Archive for January, 2019

Ed and Gene’s genes? How do genes contribute to the longevity of a distance runner?

January 4, 2019

It is very likely that genes played an important part in the phenomenal performances of Ed Whitlock and of Gene Dykes, the only two individuals who have run a marathon in less than 3 hours at age 70 or more.  In my recent posts I have outlined their athletic careers (here and here).   What can we learn from them?  There is nothing we can do to change our own genetic endowment.  However, it is almost certain that Ed and Gene’s successes were heavily dependent on the way in which their training shaped the way in which their genes were expressed. Similarly, we can alter the way our own genes are expressed.  Even though we can only make informed guesses about what it was that transformed Gene and Ed into great marathoners, the available scientific evidence about the way in which the expression of genes can be modified by training allows us to draw some potentially useful conclusions.

The combined effects of multiple genes

The first noteworthy point is that it is unlikely that Ed and Gene’s longevity as distance runners was due to an advantageous version of a single influential gene. They were almost certainly each blessed in separate ways by a combination of many genes that each contributed to their success.   In a review of the evidence available a decade ago, Bray and colleagues concluded that over 200 genetic variations contribute to physical fitness and athletic performance.   Subsequent evidence has confirmed that multiple advantageous genetic variants contribute to various aspects of fitness, including the ability to benefit from training.    Of particular interest, Bouchard  and colleagues identified 39 sites in the human genome at which DNA variations are associated with the magnitude of increase in VO2max in response to a 20 week cycle ergometer training program  (3 times/week with sessions increasing in duration and intensity up to 50 minutes at  75% HRmax).   In that study, Bouchard examined only about 300,000 sites of DNA variation. It is important to note that they merely demonstrated an association between variation at 39 of these sites and the  response of VO2 max to training. Because genes that are located nearby on a chromosome tend to be inherited together, it is only possible to conclude that the genetic variation that was actually responsible for the increased training response was in the vicinity of one of the 39 sites.

With regard to the question of longevity as a runner, it is probable that genes associated with the  maintenance and repair of multiple body tissues play a crucial role.  These genes are likely to contribute also to overall life expectancy.  Therefore it is relevant to consider genetic variations that are associated with long life expectancy.  Again, the evidence suggests that many genes are involved.   In a study that compared 801 centenarians with a matched control group, Sebanstiani and colleagues identified 281 locations in the genome where variation is associated with the exceptional longevity.

Perhaps even more relevant to the question of our longevity as runners, Sood and colleagues examined the relationship between expression of genes and healthy aging.  Expression of genes is the translation of the DNA code into proteins that make up your body and control its function. The process of translating a strand of DNA into protein involves the production of a ‘messenger’ RNA molecule in which the sequence of coding letters (A,C,G and U) matches the sequence of coding letters (A,C,G and T) in the DNA strand.  The degree to which a gene is expressed in body tissues can be quantified by measuring the amount of the RNA corresponding to that gene. Sood and colleagues demonstrated that the amounts of each of a set of 150 different RNA messenger molecules isolated from muscle tissue provided a reliable predictor of healthy old age. The same set of RNA molecules derived from skin or brain tissue predicted healthy aging. In other words, the degree of expression of 150 genes in several different types of tissue, including muscle, is a good predictor of healthy aging.

 

Relevant genetic variations influence the effectiveness of common bodily functions

The second point is that it is likely that the relevant advantageous genes act by increasing the effectiveness of common bodily functions rather than providing novel functions that are unique to the individuals possessing those genes. The majority of genetic variants arise from differences in a single letter of the genetic code due to a mutation at some time in human history at a single location in the human DNA sequence.  Genetic variation due to such a mutation of a single letter in the code is known as a Single Nucleotide Polymorphism (SNP)

Not all of the DNA sequence is translate into proteins. Some stretches of DNA act to control the translation of those parts of the sequence that are translated.  The role of other regions of DNA remains unknown.  If a SNP occurs in a section of the DNA that codes for a protein, it can change the amino acid at the corresponding location in the specified protein.  This is known as a mis-sense mutation.  A mis-sense mutation is likely to produce a small change in the way that the amino acid chain that makes up the protein folds to create a three dimensional structure.  The change in the three dimensional shape of the protein is has the potential to change the effectiveness with which the protein performs its function.   However, even if disadvantageous, such changes rarely abolish the function of the protein. As we shall see there are ways in which life-style and training might compensate for the less advantageous version of gene.

If the SNP occurs in a non-translated section of DNA that nonetheless controls the translation of nearby DNA that codes for a protein, the SNP is likely to effect the amount of that protein which is produced in response to the various triggers that promote translation of DNA.  Again life-style and training might compensate for less advantageous versions of the gene.  Thus, in the case of the majority of the genetic variations that account for the differences between healthy individuals, there are ways in which we might partially or even fully compensate for a less advantageous version of the gene.

The expression of genes is modified by training

The practical issue for running longevity is that the expression of genes might be modified by training.  The key point to learn from the athletic careers of both Ed and Gene is that they each achieved greatness after a marked changes in their training.  As outlined on my previous posts, the thing that made Ed into a marathoner was the adoption of a program with multiple long slow runs each week.  Nonetheless it should also be borne in mind that his greatness was not limited to marathon: his 36 masters world records covered the distance range from 1500m to marathon.  In contrast, the turning point for Gene was the incorporation of high intensity training into his training schedule.  Nonetheless, the underlying foundation was his phenomenal ability to recover from intense training and frequent demanding racing.

It appears that there were both similarities and differences in the genetic endowments of Ed and Gene.  We do not know which specific advantageous genetic variations provided the foundation for their great performances. However, it is clear that their achievements were based not only on their genetic endowment but on their training. It is plausible, indeed probable, that their genetic endowment facilitated their response to training.  We are beginning to understand the role of several specific genes or groups of genes that mediate the body’s response to training.  It is potentially informative to examine the way in which the expression of these genes is modified by training, and to review the athletic careers of Ed and Gene in light of this.

Free radical generation during running: the Nf2 system.

During physical exercise, oxygen utilization typically increases by a factor of 10 to 20 in the active skeletal muscles.  The process of oxidation of fuel (either glucose of fats) in mitochondria, involves the transport of electrons between molecules, and inevitably results in the production of so called Reactive Oxygen Species (ROS) and other ‘free radicals’ that contain atoms of oxygen or nitrogen with unpaired electrons. By virtue of having unpaired electrons available for forming new chemical bonds, these ROS and other free radicals react strongly with nearby molecules. In particular, they are prone to attack any biological macromolecules especially DNA, amino acids, proteins and unsaturated fatty acids, in the vicinity.  This potentially damaging process is known as oxidative stress.

The body has several natural defences against oxidative stress.   The nuclear erythroid 2‑related factor 2  (Nrf2) pathway is a genetic pathway that leads to the switching-on of over 200 genes that serve a critical role in protecting against the cellular stress induced by exercise.  This defensive pathway is switched on by exercise.  For example, in a study of mice, Mei and colleagues demonstrated that eight weeks of aerobic exercise training lead to an increase in Nrf2 mRNA expression in the hind‑limb muscles. This suggests that graduated increase in aerobic exercise starting at low intensity might lead to enhanced defence against the potentially damaging effects of high intensity exercise. Furthermore an athlete with a variant of any of the many genes in this pathway that promoted more effective defence would be expected to gain especially enhanced protection against oxidative damage.

Protein synthesis:  the mTOR complex

mTORC1 is a protein complex that controls the synthesis of proteins.  mTORC1 activation plays a crucial role in the growth and repair of body tissues, including skeletal and cardiac muscle. Resistance exercise induces signaling cascades in skeletal muscle cells that result in the activation of mTORC1, and subsequently initiates muscle protein synthesis, thereby facilitating muscle hypertrophy.  Growth factors such as insulin play a key role in this anabolic process.

In healthy young people, aerobic exercise does not produce a strong activation of mTORC1.  However, in the elderly, muscle protein metabolism is resistant to insulin’s anabolic effect. This is associated with reduced insulin induced vasodilation.  Fujita and colleagues demonstrated that in a group of 70 year olds, a 45-min treadmill walk at 70% HRmax restored the anabolic response of muscle proteins to insulin during amino acid infusion 20 hours later.  It did this by improving the function of the endothelial cells lining small blood vessels, thereby promoting vasodilation and mTORC1 signalling.  This suggests that in the elderly, moderate intensity aerobic exercise may improve the muscle anabolic response during subsequent feeding.

However the overall effects of mTORC1 are complex.  It has been proposed that inhibition of mTORC1 (eg by dietary restriction) might enhance life expectancy by slowing the rate of depletion of stem cells.  But irrespective of the questionable effect of inhibiting mTORC1 on overall life expectancy, longevity as a runner almost certainly requires the minimization of age-related muscle loss, and hence mTORC1 signalling during post-exercise nutrition.

Myokines

Recent studies of messenger proteins excreted from muscle tissues have revealed a large number of proteins (approximately 250 in human muscle tissue) that exert wide-ranging, potentially beneficial effects on metabolism throughout the body.  These messenger molecules are known as myokines.  Aerobic exercise promotes the expression of the genes that code for many of these myokines.  One that has recently attracted attention as a mediator of the beneficial effects of endurance exercise on cardiovascular health is myonectin.  In a study of mice, Otaka and colleagues demonstrated that treadmill exercise increased circulating myonectin levels, and reduced cardiac damage associated with impaired coronary blood supply. This effect was not observed in mice lacking the gene for myonectin.   Furthermore they demonstrated that the beneficial effect of myonectin was abolished by blocking a metabolic pathway involved in inflammation.

DNA repair and protection of telomeres

Telomeres are RNA-protein complexes that serve as protective caps on chromosomes, protecting the DNA from damage during cell replication.  Usually telomeres become shorter with age, eventually reaching a stage where cells can no longer replicate.  Thus telomere shortening is potentially an important marker of aging.  However shortening of telomeres is not inevitable. Telomerase is an enzyme that acts to increase the length of telomeres.  Although the mechanism of telomere shortening or lengthening are only partially understood, it appears that low intensity aerobic exercise promotes the lengthening of telomeres.   In part this is probably partly due to the protection against oxidative stress (discussed above). In addition,  exercise promotes the expression of genes coding for proteins that repair DNA and protect telomeres.

Several studies reveal that endurance athletes tend to have longer telomeres.  For example, in a comparison of 67 ultra-marathoners with 56 healthy non-marathon runners,  Denham and colleagues  found that the ultra-runners had significantly longer telomeres

exercise_geneexpression

Effects of aerobic exercise on resilience, achieved by modifying the expression of genes involved in aging

 

The development of resilience

The genetic evidence we have reviewed so far demonstrates that aerobic exercise switches on the transcription of many genes that are potentially helpful in strengthening tissues and in protecting against damage due to oxidative stress. These are crucial achievements if one’s goal is not only to increase longevity as a runner, but also to achieve the resilience required to withstand the effects of impact forces generated by thousands of footfalls during a marathon.

The evidence from genetics indicating that low intensity aerobic exercise has a role to play fits well with the fact that both Ed and Gene included a lot of low intensity running in their training schedules (as described in my recent posts here and here.)   However the fact they coped so well to such training suggests that their genetic endowment included especially advantageous versions of relevant genes.  We do not know which of the genes we have discussed have multiple variants differing in the degree of benefit they confer.  However, it is very likely that there are functional important variants of at least some of these genes.

According to the report by the Ensembl genome database project, by December, 2016, more than 155 million unique variations in DNA sequence had been identified from the analysis of the DNA of more than 2,500 individuals.  It is estimated that there is on average one SNP for every 20-30 letters of the genetic code. As the number of letters of code required to specify a single protein ranges from about a thousand up to several million, there is a high probability that there are SNPs giving rise to variations in the proteins specified by many of the genes of interest.   In about 5% of SNPs the changes in the structure of the protein that have appreciable functional effects. Therefore it is plausible and indeed probable that Gene and Ed were each endowed with advantageous versions of the genes whose expression promotes enhanced resilience.

This is especially likely in the case of Gene. This would provide a plausible explanation for his phenomenal ability to recover from intense training and frequent demanding racing.   Favourable variants of genes promoting resilience would be expected to facilitate greater training volume  and in turn establish a virtuous circle promoting further expression of these genes and even greater resilience.

To paraphrase Gene’s own words, to become a better runner you must run a lot.  But perhaps on account of his genetic endowment, running a lot came relatively easily to Gene.  All that was necessary to enable him to run a lot was the determination to persist when his body cried out for rest. For those of us less well endowed, such determination would be likely to lead to disaster.   We need to be a little more shrewd in planning our training and adjusting our lifestyle.

I suspect that Ed was a little less well endowed with the genes that that promote resilience.  Nonetheless, he developed a training strategy that was optimised to build his capacity to withstand multiple training runs of three hours or more on consecutive days.  Ed’s cautious approach helped to keep him at the top of the word rankings for 18 years, from his 2:51 marathon at Columbus Ohio in 1999 at age 68, until his 3:56:38 in Toronto in 2017 at age 85, shortly before his death a few months later.

Enhancing VO2max and pace at lactate threshold

Traditionally the major focus in planning training for distance running has addressed the goals of increasing VO2max and increasing pace at lactate threshold.  The evidence we have reviewed so far has focused largely on genes that are likely to enhance resilience.  It is probable that low intensity exercise is optimal for this.  In contrast, there is abundant evidence that VO2max can be achieved more efficiently with more intense training.

As mentioned above, Bouchard identified 39 genetic variants that predict the response of VO2 max to standardized exercise training programs.   Ed’s multiple age group world records across a range of distances from 1500m to marathon suggest that Ed was more strongly endowed with favourable variants of the genes that influence trainability of VO2max. At age 70, he had a VO2max of 52.8 ml/min/Kg compared with the average of 35 for a 70 year old.   It is noteworthy that he had done a large amount of intense interval training in his 40’s and 50’s but over the 18 years when he set so many world records, his high intensity training consisted of participation in fairly frequent  5K to 10K races.  In contrast Gene only became an elite runner after he introduced a substantial volume of higher intensity running into his training schedule.  It is noteworthy that since turning 70, Gene has recorded life-time personal bests times at 1500m, 10K, HM and marathon. The questions of how long he will continue to improve and whether or not he will be breaking Ed’s records at age 85 is intriguing.

The balance between protection and harm

There is something of a paradox regarding the benefits of exercise on resilience.  In particular, the increased expression of genes associated with the Nf2 system that protects against oxidative stress (described above) is triggered by exercise that produces oxidative stress.  In other words, the increased protection against damage arising for oxidative stress is triggered by the stress itself.   You develop the protection against danger by exposing yourself to the danger.   The balance between protection and harm is likely to depend on appropriately graduated build-up of the training load.   Ed was very careful in building up his training volume via low intensity running after illness or injury.  Because high intensity exercise is associated with much greater stress, illustrated by much greater production of the stress hormones adrenaline and cortisol, getting the balance right with the higher intensity exercise employed by Gene is likely to be much more tricky.

At any point in your running career, the right balance is likely to depend not only on the genes you were endowed with at birth but also on past running history.  In Gene’s case, it is almost certain that he is endowed with favourable versions of multiple protective genes. As a result his performances are still on an upwards trajectory at age 70, based on training that would probably be damaging for many of us.  Before attempting any further speculation on Gene’s likely future trajectory, we need to look more closely at the evidence regarding both local muscle damage and repair, and whole-body processes including hormonal influences and inflammation that are likely to play a key role in longevity.  I will address those topics in future posts in this series.

Implications for less gifted athletes: assessing the balance.

Speculation about the nature of the genetic endowments of Ed and Gene is of interest because it provides some insight into possible reasons how they were able to achieve the target of running sub-3 hour marathons in their 70’s. It also helps us identify potentially important commonalities in their training, and provides some pointers to the issues to consider if we wish to emulate their training.  However, for most of us, the practically important thing about genes is not the differences between individuals in their genetic endowments, but the fact that the expression of genes varies greatly over time within an individual.  Many of the factors that influence gene expression are under our own control. Most importantly, exercise is a powerful modulator of gene expression.

In the past, much of the emphasis on planning training for distance running has been on maximizing VO2max and increasing speed at lactate threshold.  However the evidence that training influences gene expression provides us with a clearer understanding of how low-intensity training might enhance the resilience that is crucial for withstanding the thousands of potentially damage impacts at footfall  during a marathon, and also crucial for optimizing running longevity.

Nonetheless the current level of understanding of the effects of training on gene expression is rudimentary.  While the current evidence does provide an understanding of why it is beneficial to run a lot, it also highlights the paradox that developing protection against damage requires exposing yourself to the risk of damage.  The evidence we have considered so far implies that an appropriately graduated build of training load is essential.  It provides a clear rationale for the base-building advocated by Arthur Lydiard on the basis of personal experience more than sixty years ago.  However before we can advance beyond the lessons based on Lydiard’s intuition we need a better understanding of how to achieve the balance between benefit and harm.  We will return to address this question after our more detailed examination of the mechanism of tissue damage and repair.

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Plans for 2019

January 1, 2019

Happy New Year.

Thanks to all who have continued to read my posts during the past year.   Despite the fact that I posted only twice in 2017 and 5 times in 2018, it appears that you, my valued readers, have not given up.  There were 36,139 page views  in 2017 and 33,733 in 2018, placing these two years among the top three since I started blogging 11 years ago.

In part the paucity of my posts in recent years has been because the energy invested by the running community in the vigorous debates of the preceding decade about issues such as running style and running shoes has almost fizzled out. Meanwhile other interesting aspects of science have continued to advance. In particular, the evidence that exercise is one of the most effective ways to enhance health and wellbeing has become increasingly compelling. Much of this evidence is relevant not only to health and well-being but also to training to achieve optimum performance.   Therefore, there is much to write about.  I hope that in 2019 I will find time to post more frequently.

In my posts in the final months of 2018 I compared and contrasted performances and training of Ed Whitlock and Gene Dykes.   The differing career paths followed by Ed and Gene have prompted me to review again the question of the optimum way to achieve longevity as a distance runner

This is a topic I have discussed at length on this blog in recent years.  It is time to return to it, not only because of the different trajectories of Ed and Gene, but also because the past few years have been a fertile period in the study of relevant basic biology.   I anticipate covering the topic in a series of several posts:

  • The role of genes
  • The role of satellite cells
  • The role of inflammation
  • Hormones and the autonomic nervous system
  • The enigmatic role of mind and brain

While I hope this intricate scientific story will prove fascinating in itself, I will nonetheless attempt to remain anchored to the evidence presented by the stories of great distance runners, not only the veterans, Ed Whitlock and Gene Dykes, but also some of the ‘younger’ runners who set the standards for distance running in the 21st century, especially Haile Gebreselassie and Paula Radcliffe.