T Allele of FOXO3 rs2802292 Increases CCL2 Concentration and Slightly Decreases TGF-β Concentration in Indonesian Elderly
Abstract
Background: Cellular senescence and the senescence-associated secretory phenotype (SASP) are pivotal factors influencing aging and age-related diseases. SASP secretes cytokines, chemokines, metalloproteinases, and growth factors that cause chronic inflammation. C-C ligand 2 (CCL2) and transforming growth factor-beta (TGF-β) are SASP markers secreted by senescent cells. This study investigated the relationship between the FOXO3 variant rs2802292 and SASP markers, focusing on CCL2 and TGF-β.
Materials and methods: A cross-sectional study involving 72 elderly individuals from Jakarta was conducted. A sandwich enzyme-linked immunosorbent assay (ELISA)was used to quantify CCL2 and TGF-β concentrations. Random blood glucose, blood pressure, and FOXO3 rs2802292 genotyping data were obtained from a previous study. Differences in CCL2 and TGF-β concentrations between genotype groups were analyzed using one-way ANOVA and the Kruskal-Wallis test. Meanwhile, differences in CCL2 and TGF-β concentrations between allele groups were analyzed using the Mann-Whitney test.
Results: The CCL2 and TGF-β concentrations of the subjects were 66.5 (10.58-190.9) pg/mL and 6,319 (2,379-13,846) pg/mL, respectively. There were significant differences in CCL2 concentrations among the FOXO3 rs2802292 genotypes (p=0.041). However, there were no significant differences in TGF-β concentrations among FOXO3 rs2802292 genotypes (p=0.955). Subjects with the G allele had significantly lower CCL2 concentrations compared with those with the T allele (p=0.033). TGF-β concentrations did not significantly differ between G and T alleles (p=0.771).
Conclusion: CCL2 concentrations are associated with the FOXO3 variant rs2802292 in the elderly population. The T allele of FOXO3 rs2802292 increased CCL2 concentration and slightly decreased TGF-β concentration in elderly individuals.
Keywords: aging, SASP, CCL2, TGF-β, SNP, FOXO3, rs2802292
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Bao JM, Song XL, Hong YQ, Zhu HL, Li C, Zhang T, et al. Association between FOXO3A gene polymorphisms and human longevity: A meta-analysis. Asian J Androl. 2014; 16(3): 446-52, CrossRef.
Stojanovic SD, Fiedler J, Bauersachs J, Thum T, Sedding DG. Senescence-induced inflammation: An important player and key therapeutic target in atherosclerosis. Eur Heart J. 2020; 41(31): 2983-96, CrossRef.
Meiliana A, Dewi NM, Wijaya A. Stem cell quiescence versus senescence: The key for healthy aging. Indones Biomed J. 2021;13(4): 337-49, CrossRef.
Kumari R, Jat P. Mechanisms of cellular senescence: Cell cycle arrest and senescence associated secretory phenotype. Front Cell Dev Biol. 2021; 9: 645593, CrossRef.
Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-κB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal. 2012; 24(4): 835-45, CrossRef.
Luciano-Mateo F, Cabré N, Fernández-Arroyo S, Baiges-Gaya G, Hernández-Aguilera A, Rodríguez-Tomàs E, et al. Chemokine (C-C motif) ligand 2 gene ablation protects low-density lipoprotein and paraoxonase-1 double deficient mice from liver injury, oxidative stress and inflammation. Biochim Biophys Acta Mol Basis Dis. 2019; 1865(6): 1555-66, CrossRef.
Cuollo L, Antonangeli F, Santoni A, Soriani A. The senescence-associated secretory phenotype (SASP) in the challenging future of cancer therapy and age-related diseases. Biology. 2020; 9(12): 485, CrossRef.
Yousefzadeh MJ, Schafer MJ, Noren Hooten N, Atkinson EJ, Evans MK, Baker DJ, et al. Circulating levels of monocyte chemoattractant protein-1 as a potential measure of biological age in mice and frailty in humans. Aging Cell. 2018; 17(2): e12706, CrossRef.
Kwak MK, Ha ES, Lee J, Choi YM, Kim BJ, Hong EG. C-C motif chemokine ligand 2 promotes myogenesis of myoblasts via the AKT-mTOR pathway. Aging. 2022; 14(24): 9860-76, CrossRef.
Kuznik BI, Chalisova NI, Guseva ES. Chemokine CCL2 and its receptor CCR2 in regulation of cognitive functions and in development of aging diseases. Biol Bull Rev. 2022; 12(4): 365-76,
Minciullo PL, Catalano A, Mandraffino G, Casciaro M, Crucitti A, Maltese G, et al. Inflammaging and anti-inflammaging: The role of cytokines in extreme longevity. Arch Immunol Ther Exp. 2016; 64(2): 111-26, CrossRef.
Kartika R, Wibowo H. Impaired function of regulatory T cells in type 2 diabetes mellitus. Mol Cell Biomed Sci. 2020; 4(1): 1-9, CrossRef.
Tominaga K, Suzuki HI. TGF-β signaling in cellular senescence and aging-related pathology. Int J Mol Sci. 2019; 20(20): 5002, CrossRef.
Ren LL, Miao H, Wang YN, Liu F, Li P, Zhao YY. TGF-β as a master regulator of aging-associated tissue fibrosis. Aging Dis. 2023; 14(5): 1633-50, CrossRef.
Rapisarda V, Borghesan M, Miguela V, Encheva V, Snijders AP, Lujambio A, et al. Integrin beta 3 regulates cellular senescence by activating the TGF-β Pathway. Cell Rep. 2017; 18(10): 2480-93, CrossRef.
Sun L, Hu C, Zheng C, Qian Y, Liang Q, Lv Z, et al. FOXO3 variants are beneficial for longevity in Southern Chinese living in the Red River Basin: A case-control study and meta-analysis. Sci Rep. 2015; 5:9852, CrossRef.
Fasano C, Disciglio V, Bertora S, Signorile ML, Simone C. FOXO3a from the nucleus to the mitochondria: A round trip in cellular stress response. Cells. 2019; 8(9): 1110, CrossRef.
Frankum R, Jameson TSO, Knight BA, Stephens FB, Wall BT, Donlon TA, et al. Extreme longevity variants at the FOXO3 locus may moderate FOXO3 isoform levels. Geroscience. 2022; 44(2):1129-40, CrossRef.
Grossi V, Forte G, Sanese P, Peserico A, Tezil T, Signorile ML, et al. The longevity SNP rs2802292 uncovered: HSF1 activates stress-dependent expression of FOXO3 through an intronic enhancer. Nucleic Acids Res. 2018; 46(11): 5587-600, CrossRef.
Nakagawa K, Chen R, Greenberg SM, Ross GW, Willcox BJ, Donlon TA, et al. Forkhead box O3 longevity genotype may attenuate the impact of hypertension on risk of intracerebral haemorrhage. J Hypertens. 2022; 40(11): 2230-5, CrossRef.
Hardiany NS, Nurfiyana W, Iswanti FC. Polymorphism of the forkhead box-O3 (FOXO3) longevity gene rs2802292 and senescence-associated secretory phenotype (SASP) in Indonesian elderly population. Nutr Healthy Aging. 2024; 9(1): 47-54, CrossRef.
Keputusan Menteri Kesehatan Republik Indonesia Nomor HK. 01.07/MENKES/603.2020 [Internet]; ©2020. Pedoman Nasional Pelayanan Kedokteran Tata Laksana Diabetes Melitus Tipe 2 Dewasa [cited 2024 March 8]. Available from: yankes.kemkes.go.id.
Keputusan Menteri Kesehatan Republik Indonesia Nomor HK.01.07/MENKES/4634/2021 [Internet]; ©2021. Pedoman Nasional Pelayanan Kedokteran Tata Laksana Hipertensi Dewasa [cited 2024 March 8]. Available from: jdih.kemkes.go.id.
Tzivion G, Dobson M, Ramakrishnan G. FoxO transcription factors; Regulation by AKT and 14-3-3 proteins. Biochim Biophys Acta. 2011; 1813(11): 1938-45, CrossRef.
Sanese P, Forte G, Disciglio V, Grossi V, Simone C. FOXO3 on the road to longevity: Lessons from SNPs and chromatin hubs. Comput Struct Biotechnol J. 2019; 17: 737-45, CrossRef.
Birch J, Gil J. Senescence and the SASP: Many therapeutic avenues. Genes Dev. 2020; 34(23-24): 1565-76, CrossRef.
Torigoe TH, Willcox DC, Shimabukuro M, Higa M, Gerschenson M, Andrukhiv A, et al. Novel protective effect of the FOXO3 longevity genotype on mechanisms of cellular aging in Okinawans. NPJ Aging. 2024; 10(1): 18, CrossRef.
He S, Sharpless NE. Senescence in health and disease. Cell. 2017; 169(6): 1000-11, CrossRef.
Gonzalez-Meljem JM, Apps JR, Fraser HC, Martinez-Barbera JP. Paracrine roles of cellular senescence in promoting tumourigenesis. Br J Cancer. 2018; 118(10): 1283-8, CrossRef.
Vicente R, Mausset-Bonnefont AL, Jorgensen C, Louis-Plence P, Brondello JM. Cellular senescence impact on immune cell fate and function. Aging Cell. 2016; 15(3): 400-6, CrossRef.
Cao G, Lin M, Gu W, Su Z, Duan Y, Song W, et al. The rules and regulatory mechanisms of FOXO3 on inflammation, metabolism, cell death and aging in hosts. Life Sci. 2023; 328: 121877, CrossRef.
Chen R, Morris BJ, Donlon TA, Masaki KH, Willcox DC, Davy PMC, et al.. FOXO3 longevity genotype mitigates the increased mortality risk in men with a cardiometabolic disease. Aging. 2020; 12(23): 23509-24, CrossRef.
Hartwig J, Loebel M, Steiner S, Bauer S, Karadeniz Z, Roeger C, et al. Metformin attenuates ROS via FOXO3 activation in immune cells. Front Immunol. 2021; :581799, CrossRef.
Prašnikar E, Borišek J, Perdih A. Senescent cells as promising targets to tackle age-related diseases. Ageing Res Rev. 2021; 66: 101251, CrossRef.
DOI: https://doi.org/10.21705/mcbs.v8i3.484
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