Physical activity may drive healthy microvascular ageing via downregulation of p66 Shc .

Background: Narrower retinal arterioles and wider venules are linked to adverse cardiovascular outcomes. The mitochondrial adaptor p66(Shc) is a major source of ageing-induced generation of reactive oxygen species. Promoter DNA methylation inhibits p66(Shc) gene transcription. This cross-sectional study was designed to investigate the link between physical activity, retinal vessel diameters and p66(Shc) expression in active and sedentary ageing subjects. Design/methods: Altogether 158 subjects were included in the study (mean age 59.4 +/- 7.0 years). Thirty-eight subjects were healthy active, 36 were healthy sedentary and 84 were sedentary with >= 2 cardiovascular risk factors. Retinal arteriolar and venular diameters were measured by means of a retinal vessel analyser. As a marker of oxidative stress, plasma 3-nitrotyrosine was determined by enzyme-linked immunosorbent assay. Gene expression of p66(Shc) and DNA methylation were assessed in mononuclear cells by real-time quantitative polymerase chain reaction and methylated-DNA capture (MethylMiner Enrichment kit) coupled with quantitative polymerase chain reaction, respectively. Results: Wider retinal arterioles (179 +/- 14 vs 172 +/- 11 and 171 +/- 14 mu m; p < 0.05 and narrower venules (204 +/- 17 vs 209 +/- 11 and 218 +/- 16 mu m; p < 0.001) were observed in healthy active subjects compared with healthy sedentary subjects and sedentary subjects with >= 2 cardiovascular risk factors, respectively. Furthermore, healthy active subjects had blunted p66(Shc) expression and lower 3-nitrotyrosine plasma levels compared with healthy sedentary and sedentary subjects with >= 2 cardiovascular risk factors. Accordingly, hypomethylation of p66(Shc) promoter observed in healthy sedentary and sedentary subjects with >= 2 cardiovascular risk factors was not found in healthy active subjects. Conclusion: Long-term physical activity-induced DNA methylation of p66(Shc) may represent a putative mechanistic link whereby active lifestyle promotes healthy microvascular ageing.