Reference Lab

July 15, 2020

Along with this publication, OneSkin is excited to share our new application programming interface (API), MolClock, the first ever skin-specific molecular clock designed to determine the chronological age of human skin.

Devised by OneSkin co-founder and Head of Bioinformatics Mariana Boroni, PhD, in partnership with the OneSkin team, MolClock has the potential to drastically transform how scientists measure an individual’s skin molecular age which indicates one’s overall health, and the efficacy of skin products and interventions from a molecular level. While OneSkin owns the proprietary rights of MolClock, the tool is available for free and public use in an effort to forward the study of molecular aging and longevity research for scientists everywhere.

We spoke with Mariana Boroni, PhD, who developed the machine learning based skin-specific molecular clock algorithm, to better understand the function of MolClock and the importance of the tool in connection with advancing aging research.

Thank you! I am very excited about our results! The algorithm behind MolClock was constructed using machine learning to detect important epigenetic alterations that occur in our skin as we age. To train and test the MolClock algorithm, we used over 500 human skin samples and over 2,000 DNA methylation (DNAm) markers, achieving a highly accurate DNAm age predictor.

“MolClock allows us to predict the molecular age of someone's skin based on their methylation profiles, which correlates strongly with one’s chronological age.”

MolClock allows us to predict the molecular age of someone's skin based on their methylation profiles, which correlates strongly with one’s chronological age. Exceptions occur when there are ongoing processes that influence one’s DNAm age such as diseases including cancer and psoriasis, inflammatory disorders and environmental exposures or lifestyle influences, such as smoking and obesity, which in most cases, will promote an acceleration of aging and increase the skin molecular age. Therefore, the DNAm age predicted by our tool is a highly accurate indicator of overall skin health.

With this new tool, we can prospect and validate new compounds and treatments that are able to rejuvenate the skin by observing their power to reduce the skin DNAm age following treatment. Our ability to scientifically measure before and after findings of treatment significantly impacts our development of new products.

Methylation is a common epigenetic signaling tool that cells use to control the gene's expression. DNA is made up of the nitrogenated bases adenine, cytosine, thymine and guanine - ATCGs. One of the bases (cytosine) has the ability to harbor methyl groups (CH3).

These methyl groups can be added (methylation) or removed (demethylation) from specific regions of our DNA due to both intrinsic (aging, genetics) and extrinsic (environmental) factors, changing how our body reads the DNA segment, thus changing gene expression, without changing the DNA sequence. In this way, methylation of DNA coding regions for a certain gene can silence gene expression. The removal of the markers can lead to the opposite effect, activating the expression of genes that were not previously expressed [ 1 ].

What we find very interesting is that during aging, there is a global loss of DNA methylation. However, specific sites become hypermethylated and certain genes that are active when we are younger, turn off and therefore become dormant due to age-induced hypermethylation [ 2 ]. One example is collagen - as we age, a gene that produces a protein important for collagen production, SEC31, becomes hypermethylated, with more and more methyl groups added to the piece of DNA coding for this gene [ 2 ]. This gene hypermethylation-associated silencing plays an important role in the age-associated skin phenotype, likely leading to a reduced capacity of the cell to export the collagen protein. This reduction in collagen in our skin is one reason why our skin tends to be less firm when we get older.

Although epigenetic alterations naturally occur as we age, scientists have proven that exogenous stimuli deriving from lifestyle, diet, and environmental exposure (such as UV radiation, smoking, physical activity, antioxidant intake, caloric restriction) or disease conditions, rather than genetics, pose greater influence over the methylation patterns of a person [ 1, 2, 3 ].

Skin is the largest organ in the human body, and is also our natural barrier against water loss, physical and chemical injury, and pathogenic infection. Our skin aide in our temperature regulation, vitamin production, protection against UV radiation, and sensation. Overall, our skin serves so many important functions, and is often overlooked as a vital component in keeping us safe and healthy.

“...our skin serves so many important functions, and is often overlooked as a vital component in keeping us safe and healthy.”

Unfortunately, our skin is highly influenced by environmental factors such as sun and pollution exposure, which is why it is extremely important to keep our skin healthy to promote overall health. Ultraviolet radiation (UVR) derived from sun exposure is well-known to be the most important cause of skin cancer and its association with environmental pollutants (including cigarette smoke) significantly increases the risk of skin cancer [ 4, 5 ]. As the incidence rate of melanoma and non-melanoma skin cancer is dramatically increasing worldwide, it is essential that we change our habits in order to prevent the onset of the disease.

The first molecular clock based on epigenetic alterations that predicted DNAm age with high accuracy across almost all human tissues and cell types was published in 2013 by Steve Horvath [ 6 ]. This algorithm, however, failed to accurately calculate the chronological age of cultured fibroblasts and epithelial cells [ 6, 7 ] which are the cells that largely makeup our skin. Recently, other important and improved epigenetic clocks were published including The Skin & Blood Clock [ 7 ], DNA methylation PhenoAge [ 8 ], and DNA methylation GrimAge [ 9 ].

Research has continued to show that each tissue (including our skin!) harbors a tissue-specific methylation landscape required for the stable maintenance of cell-type identity. Not only are overall methylation landscapes particular to each tissue, but age-related methylation changes are limited to specific local alterations highly dependent on tissue type as well. For this reason, each tissue in our body requires a tissue-specific molecular clock in order to increase measures of health accuracy and predictability.

This motivated me to develop a skin-specific algorithm that calculates DNAm age of skin samples with higher accuracy and a lower error compared to existing molecular age estimators.

Yes, we encourage scientists outside our internal team to use MolClock! Our team’s ability to share our algorithm with the scientific community at large was actually an important motivator in my development of the algorithm.

“Our new skin-specific molecular clock presents a valuable tool to investigate human skin aging, detect skin pathological conditions, and develop strategies to extend human life and healthspan.”

Our new skin-specific molecular clock presents a valuable tool to investigate human skin aging, detect skin pathological conditions, and develop strategies to extend human life and healthspan. The team at OneSkin is committed to advancing the science and knowledge underlying human aging which extends beyond the consumer products that we develop. We specifically built MolClock as a user-friendly platform where anyone across the globe can easily upload their methylation data to get the DNAm age prediction for each sample.

Our skin-specific algorithm has put us at a real advantage in our ability to drive research and gather insights in the development of our newest skin formulation, OS-1. We applied our skin-specific DNAm age predictor to identify new strategies to promote skin rejuvenation by comparing the predicted age of skin tissues before and after treatment with new compounds. It is important to mention that we used samples from different donors across various ages. This screening strategy led us to the conclusion that our topical product, OS-1, featuring our proprietary peptide, can actually reduce the molecular age of skin.

Using our MolClock, we have also studied the validity of another compound frequently used in skincare ingredients on the market that claim to rejuvenate skin. Our findings have proven that the power of rejuvenating skin by reducing the DNAm age generated by our OneSkin proprietary peptide is superior than the compound most frequently used in the market. For this reason, we really value the scientific markers behind our OS-1 product, and we feel confident sharing the science behind our proprietary formulation, as it is scientifically supported. 

MARIANA BORONI, PhD, is co-founder and Head of Bioinformatics of One Skin, a biotechnology company based in San Francisco, CA, focused on developing science-based solutions to maximize human healthspan.

References

• [1] Sen P, Shah PP, Nativio R, Berger SL. Epigenetic Mechanisms of Longevity and Aging. Cell. 2016;166(4): 822-839.
• [2] Grönniger E, Weber B, Heil O, Peters N, Stäb F, Wenck H, Korn B, Winnefeld M, Lyko F. Aging and Chronic Sun Exposure Cause Distinct Epigenetic Changes in Human Skin. PLoS Genet. 2010; 6(5): e1000971.
• [3] Quach A, Levine ME, Tanaka T, et al. Epigenetic clock analysis of diet, exercise, education, and lifestyle factors. Aging . 2017;9(2):419-446.
• [4] Fabbrocini G, Triassi M, Mauriello MC, et al. Epidemiology of skin cancer: role of some environmental factors. Cancers. 2010;2(4):1980-1989.
• [5] Burke KE, Wei H. Synergistic damage by UVA radiation and pollutants. Toxicol Ind Health. 2009 May-Jun; 25(4-5):219-24.
• [6] Horvath S. DNA methylation age of human tissues and cell types. Genome Biol. 2013;14(10):R115.
• [7] Horvath S, Oshima J, Martin GM, et al. Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging. 2018;10(7):1758-1775.
• [8] Levine ME, Lu AT, Quach A, et al. An epigenetic biomarker of aging for lifespan and healthspan. Aging. 2018;10(4):573-591.
• [9] Lu AT, Quach A, Wilson JG, et al. DNA methylation GrimAge strongly predicts lifespan and healthspan. Aging . 2019;11(2):303-327.