Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number
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Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses’ Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility variants. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below-median mtCN (OR = 1.28, 95% CI 1.00, 1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria.
KeywordsAdiposity Telomere Mitochondrion Trajectory analysis Genetic variants
We would like to thank the participants and staff of the Nurses’ Health Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY. The authors assume full responsibility for analyses and interpretation of these data.
MS and EG were responsible for study design. DH performed statistical analyses and drafted the manuscript. HN, IV, and AC contributed to acquisition of data. AK, ZH, and HS helped to interpret the results and revised the manuscript critically. All authors read and approved the final manuscript.
This work was supported by the National Institutes of Health (UM1 CA186107, P01 CA87969, R01 CA49449, R01 HL034594, and R01 HL088521) and by the American Cancer Society Mentored Research Scholar Grant (MRSG-17-220-01 - NEC to M.S.). The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- 2.Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the global burden of disease study 2013. Lancet. 2014;384(9945):766–81. https://doi.org/10.1016/S0140-6736(14)60460-8.CrossRefPubMedPubMedCentralGoogle Scholar
- 5.Houben JM, Moonen HJ, van Schooten FJ, Hageman GJ. Telomere length assessment: biomarker of chronic oxidative stress? Free Radic Biol Med. 2008;44(3):235–46. https://doi.org/10.1016/j.freeradbiomed.2007.10.001.CrossRefPubMedGoogle Scholar
- 10.Gustafsson CM, Falkenberg M, Larsson NG. Maintenance and expression of mammalian mitochondrial DNA. Annu Rev Biochem. 2016;85:133–60. https://doi.org/10.1146/annurev-biochem-060815-014402.CrossRefPubMedGoogle Scholar
- 17.Strandberg TE, Saijonmaa O, Tilvis RS, Pitkala KH, Strandberg AY, Miettinen TA, et al. Association of telomere length in older men with mortality and midlife body mass index and smoking. J Gerontol A Biol Sci Med Sci. 2011;66(7):815–20. https://doi.org/10.1093/gerona/glr064.CrossRefPubMedGoogle Scholar
- 19.Weischer M, Bojesen SE, Nordestgaard BG. Telomere shortening unrelated to smoking, body weight, physical activity, and alcohol intake: 4576 general population individuals with repeat measurements 10 years apart. PLoS Genet. 2014;10(3):e1004191. https://doi.org/10.1371/journal.pgen.1004191.CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Ding J, Sidore C, Butler TJ, Wing MK, Qian Y, Meirelles O, et al. Assessing mitochondrial DNA variation and copy number in lymphocytes of ~ 2000 sardinians using tailored sequencing analysis tools. PLoS Genet. 2015;11(7):e1005306. https://doi.org/10.1371/journal.pgen.1005306.CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Prescott J, Karlson EW, Orr EH, Zee RY, De Vivo I, Costenbader KH. A prospective study investigating prediagnostic leukocyte telomere length and risk of developing rheumatoid arthritis in women. J Rheumatol. 2016;43(2):282–8. https://doi.org/10.3899/jrheum.150184.CrossRefPubMedPubMedCentralGoogle Scholar
- 54.Janssen-Heininger YM, Mossman BT, Heintz NH, Forman HJ, Kalyanaraman B, Finkel T, et al. Redox-based regulation of signal transduction: principles, pitfalls, and promises. Free Radic Biol Med. 2008;45(1):1–17. https://doi.org/10.1016/j.freeradbiomed.2008.03.011.CrossRefPubMedPubMedCentralGoogle Scholar
- 60.Hertel JK, Johansson S, Sonestedt E, Jonsson A, Lie RT, Platou CG, et al. FTO, type 2 diabetes, and weight gain throughout adult life: a meta-analysis of 41,504 subjects from the scandinavian HUNT, MDC, and MPP studies. Diabetes. 2011;60(5):1637–44. https://doi.org/10.2337/db10-1340.CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Belsky DW, Moffitt TE, Houts R, Bennett GG, Biddle AK, Blumenthal JA, et al. Polygenic risk, rapid childhood growth, and the development of obesity: evidence from a 4-decade longitudinal study. Arch Pediatr Adolesc Med. 2012;166(6):515–21. https://doi.org/10.1001/archpediatrics.2012.131.CrossRefPubMedPubMedCentralGoogle Scholar