The Epigenetic Edge: Exploring Fitness, Aging, and Science with Prof. Nir Eynon during The Aging Science podcast by VitaDAO

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In this episode of the Aging Science podcast I talked with Prof. Nir Eynon (@nir_eynon). We touched on many topics, including elite athletes, how COVID affected working culture (for the better), the benefits of tabatas, epigenetic and muscle clocks and how they are affected by exercise, biases in research and the role of meta-analysis. I hope you will enjoy this episode as much as I did.

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Short Bio – Nir Eynon

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Nir earned his PhD degree with high distinction in 2010 from Porto University, Portugal. Early during his career, he was studying the genetics of elite athletes before switching to aging research and epigenetics.

His work on aging brought him to Victoria University where he became a program leader, at the Institute of Health and Sport (iHeS). Among other things, at Victoria he now runs the Gene SMART study on exercise through which his team aims to uncover the genetic and epigenetic responses to exercise.
https://www.vu.edu.au/institute-for-health-sport-ihes/research-areas-in-ihes/mechanisms-interventions-in-health-disease/muscle-exercise-movement/human-gene-smart-study

Let’s keep in touch - the Australian Physiological Society Meeting and more

Before we talk about epigenetics and exercise a few housekeeping notes.

Nir asked me to promote this year's AuPS Annual Scientific Meeting (@AuPhysiolSoc) which will be held in Melbourne on 26-29 November 2023. This, I am sure, would be a great opportunity to meet Nir personally so please attend if you can. I will also keep an eye on this meeting and hopefully there will be other Australian aging researchers attending. In particular I would be keen to meet with Rene Koopman who has published excellent work on iron dyshomeostasis and age-related muscle loss (Alves et al. 2021).

Would be lovely to run into other aging researchers or longevity enthusiasts there. In the meantime I suggest you can follow us on these channels if you have questions or speaker suggestions:

VitaDAO twitter account: @vita_dao
VitaDAO discord channel: https://discord.gg/vitadao
My own twitter account: @Aging_Scientist
VitaDAO telegram: https://t.me/vitadao

What is epigenetics?

The term epigenetics describes a form of gene regulation that relies on modifications to the (chemical) structure and organization of DNA and chromatin. This is in contrast to genetics which deals with changes to the DNA sequence itself.

Epigenetic marks are a type of modification that is attached to DNA that help genes to be expressed at the proper time. There are two major types of epigenetic marks, those found on histones and those found directly on the DNA. Histone modifications are highly diverse, whereas regulatory DNA modification is largely limited to the methylation of cytosines.

The different epigenetic marks are recognized by reader proteins that affect gene expression. Although these marks can have complex effects, some broad patterns are evident, like for example repression of transcription through CpG methylation.

Although methylation serves an important regulatory role, it turns out not all species have methylation at CpG sites. Bacteria have a different type of DNA methylation whereas C. elegans seems to have lost this feature altogether during evolution (2). That is one of the things I learned in this podcast!

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The rise of epigenetic clocks

When we age so does our epigenome and one way to measure this epigenetic aging is through so called DNA methylation clocks. Many studies, initially pioneered by Steve Horvath, have shown that methylation at certain sites in the genome can be used to construct a clock that closely tracks the passage of time.

These clocks are exciting because they are much better at predicting chronologic and biologic age than the biomarkers we used to have. In fact, I still remember going to conferences and listening to talks that painted a rather disappointing picture of blood based aging biomarkers (e.g. based on the MARK-AGE project [2]).

These clocks are also exciting because they promise to become a surrogate endpoint for medium sized phase II-like studies. A surrogate endpoint is a cheap, easy-to-measure marker that substitutes for something else more expensive. The hope is that a slowing of epigenetic aging in small studies would be predictive of success in larger trials that focus on harder outcomes like health and survival. If true, this would push down the cost of trials by orders of magnitude because we could pre-select promising compounds before going into large studies. However, even the best surrogate endpoints like LDL or HDL cholesterol cannot substitute for large studies, as the countless failures and disappointments in the clinic show (e.g. CETP-inhibitors for atherosclerosis and the clinical failure of most non-statin drugs).

Another reason why clocks are important is their link with the biology of aging. Understanding why methylation at certain sites changes and what harmful effects these changes have, could improve our understanding of aging and allow us to find new therapies. To give an example of such advances, as mentioned in a prior podcast, the study of epigenetics has uncovered not only the importance of entropy in the process of aging, but also ways to reset some of these age-related changes (partial reprogramming). Nir is also interested in understanding sex differences in epigenetics as well as the effects of exercise on epigenetics. This could be very important since we still cannot fully explain why women live longer than men, much less on the epigenetic level.

However, there is a world of epigenetics beyond clocks, as Nir mentioned during the podcast. He is very interested in studying sites that are not commonly selected to build clocks because these could still have important functions that are being neglected.

Biases and problems in research

"Better take your chances when young" (Nir Eynon)

We discussed two large problems in research, one was the lack of diversity in the choice of our research subjects and the second one were the working conditions for scientists.

Historically, clinical trials have included predominantly Caucasian white males. This underrepresentation of minorities and women has obvious negative consequences because the therapies and clinical practices developed for white men may not translate to other groups (also known as lack of external validity). Interestingly, the same issues plague mouse research. Many studies use one strain of mice, therefore not representing the true genetic diversity of the species and in the past most studies used almost exclusively male mice of one common strain.

In his research Nir seeks to correct these biases by recruiting at least 50% female participants for his studies. This will allow him to better understand the epigenetic differences between men and women. 

As for the second point, poor working conditions, we specifically talked about the difficulties that parents and couples face. In fact, scientists are often expected to move across the globe in search of a lab that is a good fit for them and to further their career. Modern science is extremely specialized so only a couple of labs across the whole globe may be working in your niche. Therefore, it is almost impossible to be successful without moving from position to position and country to country.

Given this, it is almost surprising that people are still willing to work as scientists. Very few jobs in the world demand constant relocation, combined with low pay, long working hours, high pressure and mediocre job stability. In our conversation with Nir we explored ways in which this is improving and what career path might be most suited for those who cannot or do not want to relocate (I won’t spoil the answer). 

Exercise and Aging - facts, controversies and open questions

I think Nir is doing brilliant work trying to figure out how exercise affects the epigenetics of aging but I would like to provide an interesting perspective worth discussing.  Does exercise really slow aging? I think some of the data Nir mentioned himself is consistent with the idea that it does not.

However, whether we believe that exercise actually slows aging or that it “only” has tremendous benefits for age-related health, we all agree that exercise is very important.

From a public health perspective exercise is still the holy grail, but from gerontologic perspective I think exercise is a bit oversold (2).

The other issue with exercise is compliance. No matter how healthy it is, many people do not have the time or motivation to actually go out and exercise. We need exercise in a pill and this is where Nir's research comes in and that of other exercise researchers. Although drugs will never fully recapitulate the benefits of exercise, we will nonetheless be able to reap some of the benefits of regular exercise if we gain an understanding of the molecular changes underlying exercise adaptation.

“I think at the end of the day, scientists that are working in aging, the differences in opinions between everyone are not that large. We want to think that they are very large and very big. But it's all nuances. Because at the end of the day, we want people to be healthy for a long time. That's the goal.” (Nir Eynon)

References

Weinhouse, Caren, et al. "Caenorhabditis elegans as an emerging model system in environmental epigenetics." Environmental and molecular mutagenesis 59.7 (2018): 560-575.

Alves, Francesca M., et al. "Iron accumulation in skeletal muscles of old mice is associated with impaired regeneration after ischaemia–reperfusion damage." Journal of Cachexia, Sarcopenia and Muscle 12.2 (2021): 476-492.

Notes

1/ There appears to be some genuine controversy whether C. elegans shows no methylation or whether they do have adenine N6 methylation (6mA).

Greer, Eric Lieberman, et al. "DNA methylation on N6-adenine in C. elegans." Cell 161.4 (2015): 868-878.

Also: https://pubpeer.com/publications/B024A9B1AFF2ED7E69DB745662382B?utm_source=Chrome&utm_medium=BrowserExtension&utm_campaign=Chrome

2/ The idea that exercise does not affect aging rate is based on studies in mice that fail to show lifespan extension with exercise and a rather pessimistic reading of the outstanding rat literature by John Holloszy. While in his studies he did usually find that exercise led to a modest extension of median lifespan in rats, this increase was lower than for caloric restriction. Furthermore, there was no improvement in maximal lifespan with exercise which led him to argue that exercise does not slow the aging rate. However, this might be over-interpretating the absence of a signal since maximal lifespan is notoriously difficult to measure due to dwindling sample sizes at old ages; and its use as a marker of aging rate remains somewhat controversial.

Garcia-Valles, Rebeca, et al. "Life-long spontaneous exercise does not prolong lifespan but improves health span in mice." Longevity & healthspan 2 (2013): 1-12.

Holloszy, John O. "Mortality rate and longevity of food-restricted exercising male rats: a reevaluation." Journal of Applied Physiology (1997).

3/ My intuition is that you can construct a clock using any type of dataset, be it epigenetic, transcriptomic, proteomic or using plasma proteins as was tried in the MARK-AGE study. However, the missing link was the combined use of multiple markers. No epigenetic clock uses a single site and it was a mistake to look for a single best blood biomarker of aging. The idea of using composite clocks is one of the big breakthroughs.

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