The age-old battle of nature versus nurture has entered new frontiers with two exciting studies exploring different mechanisms that drive “epigenetic rejuvenation” – also known as the science of how our old and creaky DNA methylation-based epigenetic clocks can be wound back into a frolicking and fancy-free state.
Together, these studies demonstrate the two faces of the epigenetic clock. The first of our time-traveling studies in this rejuvenation face-off takes inspiration from nature and studies the dynamics and mechanisms associated with the rejuvenation of DNA methylation profiles in the cells of the early mammalian embryo. Meanwhile, our second study in this epigenetic battle-royale follows a more nurturing approach to discover whether diet and lifestyle changes could rejuvenate DNA methylation profiles and turn back the epigenetic clock during adulthood!
Deciphering the Process of Epigenetic Rejuvenation during Embryogenesis
While rejuvenation may seem like a fantasy plucked out of a sci-fi flick (Cocoon comes highly recommended!), restorative research provides evidence for natural rejuvenation processes occurring at the epigenetic level during mammalian embryogenesis. For example, the rejuvenation of the germline in mammalian offspring removes any deleterious aging-associated changes passed on by parents and returns epigenetic aging to “ground zero” during early embryogenesis to prevent accumulated damage from affecting future generations.
To explore this epigenetic rejuvenation event, an ever-green team of researchers led by Vadim N. Gladyshev (Brigham and Women’s Hospital/Harvard Medical School, Boston, MA, USA) recently employed a range of epigenetic clocks to explore the dynamics of epigenetic aging during mouse and human prenatal development, given the successful application of epigenetic clocks to the analysis of aging in human fetal development using tissues such as the brain, retina, and cord blood. Fascinatingly, the young whippersnappers from the Gladyshev lab now reveal some fascinating insights into the dynamics and the mechanisms involved in the rejuvenation of DNA methylation profiles during the very early stages of mammalian embryogenesis.
Tick-tock, tick-tock. Let’s hear more about this exciting new study from Kerepesi and colleagues before our ears and eyes start failing:
- The application of various epigenetic aging clocks and a newly developed multi-tissue ribosomal DNA methylation clock enables the evaluation of epigenetic aging in human and mouse DNA methylation datasets
- The lowest epigenetic age occurs at the post-implantation stage of early embryogenesis, indicating the existence of a rejuvenation event
- This “ground zero” of epigenetic aging lies between E4.5 to E10.5, most probably corresponding to embryo gastrulation (the formation of the specific cell layers from the blastula)
- Subsequent organismal aging begins to increase during mid-embryonic development in both mouse and human
- A comparative analysis of pluripotent stem cells revealed a low epigenetic age that didn’t increase with extended in-vitro culture times
- The relative epigenetic ages of naïve and primed embryonic stem cells suggest that they may serve as a model for the early and late embryo, respectively
- The authors evaluated epigenetic aging in DNA methyltransferase (DNMT)-1 single knockout, DNMT3A and DNMT3B double knockout, and control mouse embryos at E8.5 to explore the factors involved in epigenetic rejuvenation
- All knockout embryos display an increase in epigenetic age, thereby suggesting a pivotal role of DNA methylation maintenance and de novo methylation during rejuvenation
- Knockout of the Ten-eleven translocation (TET) enzymes associated with DNA demethylation fails to reveal a similar effect
Overall, this exciting study describes the natural rejuvenation events that occur during early development and the onset of organismal aging during embryogenesis. Will this information prompt the development of advanced anti-aging therapies that could remove all your epigenetic wrinkles and grey hairs? Let’s all hope we see the fallout of this youthful study before time makes fools of us all!
Putting Diet and Lifestyle-induced Epigenetic Rejuvenation to the Test
A good healthy meal, a bit of exercise, and a sound sleep always feel rejuvenating the following day, but is the fuzzy feeling from a little extra self-nurturing reflected in our epigenetic ages, where it really counts? Interestingly, previous uncontrolled studies in healthy men, Polish women, and overweight or obese African Americans suggested that dietary restrictions and a range of dietary supplements may run back the Horvath DNAmAge clock by a significant amount.
Now the lean, mean, epigenetic machines from the lab of Ryan Bradley (University of California, San Diego) sought to more comprehensively evaluate how a regimen of diet and lifestyle interventions positively impacts epigenetic aging in a randomized controlled clinical trial in forty-three healthy adult males between the ages of 50-72. While the control group received no interventions, the experimental cohort underwent a wide-ranging eight-week program that included diet, sleep, exercise, and relaxation guidance, as well as supplemental probiotics and phytonutrients. Yum!
So put the soda and chips down, and let’s pick up all the details of this exciting new trial, as reported by Fitzgerald and colleagues:
- Analysis of epigenetic aging using the Horvath DNAmAge clock and genome-wide DNA methylation profiles from saliva samples generated using the Illumina Methylation Epic Array demonstrate reduced epigenetic age in the experimental cohort
- Changes to diet and lifestyle prompt a 3.23-year decrease in DNAmAge when compared to the control cohort
- Individuals in the experimental group possess an epigenetic age almost two years younger compared to themselves at baseline
- Control patients exhibit a non-significant increase in their epigenetic age of 1.27 years
- Overall DNA methylation levels at the 353 CpG sites evaluated in the Horvath DNAmAge clock did not differ between the experimental and control group
- Instead, diet and lifestyle changes prompt a rearrangement of DNA methylation patterns to create a more youthful profile
- Analysis of blood biomarkers revealed a correlation between diet and lifestyle changes with increased serum 5-methyltetrahydrofolate and reduced triglyceride levels
- Markers of emotional health do not change, although the authors find a non-significant increasing trend for reduced anxiety scores in the experimental group
Overall, this first randomized and controlled trial of specific diet and lifestyle interventions suggests a potentially effective means to reverse epigenetic aging in healthy middle-aged men. While we wait for the authors to confirm their findings in larger-scale and longer-duration clinical trials and other populations, let’s hit the gym, meditate a little, and watch what we eat!
Nature versus Nurture – Everyone Wins?
The outcome of this nature versus nurture face-off is a resounding win-win – while we have shed more light on epigenetic rejuvenation during embryogenesis, these findings also suggest that traveling back in time (at the epigenetic level, of course) may be as simple as switching the burgers for bulgur and swapping the couch for the climbing wall.
For more on the rejuvenating skills of early embryos, see Science Advances, June 2021, and to find out the exact recipe and way of life required to turn back your epigenetic clock, see Aging, April 2021.