LisaS
06-18-2006, 04:28 PM
Your genes (and jeans) WANT you to exercise
In reading through various papers and abstracts with regard to exercise and weight loss, insulin sensitivity and blood lipids, I came across an interesting series of papers on the evolutionary need for exercise. Most of these papers listed Frank W. Booth from U Missouri as the first or seond author. I will summarize the basis premise culled from several papers here – along with quotes and links to three that are available online.
You are all familiar with the premise put forth by the Eades in books like PPLP that our genes primarily were shaped by a pre-agricultural environment, that we are not adapted to eat grains and refined foods, etc. You might even have read some of the primary papers like those by Cordain et al. In fact, I first discovered this whole school of paleo-eating concepts through a paper by the now internet infamous Art Devany, called Evolutionary Fitness. In this paper, Devany tries to imagine (much like the Eades do in the PPLP exercise chapter) how early man might have both eaten and exercised. Here is a link to Devany's article: http://www.arthurdevany.com/webstuff/RevisedEssay.pdf . (http://www.arthurdevany.com/webstuff/RevisedEssay.pdf)
Booth takes a little different path than Devany. In the popular press, he has coined the term “Sedentary Death Syndrome” or SeDS, to bring popular attention and interest to the concept that people are designed for physical activity and that many modern diseases are the result of physical inactivity or exercise deficiency.
The three papers that I'd recommend to you are:
Exercise and gene expression: physiological regulation of the human genome through physical activity. J. Physiol. 2002 543:399-411 http://tinyurl.com/hrgbq
Waging war on modern chronic diseases: primary prevention through exercise biology J. Appl. Physiol. 88:774-787 2000 http://tinyurl.com/ko7qk
Eating, exercise and “thrify” genotypes: connecting the dots toward an evolutionary understading of modern chronic diseases. J. Appl. Physiol. 96:3-10 2004
http://tinyurl.com/fs2d7
The authors offer the idea that our current genome was shaped by evolutionary forces, and that these forces included “obligatory physical activity”. The ways in which exercise influences and controls gene expression in various systems is explored in some detail (but not too much detail for the non-biologist). In a systemic fashion, the authors look at specific characteristics of exercising populations and the genes that are expressed. In one interesting case, they look at cardiac hypertrophy – or the phenomenon of an “enlarged” athletes heart and contrast it with the pathological enlarged heart and the sedentary or “normal” heart. In fact, they make the case that the so-called atheletes' heart is the physiologically normal state for humans. In similar fashion, they look at other physiological systems and consider that the genes expressed in the atheletic or otherwise active individual are the norms against which other comparisons should be made.
In the second paper, the authors make the case for NIH funding of research into primary prevention of chronic diseases like heart disease, obesity, type II diabetes, and diseases of aging. The authors contend that it is “genes responding to an altered environment” that form the basis for many of these diseases, and that a major factor in this altered environment is the altered gene expression brought about by exercise deficiency.
In the third paper, the authors look at the Paleolithic life and consider that the early humans experienced cycles of feast and famine along with cycles of physical activity and rest. They explore this idea in the context of the “thrify gene” hypothesis and speculate that this cycling is a necessary part our existance and that the modern food affluent and exercise deficient lifestyle has disrupted and stalled these normal cycles at feast & inactivity. And they speculate that prolonged stalling and the genes expressed and underexpressed in that state may lead to many of our chronic diseases.
I'm going to reprint some quotations from these articles in hopes of whetting your appetite to read them in their original context. The papers are really quite good.
Some quotes from Exercise and Gene Expression:
The physiological and clinical significance of this misnomer [that the athletic heart is an exception rather than the rule] is that current research that is concerned with the genomic and proteomic adaptations of the compensated and failing heart to pressure overload makes comparisons with a sedentary 'control' group, when in fact the true 'control' group may be the physically active Late Paleolithic heart. Thus, incorrect differentially expressed genes may be indentified by a comparison of pathological hearts with sedentary hearts rather than the phenotype that determined the surviving genotype.
The phenotype associated with exercise deficiency often shows that thresholds of biological significance have been surpassed by altered gene expression so that overt clinical conditions occur...[Our] experience has been that a lack of understanding by the general scientific, medical, judicial and legislative communities for the magnitude of the altered gene expression by exercise deficiency has led to their underestimation or non-consideration of the significance of the functions of exercise-induced gene expressions. .
Some quotes from Waging War on modern chronic diseases:
The question remains: what altered environmental factors have elicited the increased incidence of chronic disease in the 20th century? Establishing one true causal effect is unlikely. However, what if one particular environmental factor were identified that has become dramatically more pronounced in the past century? Moreover, what if it were shown that reducing the magnitude of this environmental factor back to pre-1900 status could 1) potentially prevent most chronic diseases before they start (i.e., primary prevention), 2) profoundly and positively impact virtually all known chronic disease conditions even after their diagnosis, 3) decrease morbidity while increasing longevity and vitality in older individuals, 4) improve mental health and sense of well-being, and 5) have the ability to decrease annual US health care spending by hundreds of billions of dollars while costing little to nothing in return? Would this altered environmental factor be considered a potential origin of chronic disease(s)? Would the study of the biological effects of this environmental factor be worthy of public funding? Would it be beneficial to determine the effect of this environmental factor on gene expression at a molecular level?
Such an environmental factor does exist: physical inactivity.
The average amount of human daily physical activity has declined alarmingly over the past century. It is now known that physical exercise beneficially affects the human body in a multifactorial manner. However, the number of chronic diseases and associated financial costs potentially produced by physical inactivity is still much larger than generally appreciated. Indeed, with the possible exception of diet modification, we know of no single intervention with greater promise than physical exercise to reduce the risk of virtually all chronic diseases simultaneously. For example, only a small part of this picture was elucidated by Grundy (21 (http://jap.physiology.org/cgi/content/full/88/2/774?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=88&firstpage=774&resourcetype=HWCIT#B21)) when he wrote, "Certainly, obesity and physical inactivity are the dominant causes of insulin resistance, although genetic factors undoubtedly affect its severity. The most effective therapies for insulin resistance are weight loss and increased physical activity. Efforts to achieve a desirable body weight and to enhance physical activity are essential components of primary prevention, in both public health and clinical arenas." As we address later, an important but underemphasized concept is that the current human genome expects and requires humans to be physically active for normal function and health maintenance.
In Reality, We Study Physical Inactivity and Not Physical Activity
We propose that today's prevalently sedentary lifestyle directly contradicts one of the natural forces driving the evolution of our genes. That is to say, genes require the stimulus of physical activity to promote a state of health. We further propose that exercise biologists (including ourselves) have unintentionally made less than optimal impact on society about the profound dangers of sedentary living because we misleadingly designate physical inactivity, and not physical activity, as the traditional control condition in our experimental designs (explained further in this section). ...
We contend that the high degree of physical inactivity seen in current industrialized societies is primarily attributable to technological advances that have greatly lessened the need for physical labor over the past century. Such a society directly differs from that of our ancestors in that we must usually schedule exercise into our daily routine if any physical activity is to be experienced. ...
Chronic inactivity is physiologically abnormal. We believe that human bodies fail to function properly to maintain health in many different ways when there is a loss of adequate amounts (historically "normal" amounts) of physical activity. In other words, our genes expect the body to be in a physically active state if they are to function normally. In evolutionary terms, inactivity elicits an abnormal phenotypic expression of our genes. Evidence for this belief comes from observations that most chronic diseases are not as prevalent in societies where physical work is a large part of daily life (i.e., Mexicans compared with Mexican-Americans) as well as the fact that chronic disease progression is prevented or delayed by the reintroduction of physical exercise into populations where physical inactivity has become the norm. As biologists studying the molecular and biochemical bases of exercise, we further believe that we have been viewing research on physical activity in the wrong manner when we claim that we are "studying the effects of physical activity." We submit that it would be more accurate to state that we are "studying the effects of physical inactivity." In other words, because being sedentary is a physiologically abnormal state, it is from a population of sedentary individuals that the true experimental group should be taken. The control sample should be taken from a physically active population instead of the currently used sedentary population
False stereotype of exercise physiology. An active lifestyle is associated with a dramatically reduced risk for many chronic diseases. Appropriately performed physical activity can delay, and in some cases even prevent, early death and/or the need for drugs, assisted-living care, hospitalization, or other health care burdens. Yet, despite these obvious public health implications, biomedical exercise research as a viable discipline integral to preventive medicine may be underemphasized. Why? Part of the problem may be that "exercise physiology" is often perceived by medical scientists to be a field that exclusively studies elite athletes. "Sports medicine" refers to treatment and rehabilitation of sports-related injuries, generally orthopedic in nature. Furthermore, as exercise physiologists, we ourselves may be unwittingly contributing to the false notion that we study only physical training in athletes by purporting, as mentioned above, to study the "effects of physical activity" instead of the "effects of physical inactivity." In other words, an exercise physiologist's typical experimental condition (physical activity) does not connote the state of health. Whereas other health-related research fields designate a physiologically abnormal (i.e., disease) condition as the experimental group, exercise physiologists define the physiologically abnormal condition (physical inactivity) as the control group. The general "take-home message" of most scientific studies is more highly associated with the experimental condition within the study. For example, stating that "physical inactivity increases your risk of premature death" has greater public impact than stating that "physical activity decreases your risk of premature death." Thus we believe that our experimental approach to physical activity has unfortunately detracted from the fact that the majority of exercise-related research is actually health oriented and not performance oriented. We must emphasize the fact that physical activity induces a gene expression pattern that primarily promotes health; secondary to this effect is the coincidence that this gene expression also concomitantly serves to enhance physical performance.
Some quotes from Eating, exercise & “thrifty” genotyps:
As a result of the introduction of habitual physical inactivity into the pattern of daily living, the risks of at least 35 chronic health conditions have increased (6 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF6), 9 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF9)). Therefore, prevention of these chronic health conditions requires an in-depth understanding of the cellular and molecular details of all genes requiring physical activity for physiological levels to be maintained. To achieve such knowledge, the subpopulation of genes that express pathologically during physical inactivity must be known before the biological basis of physical inactivity-mediated diseases can be elucidated at the molecular level and the most appropriate next clinical preventive and therapeutic steps can be taken.
Thus we hypothesize that a threshold of physical activity is required for the proper expression of the inherited genes and genotypes, which was selected by evolution to support physical activity in part by the efficient usage of fuels, since survival was almost exclusively dependent on physical activity to procure food. Falling below this threshold has been designated as physical activity deficiency (9 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF9)). Based on the discussion presented hitherto, physical activity deficiency is predicted to disrupt the optimized expression of the "thrifty" genes and genotype for the physical activity-rest cycle. Some of these "thrifty" genes could have been initially selected to conserve glycogen stores by oxidizing greater quantities of fatty acids to maximize survival during famine and exercise. Therefore, our present sedentary lifestyle and our constant food availability and abundance have led to discordance in gene-environmental interactions, thus predisposing the Paleolithically programmed genome to misexpress its genes in multiple organ systems, ultimately resulting in pathology, manifested as the epidemic of modern chronic diseases (14 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF14)-16 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF16)). n summary, an amalgamation of published concepts, not previously integrated in the context of the biochemical adaptations to physical training, were used to form the following conjectures. Oscillations of muscle glycogen and triglyceride levels with physical activity-rest cycles during feast-famine during tens of thousands of years selected some genotypes and genes to oscillate, some of which might also serve a role in efficiency during fuel usage. However, a continuous sedentary lifestyle has resulted in a stalling of glycogen and triglyceride stores at high levels in skeletal muscle and of those metabolic proteins producing their cycling with physical activity-rest cycles. Conceivably, such metabolic stalling may cause the organism to cross a biological threshold, beyond which chronic health conditions develop. Some of the biochemical responses to physical activity-rest cycles are distinctly different from those encountered in feast-starvation cycles. Thus physical activity-rest cycles are the core catalysts to physiologically regulate those genes that break the stalling of muscle glycogen and triglyceride stores at high levels and of their regulatory proteins.
In reading through various papers and abstracts with regard to exercise and weight loss, insulin sensitivity and blood lipids, I came across an interesting series of papers on the evolutionary need for exercise. Most of these papers listed Frank W. Booth from U Missouri as the first or seond author. I will summarize the basis premise culled from several papers here – along with quotes and links to three that are available online.
You are all familiar with the premise put forth by the Eades in books like PPLP that our genes primarily were shaped by a pre-agricultural environment, that we are not adapted to eat grains and refined foods, etc. You might even have read some of the primary papers like those by Cordain et al. In fact, I first discovered this whole school of paleo-eating concepts through a paper by the now internet infamous Art Devany, called Evolutionary Fitness. In this paper, Devany tries to imagine (much like the Eades do in the PPLP exercise chapter) how early man might have both eaten and exercised. Here is a link to Devany's article: http://www.arthurdevany.com/webstuff/RevisedEssay.pdf . (http://www.arthurdevany.com/webstuff/RevisedEssay.pdf)
Booth takes a little different path than Devany. In the popular press, he has coined the term “Sedentary Death Syndrome” or SeDS, to bring popular attention and interest to the concept that people are designed for physical activity and that many modern diseases are the result of physical inactivity or exercise deficiency.
The three papers that I'd recommend to you are:
Exercise and gene expression: physiological regulation of the human genome through physical activity. J. Physiol. 2002 543:399-411 http://tinyurl.com/hrgbq
Waging war on modern chronic diseases: primary prevention through exercise biology J. Appl. Physiol. 88:774-787 2000 http://tinyurl.com/ko7qk
Eating, exercise and “thrify” genotypes: connecting the dots toward an evolutionary understading of modern chronic diseases. J. Appl. Physiol. 96:3-10 2004
http://tinyurl.com/fs2d7
The authors offer the idea that our current genome was shaped by evolutionary forces, and that these forces included “obligatory physical activity”. The ways in which exercise influences and controls gene expression in various systems is explored in some detail (but not too much detail for the non-biologist). In a systemic fashion, the authors look at specific characteristics of exercising populations and the genes that are expressed. In one interesting case, they look at cardiac hypertrophy – or the phenomenon of an “enlarged” athletes heart and contrast it with the pathological enlarged heart and the sedentary or “normal” heart. In fact, they make the case that the so-called atheletes' heart is the physiologically normal state for humans. In similar fashion, they look at other physiological systems and consider that the genes expressed in the atheletic or otherwise active individual are the norms against which other comparisons should be made.
In the second paper, the authors make the case for NIH funding of research into primary prevention of chronic diseases like heart disease, obesity, type II diabetes, and diseases of aging. The authors contend that it is “genes responding to an altered environment” that form the basis for many of these diseases, and that a major factor in this altered environment is the altered gene expression brought about by exercise deficiency.
In the third paper, the authors look at the Paleolithic life and consider that the early humans experienced cycles of feast and famine along with cycles of physical activity and rest. They explore this idea in the context of the “thrify gene” hypothesis and speculate that this cycling is a necessary part our existance and that the modern food affluent and exercise deficient lifestyle has disrupted and stalled these normal cycles at feast & inactivity. And they speculate that prolonged stalling and the genes expressed and underexpressed in that state may lead to many of our chronic diseases.
I'm going to reprint some quotations from these articles in hopes of whetting your appetite to read them in their original context. The papers are really quite good.
Some quotes from Exercise and Gene Expression:
The physiological and clinical significance of this misnomer [that the athletic heart is an exception rather than the rule] is that current research that is concerned with the genomic and proteomic adaptations of the compensated and failing heart to pressure overload makes comparisons with a sedentary 'control' group, when in fact the true 'control' group may be the physically active Late Paleolithic heart. Thus, incorrect differentially expressed genes may be indentified by a comparison of pathological hearts with sedentary hearts rather than the phenotype that determined the surviving genotype.
The phenotype associated with exercise deficiency often shows that thresholds of biological significance have been surpassed by altered gene expression so that overt clinical conditions occur...[Our] experience has been that a lack of understanding by the general scientific, medical, judicial and legislative communities for the magnitude of the altered gene expression by exercise deficiency has led to their underestimation or non-consideration of the significance of the functions of exercise-induced gene expressions. .
Some quotes from Waging War on modern chronic diseases:
The question remains: what altered environmental factors have elicited the increased incidence of chronic disease in the 20th century? Establishing one true causal effect is unlikely. However, what if one particular environmental factor were identified that has become dramatically more pronounced in the past century? Moreover, what if it were shown that reducing the magnitude of this environmental factor back to pre-1900 status could 1) potentially prevent most chronic diseases before they start (i.e., primary prevention), 2) profoundly and positively impact virtually all known chronic disease conditions even after their diagnosis, 3) decrease morbidity while increasing longevity and vitality in older individuals, 4) improve mental health and sense of well-being, and 5) have the ability to decrease annual US health care spending by hundreds of billions of dollars while costing little to nothing in return? Would this altered environmental factor be considered a potential origin of chronic disease(s)? Would the study of the biological effects of this environmental factor be worthy of public funding? Would it be beneficial to determine the effect of this environmental factor on gene expression at a molecular level?
Such an environmental factor does exist: physical inactivity.
The average amount of human daily physical activity has declined alarmingly over the past century. It is now known that physical exercise beneficially affects the human body in a multifactorial manner. However, the number of chronic diseases and associated financial costs potentially produced by physical inactivity is still much larger than generally appreciated. Indeed, with the possible exception of diet modification, we know of no single intervention with greater promise than physical exercise to reduce the risk of virtually all chronic diseases simultaneously. For example, only a small part of this picture was elucidated by Grundy (21 (http://jap.physiology.org/cgi/content/full/88/2/774?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=88&firstpage=774&resourcetype=HWCIT#B21)) when he wrote, "Certainly, obesity and physical inactivity are the dominant causes of insulin resistance, although genetic factors undoubtedly affect its severity. The most effective therapies for insulin resistance are weight loss and increased physical activity. Efforts to achieve a desirable body weight and to enhance physical activity are essential components of primary prevention, in both public health and clinical arenas." As we address later, an important but underemphasized concept is that the current human genome expects and requires humans to be physically active for normal function and health maintenance.
In Reality, We Study Physical Inactivity and Not Physical Activity
We propose that today's prevalently sedentary lifestyle directly contradicts one of the natural forces driving the evolution of our genes. That is to say, genes require the stimulus of physical activity to promote a state of health. We further propose that exercise biologists (including ourselves) have unintentionally made less than optimal impact on society about the profound dangers of sedentary living because we misleadingly designate physical inactivity, and not physical activity, as the traditional control condition in our experimental designs (explained further in this section). ...
We contend that the high degree of physical inactivity seen in current industrialized societies is primarily attributable to technological advances that have greatly lessened the need for physical labor over the past century. Such a society directly differs from that of our ancestors in that we must usually schedule exercise into our daily routine if any physical activity is to be experienced. ...
Chronic inactivity is physiologically abnormal. We believe that human bodies fail to function properly to maintain health in many different ways when there is a loss of adequate amounts (historically "normal" amounts) of physical activity. In other words, our genes expect the body to be in a physically active state if they are to function normally. In evolutionary terms, inactivity elicits an abnormal phenotypic expression of our genes. Evidence for this belief comes from observations that most chronic diseases are not as prevalent in societies where physical work is a large part of daily life (i.e., Mexicans compared with Mexican-Americans) as well as the fact that chronic disease progression is prevented or delayed by the reintroduction of physical exercise into populations where physical inactivity has become the norm. As biologists studying the molecular and biochemical bases of exercise, we further believe that we have been viewing research on physical activity in the wrong manner when we claim that we are "studying the effects of physical activity." We submit that it would be more accurate to state that we are "studying the effects of physical inactivity." In other words, because being sedentary is a physiologically abnormal state, it is from a population of sedentary individuals that the true experimental group should be taken. The control sample should be taken from a physically active population instead of the currently used sedentary population
False stereotype of exercise physiology. An active lifestyle is associated with a dramatically reduced risk for many chronic diseases. Appropriately performed physical activity can delay, and in some cases even prevent, early death and/or the need for drugs, assisted-living care, hospitalization, or other health care burdens. Yet, despite these obvious public health implications, biomedical exercise research as a viable discipline integral to preventive medicine may be underemphasized. Why? Part of the problem may be that "exercise physiology" is often perceived by medical scientists to be a field that exclusively studies elite athletes. "Sports medicine" refers to treatment and rehabilitation of sports-related injuries, generally orthopedic in nature. Furthermore, as exercise physiologists, we ourselves may be unwittingly contributing to the false notion that we study only physical training in athletes by purporting, as mentioned above, to study the "effects of physical activity" instead of the "effects of physical inactivity." In other words, an exercise physiologist's typical experimental condition (physical activity) does not connote the state of health. Whereas other health-related research fields designate a physiologically abnormal (i.e., disease) condition as the experimental group, exercise physiologists define the physiologically abnormal condition (physical inactivity) as the control group. The general "take-home message" of most scientific studies is more highly associated with the experimental condition within the study. For example, stating that "physical inactivity increases your risk of premature death" has greater public impact than stating that "physical activity decreases your risk of premature death." Thus we believe that our experimental approach to physical activity has unfortunately detracted from the fact that the majority of exercise-related research is actually health oriented and not performance oriented. We must emphasize the fact that physical activity induces a gene expression pattern that primarily promotes health; secondary to this effect is the coincidence that this gene expression also concomitantly serves to enhance physical performance.
Some quotes from Eating, exercise & “thrifty” genotyps:
As a result of the introduction of habitual physical inactivity into the pattern of daily living, the risks of at least 35 chronic health conditions have increased (6 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF6), 9 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF9)). Therefore, prevention of these chronic health conditions requires an in-depth understanding of the cellular and molecular details of all genes requiring physical activity for physiological levels to be maintained. To achieve such knowledge, the subpopulation of genes that express pathologically during physical inactivity must be known before the biological basis of physical inactivity-mediated diseases can be elucidated at the molecular level and the most appropriate next clinical preventive and therapeutic steps can be taken.
Thus we hypothesize that a threshold of physical activity is required for the proper expression of the inherited genes and genotypes, which was selected by evolution to support physical activity in part by the efficient usage of fuels, since survival was almost exclusively dependent on physical activity to procure food. Falling below this threshold has been designated as physical activity deficiency (9 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF9)). Based on the discussion presented hitherto, physical activity deficiency is predicted to disrupt the optimized expression of the "thrifty" genes and genotype for the physical activity-rest cycle. Some of these "thrifty" genes could have been initially selected to conserve glycogen stores by oxidizing greater quantities of fatty acids to maximize survival during famine and exercise. Therefore, our present sedentary lifestyle and our constant food availability and abundance have led to discordance in gene-environmental interactions, thus predisposing the Paleolithically programmed genome to misexpress its genes in multiple organ systems, ultimately resulting in pathology, manifested as the epidemic of modern chronic diseases (14 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF14)-16 (http://jap.physiology.org/cgi/content/full/96/1/3?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&andorexactfulltext=and&searchid=1&FIRSTINDEX=0&sortspec=relevance&volume=96&firstpage=3&resourcetype=HWCIT#REF16)). n summary, an amalgamation of published concepts, not previously integrated in the context of the biochemical adaptations to physical training, were used to form the following conjectures. Oscillations of muscle glycogen and triglyceride levels with physical activity-rest cycles during feast-famine during tens of thousands of years selected some genotypes and genes to oscillate, some of which might also serve a role in efficiency during fuel usage. However, a continuous sedentary lifestyle has resulted in a stalling of glycogen and triglyceride stores at high levels in skeletal muscle and of those metabolic proteins producing their cycling with physical activity-rest cycles. Conceivably, such metabolic stalling may cause the organism to cross a biological threshold, beyond which chronic health conditions develop. Some of the biochemical responses to physical activity-rest cycles are distinctly different from those encountered in feast-starvation cycles. Thus physical activity-rest cycles are the core catalysts to physiologically regulate those genes that break the stalling of muscle glycogen and triglyceride stores at high levels and of their regulatory proteins.