Premature Senescence and Increased Oxidative Stress in the Thymus of Down Syndrome Patients

Abstract

Down syndrome (DS) patients prematurely show clinical manifestations usually associated with aging. Their immune system declines earlier than healthy individuals, leading to increased susceptibility to infections and higher incidence of autoimmune phenomena. Clinical features of accelerated aging indicate that trisomy 21 increases the biological age of tissues. Based on previous studies suggesting immune senescence in DS, we hypothesized that induction of cellular senescence may contribute to early thymic involution and immune dysregulation. Immunohistochemical analysis of thymic tissue showed signs of accelerated thymic aging in DS patients, normally seen in older healthy subjects. Moreover, our whole transcriptomic analysis on human Epcam-enriched thymic epithelial cells (hTEC), isolated from three DS children, which revealed disease-specific transcriptomic alterations. Gene set enrichment analysis (GSEA) of DS TEC revealed an enrichment in genes involved in cellular response to stress, epigenetic histone DNA modifications and senescence. Analysis of senescent markers and oxidative stress in hTEC and thymocytes confirmed these findings. We detected senescence features in DS TEC, thymocytes and peripheral T cells, such as increased β-galactosidase activity, increased levels of the cell cycle inhibitor p16, telomere length and integrity markers and increased levels of reactive oxygen species (ROS), all factors contributing to cellular damage. In conclusion, our findings support the key role of cellular senescence in the pathogenesis of immune defect in DS while adding new players, such as epigenetic regulation and increased oxidative stress, to the pathogenesis of immune dysregulation.

Modeling Down syndrome neurodevelopment with isogenic cerebral organoids

“…(Note that if just two disomic and two trisomic clones were compared, results would depend on which cell lines/experiments were compared.) Our own observations comparing normal and DS human fibroblast lines suggested that trisomic cells were more susceptible to replicative senescence (Swanson,2014) (Dissertation Chapter IV), consistent with other recent evidence that trisomy 21 can increase cell senescence under stress (Oromendia et al,2012;Marcovecchio et al,2021). However, while senescence was not directly studied in this stem-cell based study, we did not detect increased expression of p16 or p21, markers of senescent cells.…”

AKT Hyperphosphorylation and T Cell Exhaustion in Down Syndrome

“…T-cell exhaustion and senescence appear to be related phenomena as shown by increased CD57 expression of T-cells in DS. Recently it has been shown that premature senescence in DS thymocytes plays a key role in the pathogenesis of immune defect in DS in the context of increased oxidative stress and epigenetic regulation ( 33 ). Accelerated aging in DS thymocytes has likely contributed to the T-cell exhaustion and senescence we observed in our cohort.…”

Biochemical Discrimination of the Down Syndrome-Related Metabolic and Oxidative/Nitrosative Stress Alterations from the Physiologic Age-Related Changes through the Targeted Metabolomic Analysis of Serum

“…The common features of these pathological conditions are mitochondrial dysfunction with energy metabolism imbalance and the presence of sustained oxidative/nitrosative stress. This implies that changes in the serum levels of purines, lactate, antioxidants and nitric oxide metabolites (nitrate + nitrate) reflect the alterations of numerous biochemical functions in DS patients, potentially contributing to their accelerated aging processes [ 67 ] and to the associated decline in their neurocognitive functions [ 68 ]. It is significant to observe that the ROC curves, calculated for purines (hypoxanthine, xanthine, uric acid, sum of oxypurines and inosine), lactate, and nitric oxide metabolites (nitrate and nitrate + nitrate) have high specificity and sensitivity to discriminate PnonDSP from PDSP, whilst only the ROC curve of xanthine allows the discrimination of YDSP from ADSP.…”

“…Previous studies reported anomalies of various amino acids in the serum samples of DS patients, compared to those that were measured in non-DS patients [ 19 , 38 , 39 , 40 ]. Again, in none of these studies was the accelerated aging process characterizing DS patients considered [ 47 , 48 , 67 ], so that the comparisons were performed between groups of non-DS and DS patients that were matched for sex and, most importantly, age.…”