Research Article Sulforaphane Delays Fibroblast Senescence by Curbing Cellular Glucose Uptake, Increased Glycolysis, and Oxidative Damage Florence Hariton, 1 Mingzhan Xue, 1 Naila Rabbani, 1 Mark Fowler, 2 and Paul J. Thornalley 1,3 1 Clinical Sciences Research Laboratories, Warwick Medical School, University of Warwick, University Hospital, Coventry CV2 2DX, UK 2 Unilever Research & Development Colworth, Sharnbrook, Bedford MK44 1LQ, UK 3 Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, P.O. Box 5825, Doha, Qatar Correspondence should be addressed to Paul J. Thornalley; p.j.thornalley@warwick.ac.uk Received 1 August 2018; Accepted 3 October 2018; Published 22 November 2018 Academic Editor: Grzegorz Bartosz Copyright © 2018 Florence Hariton et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Increased cell senescence contributes to the pathogenesis of aging and aging-related disease. Senescence of human fibroblasts in vitro may be delayed by culture in low glucose concentration. There is also accumulating evidence of senescence delay by exposure to dietary bioactive compounds that activate transcription factor Nrf2. The mechanism of cell senescence delay and connection between these responses is unknown. We describe herein that the cruciferous vegetable-derived metabolite, sulforaphane (SFN), activates Nrf2 and delays senescence of human MRC-5 and BJ fibroblasts in vitro. Cell senescence is associated with a progressive and marked increased rate of glucose metabolism through glycolysis. This increases mitochondrial dysfunction and overwhelms defences against reactive metabolites, leading to increasing proteomic and genomic oxidative damage. Increased glucose entry into glycolysis in fibroblast senescence is mainly mediated by increased hexokinase-2. SFN delayed senescence by decreasing glucose metabolism on the approach to senescence, exhibiting a caloric restriction mimetic- like activity and thereby decreased oxidative damage to cell protein and DNA. This was associated with increased expression of thioredoxin-interacting protein, curbing entry of glucose into cells; decreased hexokinase-2, curbing entry of glucose into cellular metabolism; decreased 6-phosphofructo-2-kinase, downregulating formation of allosteric enhancer of glycolysis fructose-2,6-bisphosphate; and increased glucose-6-phosphate dehydrogenase, downregulating carbohydrate response element- (ChRE-) mediated transcriptional enhancement of glycolysis by Mondo/Mlx. SFN also enhanced clearance of proteins cross- linked by transglutaminase which otherwise increased in senescence. This suggests that screening of compounds to counter senescence-associated glycolytic overload may be an effective strategy to identify compounds with antisenescence activity and health beneficial effects of SFN in longevity may involve delay of senescence through glucose and glycolytic restriction response. 1. Introduction Human diploid fibroblasts exhibit a progressive decreased replication rate in culture, eventually reaching a maximum cumulative number of cell replications called the limiting population doubling level or Hayflick limit [1]. This process is called replicative senescence (RS). It reflects the dysfunc- tion of mitotic control of dividing cells and reflects the aging process, with also metabolic relevance to the aging of postmitotic cells. Phenotypic characteristics of the approach to RS are exit from the cell cycle, unresponsiveness to growth factors, shortening of telomeres, increase in cell size and het- erogeneity, expression of β-galactosidase (β-gal), senescence- associated secreted phenotype (SASP), and others [2]. Senescence may be activated independent of shortening of telomers where an abnormal response to DNA replication stress or telomer damage may be involved [3, 4]. The rele- vance of the RS model to human ageing is claimed through Hindawi Oxidative Medicine and Cellular Longevity Volume 2018, Article ID 5642148, 16 pages https://doi.org/10.1155/2018/5642148