DDIT4 and HDAC4 Overexpression Reduces Harmful Signaling of Senescent Cells in Aged Tissues
Accumulation of senescent cells is an important aspect of degenerative aging. While never present in very large numbers, relative to the overall count of all cells in a tissue, senescent cells generate a potent mix of signals that induce inflammation and disrupt normal tissue maintenance and function. Clearance of senescent cells via senolytic therapies is the presently favored approach to this issue, but a sizable faction in the research community are instead interested in suppression of senescent cell signaling. Research into the detailed biochemistry of senescence may lead in either direction, both of which can give rise to potential new therapies.
Several studies have reported the potential of epigenetic regulation in delaying senescence. Our previous studies showed that UV irradiation decreased HDAC4 expression in primary human dermal fibroblasts, and HDAC4 expression was reduced in aged skin in vivo. These results suggest that HDAC4 may play an important role in skin aging. However, there is a paucity of research on how HDAC4 causes skin aging.
By integrating our RNA-Seq data and previously reported transcriptome datasets from UV- and H2O2-induced senescence models, we identified DDIT4 as a promising candidate target of HDAC4 involved in HDAC4-dependent epigenetic regulation of skin aging. DDIT4 regulates cell growth, oxidative stress, autophagy, mitochondrial function, and apoptosis. We found that DDIT4 expression was markedly reduced in aged skin in vivo, in replicative senescent HDFs, and in senescent fibroblasts under repeated H2O2 treatment or UV irradiation. HDAC4 expression was positively correlated with DDIT4, and also significantly decreased in aged skin in vivo.
Our data indicate that the knockdown of DDIT4 prevented the HDAC4-induced reduction of SA-β-gal in senescent cells. Moreover, DDIT4 overexpression could restore the senescence-associated alterations of senescence-associated secretory phenotype components such as IL-β, IL-6, IL-8, MMP-1, and CXCLs, as well as aging-related genes, suggesting that DDIT4 may contribute to the skin aging process by regulating senescence-associated microenvironments. Therefore, DDIT4, known as an important negative regulator of mTOR, may play an essential role in suppressing cell senescence by inhibiting mTOR activity or p21.