Highly accurate skin-specific methylome analysis algorithm as a platform to screen and validate therapeutics for healthy aging

Abstract

Background DNA methylation (DNAm) age constitutes a powerful tool to assess the molecular age and overall health status of biological samples. Recently, it has been shown that tissue-specific DNAm age predictors may present superior performance compared to the pan- or multi-tissue counterparts. The skin is the largest organ in the body and bears important roles, such as body temperature control, barrier function, and protection from external insults. As a consequence of the constant and intimate interaction between the skin and the environment, current DNAm estimators, routinely trained using internal tissues which are influenced by other stimuli, are mostly inadequate to accurately predict skin DNAm age. Results In the present study, we developed a highly accurate skin-specific DNAm age predictor, using DNAm data obtained from 508 human skin samples. Based on the analysis of 2,266 CpG sites, we accurately calculated the DNAm age of cultured skin cells and human skin biopsies. Age estimation was sensitive to the biological age of the donor, cell passage, skin disease status, as well as treatment with senotherapeutic drugs. Conclusions This highly accurate skin-specific DNAm age predictor constitutes a holistic tool that will be of great use in the analysis of human skin health status/molecular aging, as well as in the analysis of the potential of established and novel compounds to alter DNAm age.

ARDD 2020: from aging mechanisms to interventions

“…Cell-based drug screening identified a lead compound, OS-1, that was able to reduce senescent cell burden and protect cells from UVB-induced photoaging. In addition, OS-1 was shown to reduce the molecular age of the skin using their developed skin-specific epigenetic clock [102] and showed benefits for skin health in a clinical study. Further experiments are being performed to examine whether OS-1 affects lifespan and healthspan in model organisms.…”

Senotherapeutic peptide reduces skin biological age and improves skin health markers

“…In order to have a more in depth understanding of how both peptide 14 and Rapamycin treatments might alter skin's biological age, the 79 year old ex vivo skin biopsies were processed for DNA isolation and methylome analysis. Using the Skin-Specific DNA methylation algorithm developed by our group 32 , we observed that while Rapamycin treatment did not generate any significant alterations (p=0.21), peptide 14 treatment significantly reduced the DNA methylation age (p<0.01) ( Fig. 3H).…”

“…Measuring the approximate number of senescent cells in the skin can be challenging and current studies indicated that epigenetic changes comprise a significant component of the aging process. Therefore, we proposed the use of a Skin-Specific DNA methylation clock that can offer a comprehensive and highly accurate alternative method to analyze human skin health status and aging 32 .…”

“…Raw methylation files (idat) were converted to beta values using the “minfi” package version 1.32.0 74 after the quality control and quantile normalized using the function betaqn from the “wateRmelon” package version 1.30.0 75 . Quantile-normalized beta values for all samples were used as input for the Skin-Specific DNAm predictor MolClock 32 . Box plots were used to compare age predictions among groups in different datasets.…”

“…Total DNA samples were obtained from human skin biopsy samples (XX, caucasian, 79 yr) using the QIAamp DNA Mini Kit (Qiagen) and applied to the human Illumina Infinium EPIC 850K chip, as described previously 32 . DNA samples included control, 5 days treatment with 12.5 μM Peptide 14, and 5 days treatment with 100 nM Rapamycin.…”