New research from a team of respected researchers at the company Intervene Immune, Stanford, the University of British Columbia, and UCLA suggests that epigenetic age can be reversed, providing hope that there might be ways for humans to take steps to live longer and healthier lives.
This article covers what epigenetic age is and how it’s measured, summarizes the findings in the recent scientific publication, and discusses what’s next in the exciting research area of epigenetics and aging.
What are Epigenetic Clocks?
Epigenetic clocks are a measure of biological age and can be used to determine or estimate the chronological age of humans or other organisms based on molecular testing. Epigenetic clocks usually involve testing for certain patterns of DNA methylation. While the ages estimated by epigenetic clocks often correlate very well with chronological age, it is not clear whether the DNA methylation profiles in the clocks directly contribute to the aging process.
Age-related changes in epigenetic modifications, and DNA methylation, in particular, have been observed for decades. However, the idea of “epigenetic clocks” and being able to predict chronological age based on patterns of DNA methylation was first proposed by Steve Horvath and started gaining popularity following his 2013 paper on how to determine DNA methylation age in the journal Genome Biology.
Some real-world applications of epigenetic clocks include their use in forensic studies to determine the age of an unknown person from blood or other biological samples at the scene of a crime, tests to determine the age of undocumented refugees or immigrants, and diagnostic screens to determine increased risks for diseases of aging, including various types of cancers.
Epigenetic clocks can also highlight whether certain behaviors or treatments have an impact on epigenetic age. For example, unhealthy behaviors like smoking and poor diet can accelerate your epigenetic or biological age, and healthy behaviors like exercise and certain therapeutic approaches can slow or potentially reverse the epigenetic aging process.
How Well Does Epigenetic Age Correlate with Chronological Age?
The primary reason that using epigenetic clocks and DNA methylation age estimations have become so popular is that they correlate extremely well with the chronological ages in the subjects tested.
The original epigenetic clock that Steve Horvath published in 2013 included 353 individual CpG sites that were identified from previous studies performed using Illumina’s 27K and 450K Infinium BeadChip array technology. Of these sites, 193 become more methylated with age and 160 become less methylated, and a computational algorithm that uses a weighted average of the DNA methylation status at these 353 sites leads to the DNA methylation age prediction that is the basis of the epigenetic clock.
Across all test data, including all ages of subjects and all sample types, Horvath observed a 0.96 correlation between the epigenetic age he calculated and the true chronological age, with an error rate of 3.6 years.
Newer and better clocks are also being evaluated using specific sample types and additional or different CpG sites in efforts to improve age prediction and the diagnostic or prognostic abilities of these tests. For example, the initial epigenetic clock that Horvath developed was using a many different data sets, but these data sets contained a relatively limited amount of DNA methylation data because they were generated using older array-based technology rather than next-generation sequencing (NGS). Further efforts using NGS approaches have the potential to improve epigenetic clocks, making them more comprehensive by extending the analysis of methylation sites to potentially all CpG sites in the genome.
Can Epigenetic Clocks Be Turned Back So We Can Live Longer?
Previous studies have demonstrated that certain tissues, such as breast tissue in women, and certain disease states, such as cancer and progeria (a disease characterized by accelerated aging), result in different “ticking rates” of the epigenetic clock. These observations suggested that the epigenetic clock is dynamic and that it can change under certain conditions. Therefore, it is possible that the clock can be manipulated through changes in behavior or treatment strategies to slow it down or potentially reverse it, allowing humans to live longer and healthier lives.
A recent study published in the journal Aging Cell from a team of researchers reported on the results of a clinical trial that was designed to slow or reverse the epigenetic clock. This study used a therapeutic treatment approach that involved a cocktail of three drugs that were given to target the thymus because this tissue is known to shrink with age, a phenomenon referred to as thymic involution. Thymic involution leads to immunosenescence, which is essentially the immune system slowing down and is linked to increases in several age-related diseases including cancer, increased occurrences of infectious diseases, and autoimmune conditions.
Epigenetic Aging Reversal Clinical Trial Design
The treatment cocktail used in the clinical trial included recombinant human growth hormone (rhGH) to reverse or slow down the immunosenescence, and two other diabetes drugs, DHEA and metformin, to counter some unwanted side effects that could be caused by increased insulin production as a result of the rhGH treatment.
The study was relatively small, it included 10 healthy white men aged 51-65, but one subject did not complete the trial, so the trial had a total of 9 participants. It’s hard to make big conclusions from the results of the trial data based on its size, and the fact that there were no control or placebo groups, but the results were generally very positive and the side effects of treatment were minimal.
Results of the Epigenetic Aging Reversal Clinical Trial
The researchers observed an increase in the size of the functional thymic mass following treatment, which is consistent with a reversal of immunosenescence. There were also other results that suggested the immune system was being rejuvenated, such as a small but statistically significant increase in the number of bone marrow cells, and increases in the ratios of lymphocytes to monocytes.
Perhaps the most interesting finding of the study was that after 12 months of participation in this clinical trial, the subjects on average showed a decrease in their epigenetic age of 2.5 years. This means that after the one-year trial, their epigenetic age was 2.5 years younger than when they started. This result was surprising – the study authors thought that the aging process might be slowed as a result of the trial, but such a reversal in aging was unexpected.
What’s Next for Epigenetic Clocks and Aging Research?
As mentioned previously, while the results of this study are exciting, more research is clearly needed with larger study cohorts, additional groups of subjects from wider demographic and ethnic backgrounds, as well as control groups in the studies.
We expect the research at the interface of epigenetics and aging will continue to increase in the next few years. It seems likely that more research groups will contribute to the development of additional epigenetic clock biomarkers using next-generation sequencing and other state-of-the-art technologies. Furthermore, translational researchers will almost certainly initiate additional clinical trials in the future using other therapeutic approaches to slow or reverse the ticking of our epigenetic clock to promote longer and healthier lives.
Aging and age-related diseases create a huge burden on our public health system, and increasing problems related to population aging have the potential to severely impact many areas of our lives, including healthcare, social issues, and psychological wellbeing. Therefore, a more detailed understanding of the aging process will help our society adapt to and potentially solve these problems.
While it’s unclear what the solutions will be, it seems almost certain that epigenetics and epigenetic regulation will be involved. Active Motif will be watching the developments closely, and we will continue to develop the next generation of products and services that will be necessary to fully understand the epigenetic clock and the aging process.
(c) 2019 by Active Motif