Fighting the epigenetic clock of aging

Epigenetics can be defined as the structural adaptation of chromosomal regions so as to register, signal or perpetuate altered activity states. A variety of chromatin-altering post-translational modifications to histone proteins including acetylation, methylation, and ubiquitinylation as well as direct modifications to DNA are known to turn gene transcription off or on. To date, methylation of DNA and acetylation/deacetylation of histone lysine residues have proven to be of greatest clinical significance amongst epigenetic post-translational modifications. The approval of anti-cancer drugs such as Vorinostat and Decitabine respectively targeting histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) as well as pharma development pipelines targeting enzymes regulating post-translational modifications are evidence that reprogramming gene expression on an epigenetic level holds great clinical promise.

It is now understood that epigenetics are behind some of the genetic changes related to aging and that senescence could be delayed or inhibited by different approaches. Taking the example of a research article published in Genome Biology (2013), Steve Horvath from UCLA developed a model of age prediction based on a single type of epigenetic modification: DNA methylation at the 5 position of cytosine. This accurate age predictor was found to be independent of sex, tissue type, disease state and array platform as well as a strong indicator of the importance of epigenetics in aging. Histone deacetylases are a class of enzymes capable of removing acetyl groups from ε-N-acetyl lysine residues on histones. By acting on the latter and on chromatin structures, they have an influence on cell signaling, cell cycle, cell growth, cell death and disease. They also seem to be involved in the deacetylation of non-histone proteins, notably transcription factors whose function, activity and stability will be affected by these post-translational modifications. Recently, high expectations, notably from the personal care industry, have been placed on the anti-aging potential of modulators of histone deacetylases and most specifically NAD-dependent class III histone deacetylases (sirtuins) to promote homeostasis and preserve the levels of transcription and expression found in younger cells and younger organisms (A.M. Vaiserman et al., 2012).

Sirtuin-1, also referred to as SIRT1, is a NAD-dependent class III histone deacetylase and contributes to cellular regulation by protecting from stress events, favoring autophagy and augmenting longevity (P.D. Benech, et al., 2014). Dr. Chung and collaborators from Pusan National University and University of Texas HSC further investigated the mechanisms behind the positive effects of SIRT1 in skin fibroblasts. They demonstrated that SIRT1 protected skin cells from UVB-induced senescence both in vitro and in vivo. This protection was shown to change the transcriptional activity of FOXO3&aplha:, increase resistance to oxidative stress and suppress p53 acetylation and its transcriptional activity which has an effect on the cell cycle arrest triggered by UVB; thus making SIRT1 a very interesting biomarker for scientists working on human skin health and the development of skin care products. Several seminal studies have demonstrated the beneficial effects of the natural compound and SIRT1 activator, resveratrol, in preventing many diseases associated with aging. E.D. Lephart and colleagues from Brigham Young University decided to apply topically resveratrol on skin cells and noticed that it efficiently penetrated the human skin barrier and significantly stimulated the expression of SIRT1. It correlated with key events normally associated with healthy skin such as the increase expression of extracellular matrix proteins, tissue inhibitor of matrix metalloproteinases (TIMP1), several anti-oxidant and anti-aging biomarkers, and the inhibition of the expression of matrix metalloproteinases, aging biomarkers and pro-inflammatory biomarkers.

Altogether, these data suggest that SIRT1 and more specifically activators of SIRT1 could be hugely beneficial to both damaged and healthy but aging skin cells as a component of skin care products. Enzo Life Sciences offers a comprehensive portfolio for advancing your research in personal care such as the Fluor-de-Lys SIRT1 fluorometric drug discovery assay kit which is an ideal tool for the characterization of enzyme kinetics and the screening of modulators of SIRT1 activity. In addition, Enzo offers antibodies, enzymatic assays, immunoassays, live cell analysis assays and other small molecules, some of which are listed below:

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