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The median age of death is 17\u2009years as there is no safe, effective treatment approved. Using faithful\n                    <jats:italic>Drosophila<\/jats:italic>\n                    and murine models of MPS III, we have characterised the MPS IIIA and MPS IIIC fly metabolome, explored the ability of oral spermidine supplementation to ameliorate clinical disease in the fly models and explored its mechanism of action in MPS IIIA mice. Spermidine is a polyamine naturally synthesised by the body. Its manufacture decreases with age. Supplementation has been reported to stimulate autophagy, reduce cell senescence and increase health\/lifespan. The metabolomic evaluation confirmed that whole MPS IIIA and MPS IIIC flies exhibit a progressively deranged metabolome. Significantly up\u2010regulated metabolites were those involved in nucleotide and purine metabolism. The most significantly down\u2010regulated metabolites were those involved in ascorbate and aldarate metabolism. Further, spermidine levels decreased significantly in all fly genotypes with age. In short\u2010term studies, food enriched with 5\u2009mM spermidine improved overall fly activity and climbing ability. A 4\u2010week study in pre\u2010symptomatic MPS IIIA mice (3\u2010 or 6\u2010mM spermidine, supplemented in drinking water) revealed no improvement in microgliosis or lysosomal compartment size; however, we observed a significant reduction in the astroglial response in the brain, which is believed to drive disease progression. Longer\u2010term confirmatory studies in larger cohorts of MPS III animals are now warranted to determine whether spermidine supplementation is of benefit in preventing or slowing clinical disease in this and other childhood dementias.\n                  <\/jats:p>","DOI":"10.1002\/jimd.70195","type":"journal-article","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T05:09:58Z","timestamp":1777439398000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Short\u2010Term Oral Spermidine Supplementation Modifies Aspects of Neurodegenerative Disease in Flies and Mice With\n                    <scp>MPS III<\/scp>"],"prefix":"10.1002","volume":"49","author":[{"given":"Helen","family":"Beard","sequence":"first","affiliation":[{"name":"Childhood Dementia Research Group, Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University  Bedford Park South Australia 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