Ally Sulfide Epigenetically Targets Cellular Senescence and Prevents Age‐related Bone Loss in Mice

Abstract

Aging is the process of becoming older through an increase in detrimental changes eventually both at the cellular and molecular levels, which finally leads to different pathophysiological consequences. In particular, aging is associated with increased cellular senescence, via an increase in ROS generation as well as hyperactivity of the transcription factor nuclear factor (NF)‐κB. Thereby it triggers the inflammatory response leading to multiple comorbidities. While the protective role of aged garlic‐derived ally sulfide on several disease pathology are well established, the anti‐senescence activity in age‐related bone loss has not yet been elucidated. In the current study, we aimed to investigate the anti‐senescence role of allyl sulfide (AS) to target cellular senescence during age‐related bone loss through the molecular and epigenetic mechanism. The experimental groups were: (i) young (8‐months‐old), (ii) aged mice (20‐month‐old) and (iii) aged mice (20‐month‐old) with AS. To test this hypothesis, aged mice were treated for 12‐weeks with vehicle or the natural garlic extract derived allyl sulfide or senolytic’ compounds like Tocotrienols + Quercetin at the dose of 100mg/kg body weight/animal. Our in vivo study revealed that the trabecular bone loss is very prominent in aged mice (20‐month old) assessed by μCT measurements. However, administration of AS found to prevent the age‐related trabecular bone mass phenotype, and improved better bone microarchitecture. We also identified the beneficial effects of AS that can target senescence cells (low Senescence‐Associated β‐Galactosidase (SA‐β‐gal)) in vivo as evident through identification of lower bone resorption (TRP‐5b activity) in AS treated mice as compared to aged mice. In vitro co‐culture studies demonstrated that senescent‐cell derived conditioned medium impaired BMMSC‐derived osteoblast mineralization and enhanced osteoclastogenesis. Proinflammatory secretome profiling of senescent cells reveals revealed that cytokines ( TNF‐α, IL‐1β, and IL‐6) expression were abundantly upregulated in senescent cells of the aging mice than vehicle‐treated mice. Western blots and ChIP assays revealed that the acetylation and activation of nuclear factor κB [NFkappaB p65 (Acetyl‐Lys310)] were also increased in the senescent cell of aging mice and directed proinflammatory cytokine signaling. In vivo blockade of NF‐kB transcriptional activity in aged mice by using small molecule inhibitor suppressed the production of the proinflammatory secretome of senescent cells resulted in higher bone mass than in vehicle‐treated mice. In conclusion, administration of AS abolished the age‐related cellular senescent and enhances bone mass. Our studies strongly suggest that AS could be a potential therapeutic agent against age‐related osteoporosis.Support or Funding InformationThis work is financially supported by National Institute of health grant AR‐067667 and HL‐107640‐NT are greatly acknowledgedThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.