A biological clock to measure skin’s anti-ageing interventions

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Epigenetic clocks are a groundbreaking tool in biogerontology, measuring biological ageing through DNA methylation patterns at specific CpG sites, which can differ significantly from chronological age. The first-generation clocks, such as Horvath’s clock, estimate biological age based on methylation at numerous sites. However, second-generation clocks like GrimAge, DunedinPACE, and PhenoAge have enhanced this approach. They not only offer more precise age predictions but also integrate additional factors, including lifestyle biomarkers and phenotypic ageing measures. These advanced clocks are crucial for understanding the disparity between biological and chronological age, aiding in ageing research, disease prediction, and evaluating anti-ageing therapies. Their development represents a major advance in unravelling the molecular intricacies of ageing and the field of personalised medicine.

The pursuit of maintaining youthful skin and potentially reversing the ageing process is gaining substantial momentum in the skincare industry. This surge in interest aligns with a broader consumer shift towards prioritising healthy ageing, with longevity emerging as a focal point of interest. 

In light of this, our article seeks to delve deeper, offering detailed guidance on the critical factors to consider when selecting the most suitable epigenetic clock. This selection is vital for effectively validating the efficacy of anti-ageing interventions targeted at human skin, ensuring that these treatments are not only innovative but also scientifically grounded in their approach to combating skin ageing.

1. Use a clock in conjunction with gold-standard biomarkers to validate overall health

To effectively develop age-reversing skin interventions, it’s essential to establish a biomarker that accurately tracks age reversal. Companies involved in this field are combining epigenetic clocks with various clinical end-points, while also collecting detailed metadata during human clinical trials. In the context of skin trials, this involves conducting before-and-after assessments of wrinkle depth, capturing photographic evidence, measuring Trans-Epidermal Water Loss (TEWL), and evaluating skin elasticity. These methodologies are crucial for a thorough evaluation of the effectiveness of anti-ageing skin treatments.

A few recent studies measured the reduction of epigenetic age with oral supplements; for instance, vitamin D3, and other supplements have been shown to reduce the epigenetic age. The studies used second-generation clocks such as DunedinPACE and PhenoAge by correlating gold-standard biomarkers such as HbA1C, and creatinine with clock measurements. In some cases, a study show that second-generation clocks can even replace gold standard biomarkers with an epigenetic test for measuring inflammation.

2. Use a clock trained on facial skin

It’s important to note that epigenetics is tissue-specific. Therefore, when conducting studies on skin, it’s crucial to use skin samples to measure biological age. Using blood or saliva samples won’t provide an accurate epigenetic signal for the skin, as these tissues have different ageing markers and processes.

One limitation of using blood-based epigenetic clocks is the inherent diversity in cell compositions within the blood. This means that in longitudinal studies, changes observed in blood-based biomarkers might be indicative of alterations in tissue composition rather than ageing itself. For instance, biological age derived from blood could be significantly higher after a cold!

For skin, there is a big bonus. The clock can be trained on the accessible tissue to report biological age using clinical end-points on the skin (wrinkles grade, hyperpigmentation, hydration). To strengthen the value to the industry, skin tissue from the face could be used with a focus of validating many skin anti-ageing interventions.

Skin tissue, particularly from the face, is significantly affected by external factors such as UV exposure and pollution, which profoundly influence its biological age. Given these considerations, it’s crucial to understand that skin from other parts of the body does not age in the same way as facial skin. The ageing process varies across different body sites, with each area experiencing ageing at a unique pace, making them incomparable. Therefore, when studying skin ageing, the specific location of the skin tissue must be taken into account, as the factors impacting each area differ markedly.

We observed this in our previous study. We conducted a detailed analysis using skin samples from two distinct areas of the same individual: the back, which is typically protected from the sun, and the forehead, a region regularly exposed to sunlight. Our findings revealed substantial differences in methylation patterns of the top 100 CpG sites between the two sampling sites. This observation underscores the significant impact that varying levels of sun exposure can have on the epigenetic ageing of skin tissues in different body areas.

3. Use the same clock throughout trials

An additional challenge with using epigenetic clocks is the variation in calculated biological ages depending on the specific clock used. This is because each clock is calibrated using different CpG sites, making the calculated age a relative measure that varies with the chosen clock. For consistency, especially when assessing interventions on human skin, it’s advisable to use the same clock throughout the study. 

4. Beware of small effect sizes

While epigenetic clocks are highly accurate, they still have a limited accuracy in the region of 2-4 years. This is partly due to measurement error but other factors such as true biological variability may be at play. As we strive to measure someone’s biological age, it is likely that this will vary over time, sometimes being older than their chronological age and sometimes being younger. Presently there have been limited longitudinal studies to really understand how variable this could be. Therefore when looking at differences in epigenetic age due to some compound, its best to take a conservative approach with choosing those that give a large difference.

In essence, the reliability of different clocks can vary due to both biological and technical factors. The most effective and accurate clocks in the future will likely be those supported by substantial clinical data, top-tier instruments, and comprehensive metadata.


Mitra Bio developed a non-invasive skin diagnostics platform capable of measuring skin ageing.  We believe solving skin ageing could be a big boon to the field of ageing as it is a biomarker that is very visible externally. 

 At the moment biopsies are necessary to get good skin ageing measurements which makes clinical trials expensive and hard to recruit for. 

With cheaper/easier skin ageing diagnostics, we will start to see better data around the efficacy of potential anti-ageing dermatological treatments which may help both accelerate the development of such therapies and improve adoption once therapies are developed.


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