Abstract
Δ133p53α is a naturally occurring isoform of the human p53 protein that inhibits p53-mediated cellular senescence. We recently reported that transgenic expression of this senescence-inhibitory p53 isoform counteracts aging-associated pathological changes and extends lifespan in progeria model mice (heterozygous Lmna (G609G/+)). The anti-aging effect of Δ133p53α was attributed in part to reduced levels of the proinflammatory cytokine IL-6. To comprehensively profile Δ133p53α-induced changes in cytokines and chemokines, we in this study performed a Luminex-based multiplex quantitative assay of mouse sera collected from transgenic Δ133p53α-expressing Lmna (G609G/+) mice and non-expressing controls. This assay not only confirmed the Δ133p53α-mediated repression of IL-6 but also showed that Δ133p53α reduced the levels of CXCL1 (also known as KC), IL-1α, and CXCL10 (also known as IP-10). Among these factors, we further characterized CXCL10, which has not previously been associated with progeria in mice or humans. Consistent with reduced serum CXCL10 levels, both young (15-week-old) and old (10-month-old) Δ133p53α-expressing Lmna (G609G/+) mice showed reduced Cxcl10 expression, compared with age-matched non-expressing controls, in the liver, spleen, and brain, major organs known to produce CXCL10. In naturally aged wild-type mice (2-year-old), Cxcl10 expression was also significantly repressed by transgenic Δ133p53α in the spleen and brain. Analysis of gene expression datasets from human tissues demonstrated an inverse association between CXCL10 and Δ133p53α levels, suggesting physiological relevance to human aging. This study defines CXCL10 as a proinflammatory chemokine elevated in both accelerated and natural aging and as a potential target of the anti-inflammatory activity of Δ133p53α.