First evidence for STING SNP R293Q being protective regarding obesity-associated cardiovascular disease in age-advanced subjects – a cohort study

Immunity & Ageing - Tập 17 - Trang 1-6 - 2020
Lutz Hamann1, Malgorzata Szwed2, Malgorzata Mossakowska3, Jerzy Chudek4, Monika Puzianowska-Kuznicka2,5
1Institute for Microbiology and Infection Immunology, Charité University Medical Center, CBF, Berlin, Germany
2Department of Human Epigenetics, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland
3PolSenior Project, International Institute of Molecular and Cell Biology, Warsaw, Poland
4Department of Internal Medicine and Oncological Chemotherapy, Medical School in Katowice, Medical University of Silesia, Katowice, Poland
5Department of Geriatrics and Gerontology, Medical Centre of Postgraduate Education, Warsaw, Poland

Tóm tắt

Obesity is a risk factor for several aging-related diseases such as type 2 diabetes, cardiovascular disease, and cancer. Especially, cardiovascular disease is triggered by obesity by inducing vascular senescence and chronic low-grade systemic inflammation, also known as inflamm-aging. Released molecules from damaged cells and their recognition by the innate immune system is one of the mechanisms driving inflamm-aging. Obesity results in mitochondrial damage, leading to endothelial inflammation triggered by cytosolic mtDNA via the cGAS/STING pathway. Recently, we have shown STING SNP R293Q to be associated with a decreased risk for aging-related diseases in current smokers. Since current smoking triggers DNA damage that, similar to obesity, may result in the release of DNA into the cytoplasm, we hypothesized that the cGAS/STING pathway can modify the phenotype of aging also in obese subjects. Therefore, the objective of our study was to investigate whether STING R293Q is associated with aging-related diseases in obese individuals. We indeed show that STING 293Q is associated with protection from combined aging-related diseases (P = 0.014) and, in particular, cardiovascular disease in these subjects (P = 0.010). Therefore, we provide the first evidence that stratification for obesity may reveal new genetic loci determining the risk for aging-related diseases.

Tài liệu tham khảo

Global Health Estimates 2016: Death by Cause A, Sex, by County and by Region, 2000–2016. Geneva, World Health Organization; 2018. PubMed PMID: 8065313. PMCID: 359104. Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217 PubMed PMID: 23746838. PMCID: 3836174. Moskalev AA, Shaposhnikov MV, Plyusnina EN, Zhavoronkov A, Budovsky A, Yanai H, et al. The role of DNA damage and repair in aging through the prism of Koch-like criteria. Ageing Res Rev. 2013;12(2):661–84 PubMed PMID: 22353384. Kreienkamp R, Graziano S, Coll-Bonfill N, Bedia-Diaz G, Cybulla E, Vindigni A, et al. A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin. Cell Rep. 2018;22(8):2006–15 PubMed PMID: 29466729. PMCID: 5848491. Salminen A, Kaarniranta K, Kauppinen A. Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging. 2012;(3):166–75 PubMed PMID: 22411934. PMCID: 3348477. Singh T, Newman AB. Inflammatory markers in population studies of aging. Ageing Res Rev. 2011;10(3):319–29 PubMed PMID: 21145432. PMCID: 3098911. Stegeman R, Weake VM. Transcriptional Signatures of Aging. J Mol Biol. 2017;429(16):2427–37 PubMed PMID: 28684248. PMCID: 5662117. Harman D. The biologic clock: the mitochondria? J Am Geriatr Soc. 1972;20(4):145–7 PubMed PMID: 5016631. Panel M, Ghaleh B, Morin D. Mitochondria and aging: A role for the mitochondrial transition pore? Aging cell. 2018;11:e12793 PubMed PMID: 29888494. PMCID: 6052406. Pinti M, Cevenini E, Nasi M, De Biasi S, Salvioli S, Monti D, et al. Circulating mitochondrial DNA increases with age and is a familiar trait: implications for "inflamm-aging". Eur J Immunol. 2014;44(5):1552–62 PubMed PMID: 24470107. Picca A, Lezza AMS, Leeuwenburgh C, Pesce V, Calvani R, Landi F, et al. Fueling Inflamm-Aging through Mitochondrial Dysfunction: Mechanisms and Molecular Targets. Int J Mol Sci. 2017;18(5) PubMed PMID: 28452964. PMCID: 5454846. Osborn O, Olefsky JM. The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med. 2012;18(3):363–74 PubMed PMID: 22395709. Hubert HB, Feinleib M, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham heart study. Circulation. 1983;67(5):968–77 PubMed PMID: 6219830. Wang CY, Kim HH, Hiroi Y, Sawada N, Salomone S, Benjamin LE, et al. Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR. Sci Signal. 2009;2(62):ra11 PubMed PMID: 19293429. PMCID: 2667954. Mao Y, Luo W, Zhang L, Wu W, Yuan L, Xu H, et al. STING-IRF3 Triggers Endothelial Inflammation in Response to Free Fatty Acid-Induced Mitochondrial Damage in Diet-Induced Obesity. Arterioscler Thromb Vasc Biol. 2017;37(5):920–9 PubMed PMID: 28302626. PMCID: 5408305. Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, et al. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017;550(7676):402–6 PubMed PMID: 28976970. PMCID: 5850938. Gluck S, Guey B, Gulen MF, Wolter K, Kang TW, Schmacke NA, et al. Innate immune sensing of cytosolic chromatin fragments through cGAS promotes senescence. Nat Cell Biol. 2017;19(9):1061–70 PubMed PMID: 28759028. PMCID: 5826565. Bledowski P, Mossakowska M, Chudek J, Grodzicki T, Milewicz A, Szybalska A, et al. Medical, psychological and socioeconomic aspects of aging in Poland: assumptions and objectives of the PolSenior project. Exp Gerontol. 2011;46(12):1003–9 PubMed PMID: 21979452. Hamann L, Ruiz-Moreno JS, Szwed M, Mossakowska M, Lundvall L, Schumann RR, et al. STING SNP R293Q is associated with a decreased risk of aging-related diseases. Gerontology. 2019;65(2):145–54 PubMed PMID: 30368497. Manolio TA, Collins FS, Cox NJ, Goldstein DB, Hindorff LA, Hunter DJ, et al. Finding the missing heritability of complex diseases. Nature. 2009;461(7265):747–53 PubMed PMID: 19812666. PMCID: 2831613. Bentley AR, Sung YJ, Brown MR, Winkler TW, Kraja AT, Ntalla I, et al. Multi-ancestry genome-wide gene-smoking interaction study of 387,272 individuals identifies new loci associated with serum lipids. Nat Genet. 2019;51(4):636–48 PubMed PMID: 30926973. PMCID: 6467258. Kim YK, Kim Y, Hwang MY, Shimokawa K, Won S, Kato N, et al. Identification of a genetic variant at 2q12.1 associated with blood pressure in East Asians by genome-wide scan including gene-environment interactions. BMC medical genetics. 2014;15:65 PubMed PMID: 24903457. PMCID: 4059884. Gluck S, Ablasser A. Innate immunosensing of DNA in cellular senescence. Curr Opin Immunol. 2019;56:31–6 PubMed PMID: 30296662. DeMarini DM. Genotoxicity of tobacco smoke and tobacco smoke condensate: a review. Mutat Res. 2004;567(2–3):447–74 PubMed PMID: 15572290. Wlodarczyk M, Nowicka G. Obesity, DNA Damage, and Development of Obesity-Related Diseases. Int J Mol Sci. 2019;20(5):1146. PubMed PMID: 30845725. PMCID: 6429223.