Epigenetic modifications such as DNA methylation and histone modification play an important role for cellular senescence and aging including skin aging. DNA can be methylated at cytosine residue (CpG). DNA methylation provide an mechanism for the regulation of programmed progressive alterations in the course of aging because genes can be turned off upon after DNA methylation. Studies have indicated that the global DNA methylation level decreases upon aging. It was also shown that the the methylated cytosine content decreased upon long-term culture of fibroblasts. However, a number of specific loci become hyper-methylated during aging indicating that age-associated methylation changes are different from the random deterioration during ontogenic development although it is yet unknown how site-specific methylation changes are regulated.Distinct age-related phenotypes such as wrinkle formation as well as the accessibility of samples from differently aged healthy human skin make the skin fibroblast an ideal model system for the analysis of age-related epigenetic changes.
DNA methylation profiles in fibroblasts isolated from different dermal regions were examined to investigate age-associated changes. 766 CpG sites were hyper-methylated in fibroblasts whereas 752 CpG sites were hypo-methylated. These CpG sites corresponded to 521 and 499 non-redundant genes. Hyper-methylated CpG sites in fibroblasts were significantly over-represented in genes of categories that mediate development, immune response and hormone secretion. Hypo-methylated genes were rather involved in immune response, defense response and wound healing.
Comparison of DNA methylation profiles in fibroblasts derived from young (<23) or elderly skin (>60). Strikingly, global DNA-methylation profiles of fibroblasts from the same anatomical site clustered closely together indicating that fibroblasts maintain positional memory even after in vitro culture. There are some age-associated DNA methylation changes at specific CpG sites in fibroblasts. Specific genes with hypermethylation and hypomethylation were identified. Fibroblast DNA methylation profile changes are linked to fibroblast senescence. DNA methylation profiles of passage 3 and passage 21 of fibroblasts were compared. Comparison of DNA methylation profiles in fibroblasts derived from young or elderly donors revealed that 75 CpG sites change their methylation level more than 15% upon aging. There was a significant correlation between DNA methylation changes in fibroblasts upon long-term culture in vitro and aging in vivo.
Fibroblasts are diverse with various functions in different anatomic dermal regions. This diversity is also reflected in global DNA methylation patterns: epigenetic modifications at specific CpG sites correlates to their anatomic sampling location. There are age-associated DNA methylation changes that may contribute to aging of the skin. Overall, age-associated DNA methylation changes occurred at similar sites upon aging in fibroblasts. The significant interrelation of age-associated methylation changes in fibroblasts and MSC is noteworthy.
Various molecular mechanisms have been implicated in aging including telomere-shortening, accumulation of mutations, oxidative stress and alteration of molecular pathways. The age-related DNA methylation pattern may include the regulation of genes that are involved in the molecular mechanisms of skin aging such as free radical (oxidative stress), telomere-shortening, the molecular and cellular pathways associated with chronic inflammaging, cellular energy metabolism.