Vigorous Exercise: Not only for the young

We all know that muscular weakness and wasting will eventually catch up with us because a decline in physical vigor is an inevitable part of the aging process.  After all, we have seen our parents and grandparents slowly deteriorate, and many studies show a correlation between aging, muscular weakness, and loss of lean muscle mass.  Might as well just accept it . . . right?

But what if the frailty that we see in senior citizens is mainly due to a sedentary lifestyle, and the loss of muscular strength and endurance is the result of disuse?  What if the progression from vitality to frailty is just a self-fulfilling prophecy?

Surprisingly, it has been shown that sitting on our fannies is a significant factor in the aging syndrome—perhaps the major factor.  Some pretty remarkable studies indicate that lean muscle mass and strength, as well as muscular and cardiovascular endurance, may be maintained well into advanced age. 

But before we get into the juicy details, first some vocabulary and basic concepts.

Physical fitness can be assessed different ways, but the two we are most familiar with are cardiovascular function and musculature.

Cardiovascular Function.  The most widely used measure of cardiovascular fitness is “V0₂ max,” the maximum amount of oxygen that is available for the performance of  a task.  V0₂ max is generally measured by having the subject run on a treadmill while wearing a mask that delivers oxygen and tracks consumption.  For those of you who don’t have a treadmill and an oxygen mask readily available, you can estimate your V0₂ max as follows:  divide your maximum heart rate by your resting heart rate and multiply by 15.  The result is an estimate of your V0₂ max. 

The average untrained male has a V0₂ max of 35-40 ml/kg/min, meaning that he consumes 35 to 40 milliliters of oxygen per kilogram of weight each minute.  Elite male runners can consume 85 ml/kg/min.   Remarkably, thoroughbred horses have a V0₂ max of around 180 ml/kg/min, and sled dogs that run the Iditarod have a V0₂ max of 240 ml/kg/min.  At the other end of the spectrum, a human must have a V0₂ of 15-20 ml/kg/min to live independently, and a decline of 0.4-0.5 ml/kg/min per year, or 5-10% per decade, is normal after age 50.

Musculature.  Muscular fitness is measured not only by muscle size and fat concentrations, but also by strength, power, and endurance.  Strength is an easy concept—how much you can lift or push—and it is measured in pounds or the equivalent.  Power is more complicated though; expressed in watts, it tells you how much weight you can move in a given amount of time.  And endurance, of course, refers to how long you can make a particular muscle perform.

So now, what is the effect of exercise on aging adults?  One of the best ways to answer this question is by studying “masters athletes,” defined as individuals who are over 40 and train for fitness and sports competitions.

A 2011 study* looked at 20 men and 20 women who were (a) over 40 years old, (b) trained for competitions MORE than 4-5 times per week, and (c) did not have an injury that limited their ability to compete.  They were divided into four age groups with 5 men and 5 women in each group: 40-49 years, 50-59 years, 60-69 years, and over 70 years.  Using the cross-sectional images of each subject’s upper leg provided by MRI (magnetic resonance imaging) scans, researchers calculated the amount of fat and muscle in the thigh as well as the extent to which the fat had penetrated the muscle.

And what did they find?  Here are the shockers:

Total mid-thigh mass (muscle and fat):   no difference between age groups.

Lean mass (muscle without fat):   no difference between age groups.

Size of quadriceps (the big muscle on the top of your thigh):  no difference between age groups except in those over 70, who had a 20% decrease compared to the other groups.

Physical torque (the amount of force that can be generated by pushing your leg against resistance):  no difference between the 40-49 and the 50-59 age groups and no difference between the 60-69 and the over-70 age groups, but the 40-59 group exerted more force than the over-60 group.

In summary, no muscular decline was observed until age 60, and after 60 it did not deteriorate further except for a 20% decrease in quadriceps size in those over 70.

A 2008 paper that looked at previous studies comparing elite male athletes with untrained “normal” men concluded that elite athletes can achieve remarkable performance into their 90’s.  For example, knee strength in 90-year-old weightlifters was higher than that of 40-year-old normal males.  The VO₂ max of 70-year-old elite runners was equal to that of untrained 25-year-olds.  The power generated by 75-year-old weightlifters was equal to that of ordinary 25-year-olds.

Now, my purpose in going through these statistics is NOT to suggest that we can all look like Arnold Schwarzenegger as we slide into our golden years.  Unfortunately, there are very real events that occur as we age—and the list is depressingly long! 

What is known, again by looking at the performance of elite athletes, is that all of the above measures—strength, power, V0₂ max—decrease with age.  A weight-trained 90-year-old is never going to be able to compete with a weight-trained 20-year-old.  In fact, in all these studies the trained youngsters outperformed the trained oldsters by great margins in all age categories.  Peak endurance running, for example, is maintained until approximately 35 years old, with modest decreases thereafter until 50-60 and larger drop-offs after that.  This decline in athletic performance is well known in all sports.

My intent is to make the point that recent studies reveal that people of all ages show remarkable improvement with training, and therefore some aspects of the aging stereotype are simply WRONG.  What is going on at the biochemical level is not yet fully known, but it appears that the capacity for protein synthesis may remain essentially unchanged as we age.   Think about THAT!

So what is the evidence?  Looking at masters athletes is useful in many ways—but maybe there is something different about them other than their capacity for continuous training.  What we really need to know is how “normal” people respond to training.

But first, a little vocabulary that is used in the exercise world.  “Resistance training” essentially means lifting weights by any mechanism—a mechanical apparatus (think Nautilus machines) or free weights (barbells, for example) or “body weight” (such as pull-ups or push-ups).  Resistance training with free weights or machines is often structured around percentages of  the “one rep maximum” (1RM), which is the maximum weight that can be lifted or pushed one time for a given exercise.  A “low” workout could incorporate groups of repetitions (reps) at 60% 1RM, so your exercise on a given day might consist of three sets of 10 reps at your 60% 1RM.   Obviously the possible variations on this theme are endless.

A 2010 meta-analysis of 47 studies covered 1079 subjects ranging in age from 50-92 (average age 67) who were subjected to resistance training.   Depending on the parameters of each individual study, the subjects worked out 1-3 times per week (average 2.7) at 40%-85% of their 1RM.  The number of exercises ranged from 5 to 16 (average 8.3). The number of sets per exercise ranged from 1 to 6, (average 2.5) and the number of repetitions per set ranged from 2 to 20 (average 10).  The length of the rest periods between sets varied from 60 seconds  to 360 seconds.  The types of exercises performed were leg presses, chest presses, knee extensions, and “lat” (latissimus dorsi) pull-downs.  The studies varied in length from 6 to 52 weeks. 

It is clear that some of these studies involved workouts that were pretty intense by any standard.  And remember, these were folks who were, on average, 67 years old!

So what were the results?

Statistically significant improvements were found across the board.  Strength increased by 29% for the leg press, 24% for the chest press, 33% for the knee extension, and 25% for the lat pull-down.   And get this:  as the intensity of the training increased, so did the rate of improvement (an average 5.3% increase in strength from one level of intensity to the next).

These are huge improvements, especially when you consider that the test subjects were assumed to be declining in strength because of “aging.”  The good news is that when their muscles were strained and their tissues torn (which always happens with resistance training), their bodies recovered and were even better afterwards.  It means protein synthesis was going on.  And surprisingly, the level of improvement was the same for both men and women in all age groups (although some studies have found that youngsters gain strength more rapidly than oldsters).

Clearly these results suggest whole new types of exercise programs for the elderly, not only modifying exercise intensity but also varying the exercise program over time—what’s called “periodization.”  An exercise program that incorporates “periodization” would involve, for example, two weeks of high-intensity training followed by a week at low intensity, followed by high intensity, etc.  Periodization has been well-studied in young athletes, but among the aged not at all.  Why?  Because, I guess, they weren’t expected to respond.  Because they are OLD, you know? 

The general importance of exercise, even very moderate exercise, is well known—case closed on that.  What these studies show is that for all ages, the more you exercise the better.  And the harder it is, the more you gain.  The old saying “no pain no gain” apparently applies no matter what your age (up to a certain point that is, which I’ll discuss in another blog).

Finally, I’d like to share another study supporting the benefits of exercise—not only cardiovascular fitness but muscular fitness as well.  The two are different, but certainly related.

From 1980 to 1989, 10,265 men entered the study and were categorized by age, weight, minimal ability to work out on a treadmill (as a measure of cardiovascular fitness), and ability to perform leg and chest presses (as a measure of muscular fitness).  By the end of the study in 2003, 8,762 subjects remained, ranging in age from 20 to 80.   Some of them had died or suffered heart attacks, strokes, cancer, or diabetes, but the average man was followed for 19 years.

The researchers divided the men into three groups (low, middle, and high) according to their muscular strength at the time they entered the study.  Basically they found that the stronger the group, the less mortality there was from any cause, including cancer and cardiovascular disease.  This was true even after controlling for varying initial levels of cardiovascular health (although greater cardiovascular health was correlated with higher muscular strength).  

This study’s focus on muscular strength makes it different from many others because the majority have focused on the health benefits of cardiovascular exercise (running, walking, etc.).   It is not known how muscular strength protects against disease, but some researchers believe that it may be due to the type of muscle fibers one has.

Given the fact that aging baby boomers constitute 26% percent of the United States population, these kinds of studies are very important.  The results are changing the paradigms of aging as well as the vocabulary, as evidenced by the fact that terms like “successful aging,” “active aging,” “positive aging,” and “active living” are increasingly in use.

And those of us who are no longer young need to actively counter stereotypes of aging and the cultural expectations about “what we can do.”

The Pepsi Generation may be getting old, but we are still a force to be reckoned with!

Useful References:

https://physsportsmed.org/sites/default/files/rpsm.2011.09.1933_secure.pdf

http://kines.umich.edu/sites/webservices.itcs.umich.edu.drupal.kinesprod/files/resource_files/CJSMAgingEliteMaleAthletes.pdf

http://www.sciencedirect.com/science/article/pii/S1568163710000279

http://www.bmj.com/content/337/bmj.a439

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PATENTING HUMAN GENES: The Myriad Case

The U.S. Supreme Court has made a number of important decisions in the last few months, two of which are relevant to topics on this blog:  (1) Bowman v. Monsanto; and (2) Association for Molecular Pathology v. Myriad Genetics.

I wrote about the Bowman v. Monsanto case last February, and I won’t repeat myself here—except to say that the Supreme Court ruled that farmers can’t save patented seeds and reproduce them by using them to grow a new generation of plants.  In my opinion, that case was almost a no-brainer, in that prohibiting others from copying your patented inventions or copyrighted works is central to intellectual property law, and the Court HAD to rule in favor of Monsanto.

The second case is more far reaching in its consequences.

The Supreme Court made two basic rulings in Myriad:  you can’t patent human DNA sequences as they occur in humans (“native DNA”), but you CAN patent human DNA that has been changed artificially.

The Myriad case was directed to two genes involved in causing breast cancer:  BRCA1 and BRCA2.  There were three patents in question:  U. S. Patent 5,747,282, U.S. Patent 5,693,473 and U. S. Patent 5,837,492.  It is historically interesting to note that these patents were filed way back in the early 1990’s—at a time when the human genome  had not yet been sequenced and published, which didn’t happen until the early 2000’s.  So the Myriad patents were revolutionary at the time—but by today’s standards, not so much.  In fact, the Myriad genes could not be patented today.  In order to be patentable, an invention has to be “novel”, and the publication of the human genome made the native DNA sequences of all human genes “not novel.”

Since Myriad’s patent applications on the BRCA genes were filed before publication of the human genome, Myriad couldn’t be denied a patent on those grounds.  But the Supreme Court’s ruling was not based on “novelty,” but rather on the assertion that a native DNA sequence is a “product of nature.”  And U.S. patent law says that that a product of nature is not eligible for patenting, the logic being that it is not a human invention—nature made it. 

The problem is that actually discovering at least SOME products of nature requires a heck of a lot of inventiveness.  It is not entirely clear to me where a “product of nature” that has been identified and laboriously extracted from nature differs from an “article of manufacture”, which is one of the categories of things that CAN be patented.  And, in fact, many naturally-occurring products have been patented in the past—aspirin, insulin, vitamin B12, and adrenalin, to name just a few.  Actually isolating these compounds required inventive activity and a recognition that they would be useful.  And back 1990’s when Myriad’s patents were issued, the U.S. Patent and Trademark Office obviously thought that isolated DNA sequences were patentable subject matter.  In fact, their identification and isolation required a high degree of inventiveness.

In their native state, the BRCA1 and BRCA2 genes are wrapped up with various proteins—scaffolding proteins such as histones that help maintain a 3-dimensonal structure.  Additionally, each gene has methyl groups spread around particular nucleotides, particularly the cytosines, to help regulate gene expression.  But the Myriad BRCA patents in question only cover the gene sequences (each consisting of about 80,000 base pairs), but NOT the methyl groups or the histones.

So the patented BRCA1 and BRCA2 genes don’t look anything like the BRCA1 and BRCA2 genes found on a human chromosome.  It’s kind of like the difference between a baseball bat and the limb of the ash tree from which it was made.  Certainly the baseball bat existed within the tree limb—but getting it out took skill and inventiveness, wouldn’t you agree?  (Unfortunately I can’t take credit for that great metaphor.  Wish I had thought of it though.) 

The bottom line is that the Supreme Court says “native gene sequences” are not patentable, and that’s that.  Also, a narrow reading of the Court’s opinion indicates that its decision is restricted to human gene sequences.

But even so, and this is an important point, it is possible that the Myriad decision could put the entire field of “natural product” patents in jeopardy.  Take, for example, natural products that have medicinal uses.  The same logic used by the Supreme Court to invalidate Myriad’s  patents also could be used to preclude patenting of a plant-derived cure for AIDS, for example.  I just don’t see the difference.  And if pharmaceutical companies can’t get patent protection on plant-based drugs, they might just quit doing the costly research that leads to the discovery of those drugs in the first place.

Want some cool examples of natural products that have been patented, and may not be in the future?  Here are a few:

(1) Sirolimus, a chemical isolated from a bacteria found on Easter Island (how cool is that?), is both an antifungal and antibiotic, as well as an immunosuppressant that is used to prevent organ rejection in kidney transplants.  Sold by the trade name Rapamune.  U.S. Patent 3,929,992.

(2) Aplidine was first isolated from sea squirts (even cooler!) is a novel antitumor agent that has received orphan drug status for the treatment of multiple myeloma, a blood cell cancer.  U.S. Patent 5,834,586.

(3)  Exenatide is a chemical compound first found in the saliva of Gila monsters (way cool!) that is used for the treatment of diabetes.  U.S. Patent 5,424,286.

I could go on and on with such examples, but you get the idea.

As mentioned at the beginning of this blog, the Supreme Court ruled in Myriad that human DNA could be patented if it had been artificially changed from its native state.  Well, this almost had to be the case.  If something is artificially changed, it becomes an article of manufacture, and articles of manufacture ARE patentable.  No controversy there.

So what are the consequences of the Myriad decision?

Thousands of gene-related patents have been issued in the last 30 years, and even more “natural product” patents have been issued in the last 100 years.  Since the biotechnology industry is very dependent on products of nature, some areas of biotechnology, such as stem cell research, for example, could be in jeopardy.  After all, deriving a stem cell line from a skin cell or umbilical blood is about as “natural” as you can get.  Since patent protection can be a big part of what makes new ventures profitable, certainly investors will be, or should be, more cautious than they have been in the past about putting money into these types of products. 

Another potential unintended consequence of the Court’s decision is that inventors may decide to keep their discoveries secret rather than publish them.  The patent system is really a trade-off in which the government says, “In exchange for disclosing your invention to the public in a patent application, we will give you the right (a patent) to keep others from making, using, or selling that invention for a limited period of time.”  But if the government doesn’t keep its side of the bargain by issuing a patent, can inventors really afford to let everybody else in on their secrets?

Then again, the stock price of Myriad is trading at nearly all-time highs.  The market seems to have taken the Supreme Court’s decision in stride, and we may very well find that it was mainly a political decision, and thus without significant consequence.

But I doubt it. 

Climate Change (Part 4)

In this post, the last of a four-part series on climate change, I’ll start with the conclusions reached so far:

1.            There is overwhelming data indicating that the planet is in a warming trend—at least up until the last 10 years or so.

2.            Warming trends are historically correlated with increasing levels of CO₂, with emphasis on “correlated with” (not “caused by”).

3.            Mathematical models of future global temperatures are now predicting less warming than previously thought.

4.            Natural “forcings” of climate are significant.

5.            How the various natural forcings will interact with increased CO₂ and other greenhouse gases is, of course, unknown.

6.            C0₂, which acts like a natural fertilizer, stimulates plant growth significantly in some species.

7.            Plant species differ in response to elevated C0₂, with some being stimulated more than others.

8.            Elevated C0₂ increases water-use efficiency in some species.

9.            Elevated C0₂ stimulates growth in some ocean plants (e.g., phytoplankton), while other species, such as corals, may be destroyed or depleted.

10.            Ocean acidification may dissolve shells, corals, and other structures built of calcium carbonate, though some phytoplankton can apparently overcome any dissolving of their calcium carbonate structures by increased photosynthesis.

11.            Overall, ecosystems will respond to climate change by modifications ranging from slight to great, but they certainly will adapt.

In the course of researching ocean acidification, I learned of a recent report** on ocean warming.  It is proving to be very controversial, and may be wrong, but then again, it may be right.  And it does present some anomalies—like most everything else in science.  Here is the critical graph from the paper:

The lefthand side of the graph is a measure of heat, so what we have is a historical view of ocean temperatures from 1960 through 2008.

What the scientists found is that since the late 1970’s, the ocean has been getting warmer as far down as 700 meters, with the warming trend punctuated by periodic cooling caused by volcanic eruptions and a significant heat spike in the late 1980s caused by an El Nino event.  The authors conclude that the reason there hasn’t been any appreciable warming of the atmosphere during the last 10 years is because heat has been absorbed out of the atmosphere into the ocean.  In other words, the ocean is where the “missing heat” has gone.

When you look closely at the data, you can see that the region below 300 meters has warmed MORE than the upper 300 meters.  And this is the source of some criticism, since other scientists can’t figure out how the heat “skipped” detection in the upper ocean while showing up in the lower.   As a result, questions have been raised about the temperature-detection methods used by the researchers, as well as the manner in which the missing heat was calculated.

I certainly can’t evaluate the scientific integrity of this study, but it does seem strange that the upper layers didn’t warm first.  I wouldn’t be surprised if this data becomes a central part of the global warming debate.

A related issue regarding the ocean is, of course, rising sea levels.  Now this is a pretty easy concept as far as global warming is concerned:  ice melts, water flows into the sea, and the sea rises.  And as water heats up, it expands and the sea rises.

But actually measuring the sea level seems daunting, as anyone who has been to the beach can appreciate.  Tides, waves—these all need to be “smoothed out” or averaged.  However, sea height has been measured since 1700 in places like Amsterdam, where it is a daily concern due to the fact that 20% of the Netherlands—along with 50% of its population—is below sea level, and half of its land is less than 3 feet above sea level (most of the area below sea level is manmade after centuries of peat extraction). 

Sea heights were, and still are, measured by “tide gauges.”  Early calculations were made by measuring the height of the water relative to a specific point, such as a marking on a cliff.  Modern tide gauges (about 1750 of them around the world) do essentially the same thing using electronic sensors and small computers.   And incredibly, satellite measurements—using satellite altimetry—are so accurate that changes in sea level of only a few millimeters can be detected.

In any event, from 1870 to 2004, global sea levels rose by 195 mm or 7.7 inches, with an average rise of 1.4 millimeters per year.  And sea level rise seems to be noncontroversial, making it yet another proxy that provides evidence of global warming.  And given the melting of glaciers and the ice sheets of Greenland and Antarctica, sea levels should continue to rise—although, surprisingly, the rate of sea level rise has not accelerated along with increasing temperatures.  Perhaps inaccuracies in measurement would account for this.

So the planet is warming.  Ecosystems will change.  Cropping systems may also change, but they will adapt.  Forests will change.  Ocean fisheries may change.  New regions may become habitable.  Others may become less desirable.  Sea levels are rising.  Coastal communities will probably be affected.  Populations may be dislocated—and new phrases such as “environmental refugees”, “environmental migrants” and “climate refugees” have entered our vocabulary.

Because it is believed by most people that manmade greenhouse gases are responsible for the rise in temperatures, many proposals have been made to slow down the release of these gases into the atmosphere.  Complex international agreements have been developed allowing countries to trade “carbon credits,” while other proposals such as the Kyoto Protocol have tried to get commitments from countries to limit greenhouse gas production.  Other proposals have been made to slow down global warming, including methods to “absorb” gases or reflect sunlight from the planet.

But these proposals for limiting greenhouse gases are far beyond my expertise to review, summarize, or even comment on.  All I can really say is that limiting greenhouse gas production or increasing its absorption/sequestration will probably have a minimal impact on the temperature of the planet.  In fact, since the recent global recession has had no apparent impact on atmospheric C0₂, I’d say we have actually done an experiment of sorts—and found it to be ineffective.  It seems very unlikely that Homo sapiens will voluntarily agree to limit greenhouse gases if the cost equals or exceeds that of the recent recession.  I suspect that we will simply learn to adapt to a warming planet.

Assuming that the climate does not reverse itself and start getting cooler, that is.

Reference:

**http://onlinelibrary.wiley.com/doi/10.1002/grl.50382/abstract