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Longevity Briefs: Measurements Of Ageing Say You’re Younger At Midnight – Here’s Why That’s A Problem

Posted on 1 May 2024

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Longevity briefs provides a short summary of novel research in biology, medicine, or biotechnology that caught the attention of our researchers in Oxford, due to its potential to improve our health, wellbeing, and longevity.

The problem:

If we want to study the biological process of ageing, we need a way to measure it. The most common way to estimate how quickly someone is ageing involves measuring epigenetic alterations. These are changes made to the DNA that affect how it is read without affecting the genetic code itself. Since epigenetic changes correlate with age, algorithms called epigenetic clocks can be used to estimate how quickly an individual person is ageing by comparing their epigenetic profile to the population average. However, these techniques aren’t perfect. For example, epigenetic changes progress differently in different tissues, but most studies rely on blood samples to estimate rate of ageing, providing an incomplete picture. According to this new study, it appears that some research may also be overlooking a crucial variable: the time of day at which measurements of epigenetic age are made.

The discovery:

Scientists discovered that measurements of epigenetic age in white blood cells can fluctuate based on the time of day. The research began with a single 52-year-old man from whom white blood cells were collected every three hours over a period of 3 days. They tested 17 different epigenetic clocks and found that 8 of them gave significantly different estimates for epigenetic age over the course of the day. These included some of the most commonly used clocks such as GrimAge2 and the Horvath clock, the latter of which measured the man as being 3 years older at noon than at midnight.

Changes in predicted epigenetic age throughout the day, according to three different epigenetic clocks. The Horvath clock (a) and GrimAge2 (c) predict age in years. The epiTOC2 clock (b) outputs a different unit based on the estimated number of cell divisions.
Epigenetic age oscillates during the day

The researchers were able to confirm these findings by re-analysing data from another study of around 30 people, which confirmed that some epigenetic clocks give higher estimates for epigenetic age around noon. They hypothesised that this could be due to fluctuations in the proportions of different types of white blood cells throughout the day. Sure enough, further analysis showed that T and B cells were more abundant in the blood at midnight, and that these cells also gave lower estimates of epigenetic age than other types of white cells that were more abundant at noon. However, when the researchers looked at specific types of white cells, they still found that epigenetic age changed throughout the day within these subgroups, suggesting that epigenetic alterations that occurring throughout the day are also responsible for the variable measurements given by epigenetic clocks.

The implications:

It’s no surprise that epigenetic changes occur on a daily basis – epigenetic alterations play a central role in regulating the body’s response to the day/night cycle. What this study shows is that some epigenetic clocks relied on by scientists to measure ageing are using these same time-dependent epigenetic alterations to make their estimates.

The research suggests that the time of day should be taken into account to avoid misinterpreting the effects of interventions on ageing when certain epigenetic clocks are being used. Imagine for example a study that finds that people who exercise for three months reduce their epigenetic age by a year, while those who do not exercise experience no significant change. Given that some epigenetic clocks appear to fluctuate in their estimate by 3 years or more over the course of a 24 hour period, such a result might easily be explained by the time of day at which measurements were taken, not by the exercise intervention.

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    Epigenetic age oscillates during the day

    Title image by Jon Tyson, Upslash

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