biochem Sci 27:339–344
Xiao F, Zheng X, Cui M, Shi G, Chen X, Li R, Song Z, Rudolph KL, Chen B, Ju Z (2011) Telomere dysfunction-related serological markers are associated with type 2 diabetes. Diabet Care 34:2273–2278
Yu X, Jacobs DR Jr, Schreiner PJ, Gross MD, Steffes MW, Fornage M (2005) The uncoupling protein 2 Ala55Val polymorphism is associated with diabetes mellitus: the CARDIA study. Clin Chem 51:1451–1456
Zhao J, Zhu Y, Lin J et al (2014) Short leukocyte telomere length predicts risk of diabetes in American Indians: the strong heart family study. Diabetes 63:354–362
Zhou Y, Simmons D, Hambly BD, McLachlan CS (2016a) Interactions between UCP2 SNPs and telomere length exist in the absence of diabetes or pre-diabetes. Sci Rep 6:33147
Zhou Y, Ning Z, Lee Y, Hambly BD, McLachlan CS (2016b) Shortened leukocyte telomere length in type 2 diabetes mellitus: genetic polymorphisms in mitochondrial uncoupling proteins and telomeric pathways. Clin Transl Med 5:8
Acknowledgements
This work was partially supported by funds from Programma Operativo Nazionale [01 00937]-MIUR“Modelli sperimentali biotecnologici integrati per lo sviluppo e la selezione di molecole di interesse per la salute dell’uomo”.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors of the manuscript hereby declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Dato, S., De Rango, F., Crocco, P. et al. Pleiotropic effects of UCP2–UCP3 variability on leucocyte telomere length and glucose homeostasis. Biogerontology 18, 347–355 (2017). https://doi.org/10.1007/s10522-017-9690-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-017-9690-z