Health Benefits of Running by Craig Lewis, MD

My friend and ultrarunner Dr. Ben Lewis forwarded this article to a few of his friends last week. His father wrote this originally for Central Maine Striders Newsletter, and has given me permission to post here.


Health Benefits of Running by Craig Lewis, MD
I have been collecting health-benefits-of-exercise articles for five decades.  But 2012 has been the Holy Grail.
Things had become embarrassing.  In recent years the health-benefits information has become so good that no reasonably skeptical person would believe it.  It is almost as if God herself  must be a runner and therefore wants to reward her special friends, fellow runners.  Why would Nature care so much whether or not we exercise?
But I no longer need to resort to metaphysical explanations.  I now, finally, understand why Nature demands that we exercise aerobically.  The explanation depends on our prehistory.  In fact, it dates back 500 million years.
In this country during this era we do not experience hunger or famine.  In the US even if a new Dust Bowl occurs, we will merely import our food from Brazil.  Perhaps we would not be so lucky if we lived in Somalia or Mozambique.  But through all of Earth’s  history there has been periodic bounty and cornucopia of food choices at times, and blight, drought, or just bad hunting at other times.  All species, and all multicellular organisms, not just humans, and not just animals, must have a strategy for dealing with an environment that is alternately generous and sparse.
Mediating over this fickle and often cruel world is an enzyme complex called TOR (Target of Rapamycin).  Just as the hormones insulin and insulin-derived growth factor regulate extracellular body resources, TOR controls intracellular resources.  Yeast TOR and human TOR are nearly identical.  When genes do not mutate much over half a billion years, then those genes necessarily serve some essential function.
Telomeres cap the ends of chromosomes

When the rains are good and the food gathering goes well, enzymic TOR activates.  When food supplies are abundant, organisms must stock up in anticipation of the next, say, poor hunt.  It is TOR that performs this service.  When TOR turns on, cells multiply (expending telomere length, unfortunately), organs regenerate and grow, fat cells plump up.  And it makes sense that during these good times, cell housekeeping functions are postponed.

When the DNA of cells is heavily mutated from a variety of sources, such as cosmic rays, PCBs, muon showers, or X-rays, or when cells expire their telomeres, those cells become nonfunctional.  We call them “senescent cells” or “zombie cells.”  Mutated cells present a potential existential threat because they are especially prone to malignant transformation.  These damaged and useless cells must be cleared away and there are simple systems available to allow them to undergo self-suicide, hari-kari, if you will, for the sake of the whole organism.  But if the body is anticipating the next famine, TOR instructs these cells to delay their self-immolation.  After all, in a period of hunger, these useless cells make good eating.  In times of hunger it is preferable to consume senescent cells rather than functional vital organ cells.  Recent human history is the only time in the history of our planet that organisms can traverse an entire lifetime and never once perform this essential housecleaning function.
When TOR is activated for long periods, senescent cells accumulate in all organs.  They sit there and release inflammatory mediators.  They sap the strength of muscles and make them sore.  If you’ve ever wondered why your pitiful nonrunning friends complain bitterly during a 200 yard jog, this is the explanation–their muscles are laden with senescent cells.  It is as if they all have fibromyalgia.
It is not just senescent cells that demand cleaning up.  Mitochondria, the cell powerhouses, gradually undergo oxidative damage.  Their cristae become ratty.  Activated TOR blocks the disposal of damaged mitochondria.
When the protein beta-amyloid misfolds in brain neurons, this protein and tau protein gum up neurons, which undergo degeneration and eventually die.  Eventually, Alzheimer Disease or other neurodegenerative syndromes ensue.  By the time most Americans are 25, tau and beta-amyloid are starting to accumulate.  By the time most Americans are 40, sulci, the spaces between their brain folds, are starting to widen.  These neurodegenerative diseases are a horrible waste.   As long as TOR is switched on, the body postpones clearing away beta-amyloid and tau protein.  Thus, the brains of your nonrunning friends, who don’t experience this cellular cleaning, are a veritable nightmare.
When starvation intervenes, TOR is switched off and these saved up resources start to be used.  It is as if a vacuum cleaner has been switched on.  Senescent cells, deformed proteins, and decrepit mitochondria are swept away.  And when TOR is off, then cell multiplication is kept to a minimum, preserving precious telomere length, thereby improving longevity of the individual.  You will recall that distance runners have 1/3 the telomere velocity of nonrunners.  Older runners have much longer telomeres than others do and this accounts in part for 16 years of greater longevity, their relatively youthful appearance as they age, the minimization of the period of disability during extreme age, and because of preservation of the immune system, some 20-fold decrease in infectious disease death rate.
Presumably, we could reap the benefits of a low-TOR state by perpetual near-starvation.  But this is nearly impossible to do and is extremely unpleasant.  What good would it do to live longer if you’re miserable?  Have you ever seen a person with anorexia nervosa smile? And a just-released primate study showed that  extremely low calorie diets did not improve longevity.  Perhaps the stress of daily hunger counteracted any potential longevity gain.  Whether periodic fasting would work remains to be shown–I suspect it might.  But if fasting does work, then how often and how long?
Running and aerobic exercise trick the body into thinking that it is resource deficient.  Running switches TOR off.  But unlike starvation, running makes us feel good, not bad.  And folks on extremely low calorie diets cannot run–they have no energy. 
Minimizing cell division and preserving telomere length may be a good overall strategy, but this might not work in all organs.  Especially in the brain it is important  to maintain new neuronal growth throughout our lives.  Because  low-TOR  blocks cell division, brains must have separate mechanisms to allow cell division even if TOR is low.  This is why the brain releases neuronal growth mediators during aerobic exercise.  There is actually an overcompensation.  I am a runner:  My hippocampi (responsible for short term memory) are the size of walnuts, shell on.  My nonrunning friends have hippocampi the size of pistachio nuts, shell off.  My neuronal mitotic index throughout my neocortex, but especially in my frontal lobes, is 3 times higher than for my friends.   Because cell division in brains is so much less than in other organs, telomere exhaustion is not an issue for brains as we age.
An enormous percentage of our population suffer depression.  Many of these folks are treated with SSRI’s–serotonin reuptake inhibitors– such as Prozac.  It has been believed for a long time that their mechanism of action is that they boost the concentration of serotonin in some synapses.  The inconvenient truth here, however, is that naturally there is a down regulation of post-synaptic serotonin receptors.  But there is now reason to believe that SSRI’s actually do their work by promoting neuronal growth, especially in the hippocampi.  It has always been true that a far more effective method of treating depression than medication has been daily aerobic exercise.
Until now our explanation for the necessity of exercise for the maintenance of health has been a hand waving  one that addresses human history back 1.7 million years, during which time our ancestors were not just runners, but universally ultra distance runners.  Now we know that systems that determine our mortality and morbidity long predate humans.
TOR research is in its infancy.  It gives us an enormously powerful tool to answer our most important health questions.  Until now to answer a question like, “Which type of exercise is most healthful?”  was impossible–you would need to follow 20000 people over 90 years.  For purposes of health, does the intensity of exercise matter, or is long slow distance just fine?  Could you obtain the full health benefit working out 3 days a week?  And how much is enough?  Is there an optimal mileage per week?  How does diet interact with exercise?  If you run, does it matter what you eat?  To answer these questions now you no longer need many test subjects–all you need is one person and a reliable TOR activity assay.  There are now hundreds of articles per year on TOR worldwide.  Within a few years there will be tens of thousands of research papers each year.  This new information will revolutionize exercise physiology and will profoundly affect all of medicine.