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Elucidating the Relationship Between Amyloid Aggregation and Inhibition of Polyamine Synthesis and Senescence in Down Syndrome Fibroblasts

Down syndrome (DS) is a genetic condition characterized by a full or partial copy of chromosome 21 (T21) resulting in premature aging and a variety of neurodevelopmental and physical disabilities. Recent published data by others indicate that senescence-associated phenotypes in DS are linked to a global transcriptional dysregulation. The number of pathways leading to increased senescence in DS is broad and the many components involved are not well defined in their relationship with aging. Polyamines (PA), which are polycationic small molecules involved with cell proliferation, gene regulation, autophagy, and apoptosis, have been reported to be beneficial for aging. While a larger percentage of DS cells in a population becomes senescent faster than normosomic cells, we have found that they also carry a significantly increased presence of PAs. Thus, there is a lack of consensus regarding the role of PA in aging, and in this study, we investigate how PA impacts cellular senescence in DS using flow cytometry to reliably and rapidly measure levels of senescence and death. We prevented endogenous PA production through the addition of α-difluoromethylornithine (DFMO), an inhibitor for the enzyme ornithine decarboxylase, which is the rate-limiting enzyme in the PA synthesis. Next, we added exogenous PA (putrescine, spermidine, spermine) individually to investigate how each PA impacts senescence in human DS and control fibroblasts. Early experimentation showed neither PA nor DFMO alone was sufficient in altering senescence. Interestingly, when we combined DFMO with the exogenous introduction of individual PA (putrescine and spermine), senescence in trisomic cells was significantly reduced. This data describes how the altered production of PAs relates to aging and related diseases. Further dissection of the role of PAs in DS-induced cellular senescence could reveal novel therapeutic targets for altering senescence rates, a common mechanism in many age-related diseases.