Thursday, September 27, 2018 2:05 PM–3:05 PM Section on Biologics and Basic Research Abstract Presentations: 126. Systemic effects on intervertebral disc aging: increased disc degeneration in young mice when they shared blood circulation with old mice

BACKGROUND CONTEXT Aging is the main risk factor for intervertebral disc degeneration (IDD). Age-associated IDD could be due to the time-dependent accumulation of local damage to disc cells (cell autonomous) or global influences on disc tissue from the systemic degenerative changes of the surrounding and distal tissues (cell nonautonomous). While local changes, for example, disc cellular senescence and death, have been reported in aging discs, the contribution of global influences to age-related IDD has not been investigated. PURPOSE To study if disc aging can be influenced by circulating factors. STUDY DESIGN/SETTING Heterochronic parabiosis between young and old mice whereby pairing of mice is surgically performed to share blood circulation in order to test the global effects on disc aging. METHODS Three different mouse parabiotic pairs were generated: Y-Y, Y-O, O-O. Young (Y, age 3 months) and old (O, age 20 months) wildtype C57B6 mice were used. Systemic injection of Evans blue dye and fluorescent nanobeads was used to demonstrate development of shared circulation in all pairs after one day of surgery. Mice were sacrificed six weeks after surgical pairing. Key age-related IDD features were assessed by Western blots measuring disc cellular senescence (p16, p53), disc catabolic gene expression (MMP13, ADAMTS4) and disc aggrecan proteolytic fragments (MMP- and ADAMTS-mediated cleavage of the interglobular domain). Four mice were analyzed from each pair group. RESULTS Compared to the young mice in isochronic pairing (Y-Y), young mice heterochronically paired to old mice (Y-O) showed increased cellular senescence markers (37+10% increased p16, and 20+5% increased p53). In addition, pairing young mice with old mice resulted in the disc tissue of young mice an increase of MMP-13 (35+7%), ADAMTS4 (25+6%) proteins as well as the aggrecan fragments (∼53% increased of MMP-generated and ∼15% increased of ADAMTS-generated cleavage of aggrecan interglobular domain) compared to those in young mice pairing with young mice. Disc aggrecan immunofluorescence also decreased by 30% in young mice paired with old mice compared to young mice paired with young mice. CONCLUSIONS Our results show that age-related IDD is accelerated in young mice when they are exposed to blood circulation of old mice, supporting the hypothesis that disc aging is influenced by global changes and not just by local disc cell autonomous mechanism. Our results also suggest the existence of one or more blood-borne systemic factors controlling disc aging process, which once identified may represent therapeutic targets to mitigate age-associated IDD. FDA DEVICE/DRUG STATUS This abstract does not discuss or include any applicable devices or drugs.