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9.9: Exercise, Nutrition, Hormones, and Bone Tissue - Biology

9.9: Exercise, Nutrition, Hormones, and Bone Tissue - Biology



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Learning Objectives

  • Describe the effect exercise has on bone tissue
  • List the nutrients that affect bone health
  • Discuss the role those nutrients play in bone health
  • Describe the effects of hormones on bone tissue

All of the organ systems of your body are interdependent, and the skeletal system is no exception. The food you take in via your digestive system and the hormones secreted by your endocrine system affect your bones. Even using your muscles to engage in exercise has an impact on your bones.

Exercise and Bone Tissue

During long space missions, astronauts can lose approximately 1 to 2 percent of their bone mass per month. This loss of bone mass is thought to be caused by the lack of mechanical stress on astronauts’ bones due to the low gravitational forces in space. Lack of mechanical stress causes bones to lose mineral salts and collagen fibers, and thus strength. Similarly, mechanical stress stimulates the deposition of mineral salts and collagen fibers. The internal and external structure of a bone will change as stress increases or decreases so that the bone is an ideal size and weight for the amount of activity it endures. That is why people who exercise regularly have thicker bones than people who are more sedentary. It is also why a broken bone in a cast atrophies while its contralateral mate maintains its concentration of mineral salts and collagen fibers. The bones undergo remodeling as a result of forces (or lack of forces) placed on them.

Numerous, controlled studies have demonstrated that people who exercise regularly have greater bone density than those who are more sedentary. Any type of exercise will stimulate the deposition of more bone tissue, but resistance training has a greater effect than cardiovascular activities. Resistance training is especially important to slow down the eventual bone loss due to aging and for preventing osteoporosis.

Nutrition and Bone Tissue

The vitamins and minerals contained in all of the food we consume are important for all of our organ systems. However, there are certain nutrients that affect bone health.

Calcium and Vitamin D

You already know that calcium is a critical component of bone, especially in the form of calcium phosphate and calcium carbonate. Since the body cannot make calcium, it must be obtained from the diet. However, calcium cannot be absorbed from the small intestine without vitamin D. Therefore, intake of vitamin D is also critical to bone health. In addition to vitamin D’s role in calcium absorption, it also plays a role, though not as clearly understood, in bone remodeling.

Milk and other dairy foods are not the only sources of calcium. This important nutrient is also found in green leafy vegetables, broccoli, and intact salmon and canned sardines with their soft bones. Nuts, beans, seeds, and shellfish provide calcium in smaller quantities.

Except for fatty fish like salmon and tuna, or fortified milk or cereal, vitamin D is not found naturally in many foods. The action of sunlight on the skin triggers the body to produce its own vitamin D (Figure 1), but many people, especially those of darker complexion and those living in northern latitudes where the sun’s rays are not as strong, are deficient in vitamin D. In cases of deficiency, a doctor can prescribe a vitamin D supplement.

Other Nutrients

Vitamin K also supports bone mineralization and may have a synergistic role with vitamin D in the regulation of bone growth. Green leafy vegetables are a good source of vitamin K.

The minerals magnesium and fluoride may also play a role in supporting bone health. While magnesium is only found in trace amounts in the human body, more than 60 percent of it is in the skeleton, suggesting it plays a role in the structure of bone. Fluoride can displace the hydroxyl group in bone’s hydroxyapatite crystals and form fluorapatite. Similar to its effect on dental enamel, fluorapatite helps stabilize and strengthen bone mineral. Fluoride can also enter spaces within hydroxyapatite crystals, thus increasing their density.

Omega-3 fatty acids have long been known to reduce inflammation in various parts of the body. Inflammation can interfere with the function of osteoblasts, so consuming omega-3 fatty acids, in the diet or in supplements, may also help enhance production of new osseous tissue. Table 1 summarizes the role of nutrients in bone health.

Table 1. Nutrients and Bone Health
NutrientRole in bone health
CalciumNeeded to make calcium phosphate and calcium carbonate, which form the hydroxyapatite crystals that give bone its hardness
Vitamin DNeeded for calcium absorption
Vitamin KSupports bone mineralization; may have synergistic effect with vitamin D
MagnesiumStructural component of bone
FluorideStructural component of bone
Omega-3 fatty acidsReduces inflammation that may interfere with osteoblast function

Hormones and Bone Tissue

The endocrine system produces and secretes hormones, many of which interact with the skeletal system. These hormones are involved in controlling bone growth, maintaining bone once it is formed, and remodeling it.

Hormones That Influence Osteoblasts and/or Maintain the Matrix

Several hormones are necessary for controlling bone growth and maintaining the bone matrix. The pituitary gland secretes growth hormone (GH), which, as its name implies, controls bone growth in several ways. It triggers chondrocyte proliferation in epiphyseal plates, resulting in the increasing length of long bones. GH also increases calcium retention, which enhances mineralization, and stimulates osteoblastic activity, which improves bone density.

GH is not alone in stimulating bone growth and maintaining osseous tissue. Thyroxine, a hormone secreted by the thyroid gland promotes osteoblastic activity and the synthesis of bone matrix. During puberty, the sex hormones (estrogen in girls, testosterone in boys) also come into play. They too promote osteoblastic activity and production of bone matrix, and in addition, are responsible for the growth spurt that often occurs during adolescence. They also promote the conversion of the epiphyseal plate to the epiphyseal line (i.e., cartilage to its bony remnant), thus bringing an end to the longitudinal growth of bones. Additionally, calcitriol, the active form of vitamin D, is produced by the kidneys and stimulates the absorption of calcium and phosphate from the digestive tract.

Try It

Osteoporosis is a disease characterized by a decrease in bone mass that occurs when the rate of bone resorption exceeds the rate of bone formation, a common occurrence as the body ages. Notice how this is different from Paget’s disease. In Paget’s disease, new bone is formed in an attempt to keep up with the resorption by the overactive osteoclasts, but that new bone is produced haphazardly. In fact, when a physician is evaluating a patient with thinning bone, he or she will test for osteoporosis and Paget’s disease (as well as other diseases). Osteoporosis does not have the elevated blood levels of alkaline phosphatase found in Paget’s disease.

While osteoporosis can involve any bone, it most commonly affects the proximal ends of the femur, vertebrae, and wrist. As a result of the loss of bone density, the osseous tissue may not provide adequate support for everyday functions, and something as simple as a sneeze can cause a vertebral fracture. When an elderly person falls and breaks a hip (really, the femur), it is very likely the femur that broke first, which resulted in the fall. Histologically, osteoporosis is characterized by a reduction in the thickness of compact bone and the number and size of trabeculae in cancellous bone.

Figure 2 shows that women lose bone mass more quickly than men starting at about 50 years of age. This occurs because 50 is the approximate age at which women go through menopause. Not only do their menstrual periods lessen and eventually cease, but their ovaries reduce in size and then cease the production of estrogen, a hormone that promotes osteoblastic activity and production of bone matrix. Thus, osteoporosis is more common in women than in men, but men can develop it, too. Anyone with a family history of osteoporosis has a greater risk of developing the disease, so the best treatment is prevention, which should start with a childhood diet that includes adequate intake of calcium and vitamin D and a lifestyle that includes weight-bearing exercise. These actions, as discussed above, are important in building bone mass. Promoting proper nutrition and weight-bearing exercise early in life can maximize bone mass before the age of 30, thus reducing the risk of osteoporosis.

For many elderly people, a hip fracture can be life threatening. The fracture itself may not be serious, but the immobility that comes during the healing process can lead to the formation of blood clots that can lodge in the capillaries of the lungs, resulting in respiratory failure; pneumonia due to the lack of poor air exchange that accompanies immobility; pressure sores (bed sores) that allow pathogens to enter the body and cause infections; and urinary tract infections from catheterization.

Current treatments for managing osteoporosis include bisphosphonates (the same medications often used in Paget’s disease), calcitonin, and estrogen (for women only). Minimizing the risk of falls, for example, by removing tripping hazards, is also an important step in managing the potential outcomes from the disease.

Hormones That Influence Osteoclasts

Bone modeling and remodeling require osteoclasts to resorb unneeded, damaged, or old bone, and osteoblasts to lay down new bone. Two hormones that affect the osteoclasts are parathyroid hormone (PTH) and calcitonin.

PTH stimulates osteoclast proliferation and activity. As a result, calcium is released from the bones into the circulation, thus increasing the calcium ion concentration in the blood. PTH also promotes the reabsorption of calcium by the kidney tubules, which can affect calcium homeostasis (see below).

The small intestine is also affected by PTH, albeit indirectly. Because another function of PTH is to stimulate the synthesis of vitamin D, and because vitamin D promotes intestinal absorption of calcium, PTH indirectly increases calcium uptake by the small intestine. Calcitonin, a hormone secreted by the thyroid gland, has some effects that counteract those of PTH. Calcitonin inhibits osteoclast activity and stimulates calcium uptake by the bones, thus reducing the concentration of calcium ions in the blood. As evidenced by their opposing functions in maintaining calcium homeostasis, PTH and calcitonin are generally not secreted at the same time. Table 2 summarizes the hormones that influence the skeletal system.

Table 2. Hormones That Affect the Skeletal System
HormoneRole
Growth hormoneIncreases length of long bones, enhances mineralization, and improves bone density
ThyroxineStimulates bone growth and promotes synthesis of bone matrix
Sex hormonesPromote osteoblastic activity and production of bone matrix; responsible for adolescent growth spurt; promote conversion of epiphyseal plate to epiphyseal line
CalcitriolStimulates absorption of calcium and phosphate from digestive tract
Parathyroid hormoneStimulates osteoclast proliferation and resorption of bone by osteoclasts; promotes reabsorption of calcium by kidney tubules; indirectly increases calcium absorption by small intestine
CalcitoninInhibits osteoclast activity and stimulates calcium uptake by bones

A stem cell is an unspecialized cell that can divide without limit as needed and can, under specific conditions, differentiate into specialized cells. Stem cells are divided into several categories according to their potential to differentiate.

The first embryonic cells that arise from the division of the zygote are the ultimate stem cells these stems cells are described as totipotent because they have the potential to differentiate into any of the cells needed to enable an organism to grow and develop.

The embryonic cells that develop from totipotent stem cells and are precursors to the fundamental tissue layers of the embryo are classified as pluripotent. A pluripotent stem cell is one that has the potential to differentiate into any type of human tissue but cannot support the full development of an organism. These cells then become slightly more specialized, and are referred to as multipotent cells.

A multipotent stem cell has the potential to differentiate into different types of cells within a given cell lineage or small number of lineages, such as a red blood cell or white blood cell.

Finally, multipotent cells can become further specialized oligopotent cells. An oligopotent stem cell is limited to becoming one of a few different cell types. In contrast, a unipotent cell is fully specialized and can only reproduce to generate more of its own specific cell type.

Stem cells are unique in that they can also continually divide and regenerate new stem cells instead of further specializing. There are different stem cells present at different stages of a human’s life. They include the embryonic stem cells of the embryo, fetal stem cells of the fetus, and adult stem cells in the adult. One type of adult stem cell is the epithelial stem cell, which gives rise to the keratinocytes in the multiple layers of epithelial cells in the epidermis of skin. Adult bone marrow has three distinct types of stem cells: hematopoietic stem cells, which give rise to red blood cells, white blood cells, and platelets ([link]) endothelial stem cells, which give rise to the endothelial cell types that line blood and lymph vessels and mesenchymal stem cells, which give rise to the different types of muscle cells.



Graduate students in exercise physiology and exercise medicine programs, postdoctoral fellows, basic scientists and clinical investigators interested in exercise for the prevention and treatment of common chronic disease associated with a sedentary lifestyle and poor cardiorespiratory fitness.

Claude Bouchard

Claude Bouchard is Professor and Director of the Human Genomics Laboratory at Pennington Biomedical Research Center in Baton Rouge, Louisiana. He holds the John W. Barton Sr. Endowed Chair in Genetics and Nutrition. His research deals with the genetics of adaptation to exercise and to nutritional interventions as well as the genetics of obesity and its comorbidities. He has authored and coauthored several books and more than 1000 scientific papers. Among other awards, he was the recipient of the Honor Award from the Canadian Association of Sport Sciences in 1988, a Citation Award from the American College of Sports Medicine in 1992 and the Honor Award in 2002, the Benjamin Delessert Award in nutrition from France in 1993, the Willendorf Award from the International Association for the Study of Obesity in 1994, the Sandoz Award from the Canadian Atherosclerosis Society in 1996, the Albert Creff Award in Nutrition of the National Academy of Medicine of France in 1997, the TOPS award in 1998, the Friends of Albert J. Stunkard Award in 2004 and the George A. Bray Founders Award from The Obesity Society in 2008, and the EV McCollum Award from the American Society of Nutrition in 2011. He is a foreign member of the Royal Academy of Medicine of Belgium since 1996. In 2001 he became a member of the Order of Canada as well as Professor Emeritus, Faculty of Medicine, Laval University. Dr. Bouchard became a Knight in the Ordre National du Quebec and received the Earle W. Crampton Award in Nutrition from McGill University in 2005. He was awarded Honoris Causa Doctorates in Science from the Katholieke Universiteit Leuven in 1998, from the University of South Carolina in 2009, from Brock University in 2011, from the University of Guelph in 2011, and from the University of Ottawa in 2012. Dr. Bouchard is past president of the Obesity Society and past president of the International Association for the Study of Obesity. He served as the Executive Director of the Pennington Biomedical Research Center from 1999 to 2010. He is a Fellow of the American College of Sports Medicine, the American Epidemiological Society, the Obesity Society, the American Society of Nutrition, the American Heart Association, and the American Association for the Advancement of Science. His research has been funded by various agencies in Canada and the USA, but mainly by the National Institutes of Health.


How Bones Work

Bone is a composite material, consisting of crystals of mineral bound to protein. This provides both strength and resilience so that the skeleton can absorb impact without breaking. A structure made only of mineral would be more brittle and break more easily, while a structure made only of protein would be soft and bend too easily. The mineral phase of bone consists of small crystals containing calcium and phosphate, called hydroxyapatite. This mineral is bound in an orderly manner to a matrix that is made up largely of a single protein, collagen. Collagen is made by bone cells and assembled as long thin rods containing three intertwined protein chains, which are then assembled into larger fibers that are strengthened by chemical connections between them. Other proteins in bone can help to strengthen the collagen matrix even further and to regulate its ability to bind mineral. Very small changes in the shape of the bone can act on the cells inside bone (the osteocytes), which produce chemical signals that allow the skeleton to respond to changes in mechanical loading. Abnormalities in the collagen scaffold can occur as a result of a genetic disorder called osteogenesis imperfecta, while the failure of mineral deposition can be the result of rickets and osteomalacia, conditions that result in marked weakening of the skeleton (see below and Chapter 3).

To provide the body with a frame that is both light and strong, bones are hollow. The outer dense shell is called cortical bone, which makes up roughly three-quarters of the total skeletal mass. Inside the cortical shell is a fine network of connecting plates and rods called trabecular bone that makes up the remaining 25 percent (Figure 2-1). Most bones are hollow structures in which the outer cortical bone shell defines the shape of the bone. This cortical shell is essential because it provides strength, sites for firm attachment of the tendons, and muscles and protection without excessive weight. The inner trabecular network has two important functions. It provides a large bone surface for mineral exchange. In addition, trabecular bone helps to maintain skeletal strength and integrity, as it is particularly abundant in the spine and at the ends of the long bones, sites that are under continuous stress from motion and weight-bearing. Fractures are common at these sites when the bone is weakened (Kontulainen, Sievanen et al. 2003). The rods and plates of trabecular bone are aligned in a pattern that provides maximal strength without too much bulk, much in the way that architects and engineers design buildings and bridges. The shape and size of both cortical and trabecular bone can respond to different kinds of stress produced by physical activity. For example, in most people the cortex of their dominant arm is larger than that of their non-dominant arm. The difference in cortex size is even larger for tennis players and other athletes who routinely use a dominant arm in their sporting activities. Bones do not work in isolation, but rather are part of the musculoskeletal system, providing the “lever” that allows muscles to move (by pulling on the lever). Thus muscle activity is important for the normal function of the bone. When the mechanical force produced by muscle is lost𠅏or example, in patients with muscular dystrophy or paralysis𠅋one mass and strength are also rapidly lost. Many bones in the skeleton also have connecting joints that provide greater flexibility of movement. These joints are sites of great mechanical stress and are subject to injury and to degeneration with aging. The most common type of joint degeneration is osteoarthritis, a painful, degenerative condition that affects the hip, knees, neck, lower back, and/or small joints of the hand. These joint diseases result from very different causes and require very different management than do bone diseases, and consequently they are not covered in this report. However it is important to recognize that the bones, joints, and muscles are the key parts of an integrated “musculoskeletal system.” Problems with any one component of this system can affect the other components. Thus, weakness of the muscles can lead to loss of bone and joint damage, while degeneration of the joints leads to changes in the underlying bone, such as the bony spurs or protuberances that occur in osteoarthritis.

Figure 2-1

Frontal Longitudinal Midsection of Upper Femur. Source: Gray 1918.


Bone and energy metabolism

Bone and body composition

Epidemiologic studies indicate that there is an interaction between body fat and bone mass, leading to an initial perception of a positive role of adiposity on bone strength (64). However, despite a considerable body of areal BMD data, there remains controversy as to whether fat has a positive or detrimental effect on bone in both the pediatric and adult populations. There are a number of cross-sectional studies suggesting that fat mass may have a negative effect on bone during childhood and adolescence (65,66). However, there remains a need for longitudinal studies of the relationship between fat and bone from childhood to adulthood to determine whether there are key stages during which excessive fat limits bone mass accrual. The detrimental effect of excessive mechanical loading on bone from excess fat mass in children has been based on the increased risk of slipped capital femoral epiphysis (67) and tibia vary in obese children (68). But, major concerns that excess fat mass may have a detrimental effect on bone mass acquisition in children originated from observations that obese children were overrepresented in fracture groups in studies that sought to evaluate the prevalence of fractures in children (69–71). Cross-sectional studies in different age groups have also alluded to a potential change in the relationship between fat and bone from early childhood into adolescence. The Avon Longitudinal Study of Parents and Children (ALSPAC) project from Bristol in the UK is a long-term health research project that enrolled more than 14 000 mothers during pregnancy in 1991 and 1992, and subsequently studied the health and development of their children (72). Cross-sectional analysis of the relationship between fat mass and bone in this cohort of children at 9.9 years demonstrated a strong positive relationship between total body fat mass and total body (minus the skull) bone mass and area, before and after adjustment for height and lean mass. However, as girls progressed through puberty, the positive relationship between fat and bone mass was attenuated and subsequently reversed the same relationship was not observed in boys as there were an insufficient number of boys who had progressed far enough into puberty to qualify (72). There are other studies suggesting that an increase in fat mass, particularly intra-abdominal adiposity, may be detrimental to the growing skeleton, particularly during the pubertal period (73–75).

In adults, low body weight has detrimental effects on bone mass and is associated with enhanced fracture risk (76). Additionally, rapid weight loss leads to bone loss in sites that support weight, such as lumbar spine and proximal femur, but also in regions free of mechanical stress (i.e., 1/3 radius) (77,78). However, closer examination of the changes in body composition and in the hormonal profiles of the adipose tissue in obesity leads to some degree of ambiguity. For example, several studies have shown that the rate of fracture in obese postmenopausal women is far greater than would be predicted by normal or high bone mineral density often seen in obese patients (79).

In an audit of postmenopausal women presenting with low trauma fracture to a Fracture Liaison Service, the prevalence of obesity was 28% (80), whilst in the Global Study of Osteoporosis in Women (GLOW) the incidence of low trauma fractures was similar in obese and non-obese postmenopausal women (79). The distribution of fracture sites differ between obese and non-obese women fractures of the leg, ankle, and humerus being reported more commonly in obese women whereas fractures of the hip, wrist and pelvis are less prevalent in this group (81,82). The Study of Osteoporotic Fractures BMD of 1377 examined obese postmenopausal women encompassing patients from the cohort with and without nonvertebral fractures. The results showed that obese postmenopausal women who sustained nonvertebral fractures had significantly lower BMD on average than obese women without fracture, and were more likely to have a past history of fracture (83).

Visceral adipose tissue (VAT), which has been tied to insulin resistance, has also been evaluated in relation to bone mass. Although, previous study suggested a positive correlation between visceral and BMD (84), recently published data indicate a detrimental effect of VAT on bone mass. In attempt to circumvent imprecise measurement of visceral fat, Russel et al used MRI to accurately assess visceral fat in 30 adolescent girls (85). VAT was found to be a negative predictor of bone mass. Another study, with adolescent girls, supported the negative effect of visceral fat on BMD (86). In Korean healthy men and women, it was found that visceral fat, measured by computed tomography, was independently and negatively associated with bone mass (87). Aligned with these studies, Bredella et al evaluated in 68 obese (BMI=36.7±4.2 kg·m −2 ) premenopausal women the differential effects of abdominal fat depots and muscle on trabecular BMD of the lumbar spine (88). Quantitative computed tomography (QCT) was used to assess body composition and lumbar trabecular BMD. There was an inverse association between BMD and VAT, independent of age and BMI (88). Finally, in unpublished work, Shane and colleagues have shown that trunk fat, as measured by DXA, was inversely related to trabecular bone volume fraction and bone formation rate by histomorphometry (Cohen, 2012 submitted).

While the stereotype of androgenic and gynecoid patterns of obesity drew attention to visceral and subcutaneous fat as unhealthy and healthy adipose tissue, it is clear that white fat accumulation in other sites may also have adverse effects (89). For instance, intra muscular fat impairs muscle performance, and is directly involved in myocyte insulin resistance (90–92). However, two other types of adipose tissue impact energy metabolism and bone homeostasis. The brown adipose tissue (BAT), enriched with iron-mitochondria for non-shivering thermogenesis, is directly connected to temperature control in neonates. Recent evidence indicates its persistence in some adults (93,94) and a positive relationship between BAT volume and bone mass (95). The other adipose depot, bone marrow, is involved in bone remodeling by its effects, direct or indirect, on marrow mesenchymal stem cell differentiation.

Postmenopausal, senescence and glucocorticoidinduced osteoporosis are all associated with low bone mass and marrow adipose tissue (MAT) accumulation (96). Not surprisingly, aging, menopause and hypercortisolism are associated with gain of adipose tissue, especially in the visceral depot. Nonetheless, there are other circumstances that influence bone marrow micro-environmental changes, including hematopoietic, skeletal and adipogenic tissues. The transition of the hematopoietic marrow “red marrow” to one enriched in adipocytes, “yellow marrow”, takes place early in life, during bone accrual. Consequently, bone mass gain is not irreconcilable with adipogenesis in the bone marrow (97). Indeed, in appropriate physiological conditions, bone marrow adipocytes might be part of a favorable condition for bone mass formation by supporting ‘local’ energy utilization and secreting paracrine factors to stimulate osteoblast activity (98). Noteworthy, growth spurt occurs in a coordinated process that allows overall acquisition of bone, lean and fat mass.

During caloric restriction in young mice, and anorexia nervosa in humans, marrow adipose tissue increased in contraposition to the catabolic state in other compartments. Eckuland et al described unequivocal augmentation of marrow fat in a group of adolescents with anorexia nervosa in comparison to a control group (99). In another study, the investigation of the hormonal/metabolic profile of patients with anorexia nervosa showed normal insulin sensitivity and increased levels of serum adiponectin in relation to normal weight control women (100). The relevance of marrow fat expansion in conditions of negative caloric balance still is speculative a comprehensive discussion has been recently published by Devlin (2010) (101).

Cellular interactions

The bone marrow is a complex microenvironment, comprising of different cell types (e.g., macrophages, adipocytes, fibroblasts), which together secrete a specialized extracellular matrix. Critical for hematopoietic stem cell (HSC) maintenance, osteoblasts line the inner surface of the trabecular bone (102). When osteoblast-HSC contact is lost, the HSCs progress to form myeloid and lymphoid progenitors (103). The lymphoid lineage produces B, T and NK cells, whereas the myeloid lineage produces granulocytes, erythrocytes and platelets (101). By age 20, the appendicular skeleton is nearly all converted from red to fatty yellow marrow. In the axial skeleton, hematopoiesis continues into adulthood, but there is fatty infiltration of the vertebral bodies with aging (101). Changes in mammalian HSCs may affect the progression of MSCs into osteoblasts or adipocytes (104,105,106). For example, low bone mass is a feature of individuals with hemolytic anemia, a clinical condition associated with enhanced marrow adiposity (107–109).

Osteoblasts and adipocytes share a common progenitor cell, the mesenchymal stromal cell, (MSC), which also serves as a source of progenitors for marrow fibroblasts, chondrocytes, and supporting stroma for hematopoietic cells (110,111). Lineage allocation of marrow MSCs towards either adipocytes or osteoblasts is a finely tuned event in which lineage-specific transcription factors (such as Runx2 and Osterix for osteoblasts and PPARg2 for adipocytes) play critical roles. Importantly, in some but not all situations, lineage allocation of MSCs towards either of these cell types is considered to be mutually exclusive i.e. activation of PPARg2 leads to enhanced adipogenesis at the expense of osteoblastogenesis and is associated with reduced expression and function of osteogenic transcription factors such as Dlx5, Msx2, Runx2 and Osterix (112,113). In line with this, suppression of PPARγ is reported to stimulate osteoblastogenesis and represses adipogenesis (114). These observations are also consistent with the findings from aged mice models, where marrow adiposity is increased, bone mass is reduced, and there is enhanced PPARg2 expression (115). Following the expansion of preadipocytes, MSCs differentiate into mature adipocytes under the tight control of multiple transcription factors, including C/EBPβ/δ and PPARγ. Among these, PPARγ, a nuclear receptor and transcription factor, plays a central role in adipogenesis, as evidenced by the finding that the loss of PPARγ in mouse embryonic fibroblasts leads to a complete absence of adipogenic capacity (116).

Surrounding trabecular bone, bone marrow is laden with multipotent stem cells. Indeed, most progenitor and differentiated cells originate in bone marrow, and directly or indirectly, contribute to overall energy metabolism. For example, enucleated erythroid cells are specialized to transport oxygen, a crucial component for aerobic oxidation of energetic substrates in the mitochondria. Osteoclasts can secrete inflammatory factors, which could induce insulin resistance. Surprisingly, osteoclasts contain more mitochondria than any other cell type, supporting the premise that energy utilization is an essential element in bone remodeling. Although less attention has focused on energy utilization in osteoblasts, it is clear that substrate utilization is essential for a step up in mitochondrial biogenesis during collagen synthesis. Moreover, differentiation of MSCs into osteoblasts is related to increased oxidative phosphorylation, as ATP is essential for collagen matrix synthesis.

Leptin and osteocalcin: fat-bone cross-talk

Exclusively produced by adipocytes, leptin secretion is positively correlated with adipose tissue mass. Leptin crosses the blood-encephalic barrier to stimulate its receptor in the hypothalamus, thereby triggering complex actions related to energy modulation, pubertal onset and control of bone remodeling. Mice with congenital absence of leptin (ob/ob mice) or the leptin receptor (db/db mice) exhibit a complex phenotype, including obesity and high bone mass in the vertebrae (117,118). This occurs despite hypogonadism and hypercortisolism, conditions that would tend to lower bone mass in mice.

The combination of increased bone mass with leptin deficiency or resistance, respectively, in ob/ob and db/db mice serves as a basis to conclude that leptin acts centrally to inhibit the accumulation of bone mass through the sympathetic nervous system. In accordance with this observation there are studies showing: 1) mice harboring a mutation that leads to a partial gain of function in leptin signaling exhibit normal appetite, but an osteoporotic phenotype (119,120) 2) neuron-specific deletion of Lepr induces the bone phenotype of ob/ob mice, whereas an osteoblast-specific deletion has no such effect (117,119), 3) the skeletal phenotype of ob/ob mice can be corrected by leptin administration into the third ventricle (121), and 4) chemical lesion of neurons in the ventromedial hypothalamus recapitulates the bone changes observed in leptin-deficient mice (10). On the other hand, there are other studies showing that leptin has a peripheral effect of direct stimulation of bone formation. In vitro, it was demonstrated that leptin stimulates osteoblastic bone formation (122) and decreases osteoclastogenesis (123). In support of that data, it was demonstrated in vivo by the experimental administration of leptin in rodents, that leptin increases bone mass (124). In the clinical field, the peripheral beneficial effect of leptin may be defended by the increased levels of leptin in obese patients, which usually show high bone mass, and decreased leptin in young women with anorexia nervosa. Although these are important results, obesity and anorexia nervosa are complex disorders characterized by several hormonal disturbances. Thus, it is hard to attribute the bone profile in obesity and anorexia nervosa to alterations only in serum levels of leptin.

While leptin is the adipocyte messenger for the connection between adipose tissue and bone, osteocalcin is the molecule that communicates signals from bone to adipose tissue. Osteocalcin is a small noncollagenous peptide produced predominantly by osteoblasts. Osteocalcin is carboxylated post-translationally on three glutamic acid residues in a vitamin K-dependent manner by the enzyme gamma c-carboxylase. The product, the amino acid c-carboxyglutamic acid, has the capacity to bind to calcium. Decarboxylation decreases the hydroxyapatite-binding affinity of osteocalcin. Undercarboxylated osteocalcin that enters the circulation regulates energy metabolism, through increases in β-cell proliferation, insulin secretion and insulin sensitivity.

Insulin response in target tissues is strongly dependent on its capacity to trigger the tyrosine kinase activity of its own receptor. Moreover, insulin signaling may be negatively modulated by the existence of intracellular tyrosine phosphatase (125). Esp encodes a tyrosine phosphatase, osteotesticular protein tyrosine phosphatase (OST-PTP), and is expressed in a limited number of cells (e.g., osteoblasts, sertoli cells and embryonic stem cells). The silencing of Esp provokes hypoglycemia due to hyperinsulinemia, with increased serum levels of C-peptide associated with normal glucagon concentrations (126). In addition to increased glucose tolerance and insulin sensitivity, these mice exhibited an increase in mitochondrial area and mitochondrial proteins, such as Mcad, acyl-coA, UCP-2, PGC1α and NFR1, in the gastrocnemius muscle, compatible with augmented mitochondrial activity in Esp −/− mouse (127). Esp −/− mice show a lean phenotype, which most likely occurs as consequence of increased levels of adiponectin.

In addition to enhanced circulatory levels of adiponectin, Esp −/− mice also have increased serum levels of undercarboxylated osteocalcin. In view of the finding that the expression of the osteocalcin gene and the serum levels of osteocalcin were normal in these mice, it seems that OST-PTP acts on the decarboxylation of osteocalcin and its entry into the bloodstream. In contrast to the Esp −/− mice, the deletion of the osteocalcin gene confers a decrease in insulin secretion and an increase in circulatory glucose levels. Ocn −/− mice have an impairment in insulin sensitivity and a decreased number of pancreatic β-cells. Moreover, the metabolic phenotype of Esp −/− is completely reversed by crossing those mice with mice lacking one allele of Ocn (125). As expected, administration of recombinant uncarboxylated osteocalcin to Ocn −/− mice corrected the glucose intolerance and insulin secretion.

Finally, the connection between bone and energy metabolism can further be exemplified by studies showing bone loss in experimental and clinical states of insulinopenia, such as diabetes mellitus type 1 (DM1). In both cases, low serum levels of osteocalcin or decreased osteocalcin expression in bone reflect impaired bone formation and a fundamental defect in osteoblasts function during states of insulin deficiency. As noted, additional evidence of bone regulation by insulin has been acquired through specific genetic deletion of insulin receptors in osteoblasts (128). Insulin receptor silencing resulted in low bone mass and was associated with increased expression of Twist2 and decreased expression of osteocalcin and Runx2 (129). The transcriptional factor Twist2 acts as a cellular inhibitor of Runx2 the latter is a key determinant of osteoblast differentiation.


Considerations

Both bones and muscles tend to break down as an individual ages. While muscle can be built and rebuilt throughout your lifetime, bone mass typically peaks at around age 20. Eating to emphasize bone and muscle health in childhood and the teen years can help set you up for healthier bones and muscles throughout your life. This is especially important for females because women tend to lose more bone mass as they age and have a higher risk of osteoporosis later in life.

Bridget Coila specializes in health, nutrition, pregnancy, pet and parenting topics. Her articles have appeared in Oxygen, American Fitness and on various websites. Coila has a Bachelor of Science in cell and molecular biology from the University of Cincinnati and more than 10 years of medical research experience.


The trouble with visceral fat

Body fat, or adipose tissue, was once regarded as little more than a storage depot for fat blobs waiting passively to be used for energy. But research has shown that fat cells — particularly visceral fat cells — are biologically active. One of the most important developments [since the mid-1990s] is the realization that the fat cell is an endocrine organ, secreting hormones and other molecules that have far-reaching effects on other tissues.

Before researchers recognized that fat acts as an endocrine gland, they thought that the main risk of visceral fat was influencing the production of cholesterol by releasing free fatty acids into the bloodstream and liver. We now know that there's far more to the story. Researchers have identified a host of chemicals that link visceral fat to a surprisingly wide variety of diseases.

Subcutaneous fat produces a higher proportion of beneficial molecules, and visceral fat a higher proportion of molecules with potentially deleterious health effects. Visceral fat makes more of the proteins called cytokines, which can trigger low-level inflammation, a risk factor for heart disease and other chronic conditions. It also produces a precursor to angiotensin, a protein that causes blood vessels to constrict and blood pressure to rise.

Gut check

A tape measure is your best home option for keeping tabs on visceral fat. Measure your waistline at the level of the navel — not at the narrowest part of the torso — and always measure in the same place. (According to official guidelines, the bottom of the tape measure should be level with the top of the right hip bone, or ilium — see the illustration — at the point where the ilium intersects a line dropped vertically from the center of the armpit.) Don't suck in your gut or pull the tape tight enough to compress the area. In women, a waist circumference of 35 inches or larger is generally considered a sign of excess visceral fat, but that may not apply if your overall body size is large. Rather than focus on a single reading or absolute cut-off, keep an eye on whether your waist is growing (are your pants getting snug at the waist?). That should give you a good idea of whether you're gaining unhealthy visceral fat.


Bones

Bone, although strong, is a constantly changing tissue that has several functions. Bones serve as rigid structures to the body and as shields to protect delicate internal organs. They provide housing for the bone marrow, where the blood cells are formed. Bones also maintain the body's reservoir of calcium. In children, some bones have areas called growth plates. Bones lengthen in these areas until the child reaches full height, at which time the growth plates close. Thereafter, bones grow in thickness rather than in length, based on the body's need for additional bone strength in certain areas.

Flat (such as the plates of the skull and the vertebrae)

Tubular (such as the thighbones and arm bones, which are called long bones)

Some bones have combinations of these. All bones have essentially the same structure. The hard outer part (cortical bone) consists largely of proteins, such as collagen, and a substance called hydroxyapatite, which is composed mainly of calcium and other minerals. Hydroxyapatite is largely responsible for the strength and density of bones. The inner part of bones (trabecular bone) is softer and less dense than the hard outer part but still contributes significantly to bone strength. A reduction in the amount or quality of trabecular bone increases the risk of fractures (breaks). Bone marrow is the tissue that fills the spaces in the trabecular bone. Bone marrow contains specialized cells (including stem cells) that produce blood cells. Blood vessels supply blood to the bone, and nerves surround the bone.

Did You Know.

Bone structure adjusts throughout life in response to activity and mechanical stress (for example, weight-bearing exercise).

Bones undergo a continuous process known as remodeling (see Osteoporosis). In this process, old bone tissue is gradually replaced by new bone tissue. Every bone in the body is completely reformed about every 10 years. To maintain bone density and strength, the body requires an adequate supply of calcium, other minerals, and vitamin D and must produce the proper amounts of several hormones, such as parathyroid hormone, growth hormone, calcitonin , estrogen, and testosterone . Activity (for example, weight-bearing exercises for the legs) helps bones strengthen by remodeling. With activity and optimal amounts of hormones, vitamins, and minerals, trabecular bone develops into a complex lattice structure that is lightweight but strong.

Bones are covered by a thin membrane called the periosteum. Bone injuries are painful because of pain-sensing nerves located mostly in the periosteum. Blood enters bones through blood vessels that enter through the periosteum.


Exercise releases hormone that helps shed, prevent fat

If a workout feels like more pain than gain, here's some motivation: Exercise releases a hormone that helps the body shed fat and keeps it from forming.

A group led by a University of Florida Health researcher has learned more about how the hormone irisin helps convert calorie-storing white fat cells into brown fat cells that burn energy. Irisin, which surges when the heart and other muscles are exerted, also inhibits the formation of fatty tissue, according to the researchers.

The findings, published recently in the American Journal of Physiology -- Endocrinology and Metabolism, show that irisin may be an attractive target for fighting obesity and diabetes, said Li-Jun Yang, M.D., a professor of hematopathology in the UF College of Medicine's department of pathology, immunology and laboratory medicine. The study is believed to be the first of its kind to examine the mechanisms of irisin's effect on human fat tissue and fat cells, researchers said.

Irisin appears to work by boosting the activity of genes and a protein that are crucial to turning white fat cells into brown cells, the researchers found. It also significantly increases the amount of energy used by those cells, indicating it has a role in burning fat.

Researchers collected fat cells donated by 28 patients who had breast reduction surgery. After exposing the samples to irisin, they found a nearly fivefold increase in cells that contain a protein known as UCP1 that is crucial to fat "burning."

"We used human fat tissue cultures to prove that irisin has a positive effect by turning white fat into brown fat and that it increases the body's fat-burning ability," Yang said.

Likewise, Yang and her collaborators found that irisin suppresses fat-cell formation. Among the tested fat-tissue samples, irisin reduced the number of mature fat cells by 20 to 60 percent compared with those of a control group. That suggests irisin reduces fat storage in the body by hindering the process that turns undifferentiated stem cells into fat cells while also promoting the stem cells' differentiation into bone-forming cells, the researchers said.

Knowing that the body produces small quantities of fat-fighting irisin underscores the importance of regular exercise, Yang said. More than two-thirds of U.S. adults are overweight or obese, according to the National Institutes of Health. While it's possible that the beneficial effects of irisin could be developed into a prescription medication, Yang said that is uncertain and remains a long time away.

"Instead of waiting for a miracle drug, you can help yourself by changing your lifestyle. Exercise produces more irisin, which has many beneficial effects including fat reduction, stronger bones and better cardiovascular health," Yang said.

The present study builds on other findings about irisin's beneficial effects. In 2015, Yang's group found that the hormone helps improve heart function in several ways, including boosting calcium levels that are critical for heart contractions. In June, Yang and a group of scientists in China showed that irisin reduced arterial plaque buildup in mouse models by preventing inflammatory cells from accumulating, resulting in reducing reduction of atherosclerosis. Those findings were published in the journal PLOS One.

The findings about irisin's role in regulating fat cells sheds more light on how working out helps people stay slender, Yang said.

"Irisin can do a lot of things. This is another piece of evidence about the mechanisms that prevent fat buildup and promote the development of strong bones when you exercise," she said.


Hormones are chemical messengers produced by endocrine glands that travel to distant organs and tissues in our body and tell them what to do.

Hormones affect many different processes in the body, from reproduction and menstrual cycle regularity to mood and metabolism. When there’s an imbalance in certain hormones, that can set the stage for weight gain (or difficulty losing weight) and negative health consequences.

We take a look at which hormones may be affecting your weight and some tips for achieving a hormone balance that favors reaching your healthiest weight and optimal health.

In this post, we cover:

  • Some of the hormones that may impact your health and weight, including insulin, cortisol, thyroid hormones, sex hormones, and other hormones
  • The importance of blood sugar balance for hormonal health
  • Why a personalized approach is needed for hormone balance

Insulin

Insulin is a hormone produced by beta cells in the pancreas in response to elevated blood glucose (sugar). Insulin acts like a “key” that opens the door to your cells to let glucose in where it can be used for energy. As glucose travels into the cells, blood sugar goes down.

Insulin resistance happens when the cells start ignoring the signal that insulin is trying to send. As a result, blood sugar stays high, and your pancreas produces even more insulin. In the meantime, your body’s cells are literally starving for energy and sending strong signals to your brain that you need to eat carbs.

Our bodies generally exist in one of two states: fed (the postprandial state) and fasted. When we have recently eaten, food is being digested, absorbed, and used immediately for energy or stored for later. On the other hand, when it’s been more than 4 hours since a meal, we start to burn stored energy for fuel.

With insulin resistance, your body will act as if it is always in the fed state, never able to tap into that stored energy (fat) for energy.

Therefore, keeping insulin levels low and steady is a crucial part of maintaining a healthy weight.

Cortisol

Cortisol is a hormone produced by the adrenal glands. While we mainly think of cortisol as a stress hormone, it does have other functions in the body. It regulates how the body converts fats, proteins, and carbohydrates into energy and can also affect your sleep/wake cycle.

Because cortisol is a “fight or flight” hormone, it readies our bodies for those situations: blood sugar goes up, metabolism goes down. High cortisol can also worsen insulin resistance and lead to an increase in appetite. High cortisol has also been linked to an increase in belly fat.

Part of the problem is that our bodies make cortisol in response to perceived stress. Your body does not know the difference between the stress you feel when you are in life-threatening danger (such as a lion about to pounce on you) versus the stress you feel when you are, say, running late for work or have an upcoming work deadline.

Furthermore, there’s psychological stress, which we’re all too familiar with, and then there’s physiological stress — such as the stressful state of blood sugar being too low, blood sugar imbalances in general, having too much caffeine, or overexercising or under-sleeping.

Thyroid

Thyroid hormones are made by the thyroid gland in response to thyroid stimulating hormone produced by the pituitary gland. Thyroid hormones (T4 & T3) are necessary for the proper functioning of every cell in the body. Thyroid hormones influence digestion and metabolism. Our metabolism (and our ability to burn fat) turns up and down in response to more or less thyroid hormone production.

With hypothyroidism, or low thyroid hormone production, the cause can be either auto-immune (such as with Hashimoto’s thyroiditis, the most common cause of hypothyroid), or it can be non-autoimmune. When our stress hormones (including cortisol) are high, thyroid hormone production decreases.

Sex Hormones

There are various reproductive hormones that, in addition to regulating the menstrual cycle and fertility in women (and men!), can also impact weight.

Estrogens, mainly produced by the ovaries but also produced and stored in fat are one such hormone. With estrogens, there’s a sweet spot — too much can cause weight gain, and too little can also cause weight gain. An excess of estrogen promotes fat storage in the body in a female pattern (eg, on the hips and thighs). On the other hand, when estrogen drops at menopause, it promotes weight gain in the form of visceral (or belly) fat.

Progesterone, a hormone only produced immediately following ovulation by the corpus luteum in the ovaries, balances the effects of estrogen. Progesterone increases metabolism and body temperature, which burns more calories. Having progesterone that is too low in comparison to estrogen may result in increased insulin, increased belly fat, and a decreased metabolism.

Androgens such as testosterone (made by the testes in men and primarily in the ovaries in women) and dehydroepiandrosterone, or DHEA (made primarily in the adrenals), promote weight gain because they are in essence, anabolic steroid hormones. They promote muscle mass and bone density but can also promote fat gain in the excess of energy, which is primarily stored as belly fat.

Other Hormones

Other hormones that can affect weight include leptin, ghrelin, and adiponectin.

  • Leptin is “the fullness hormone” – produced by fat cells, leptin regulates appetite (when fat goes down, appetite goes up, and vice versa)
  • Ghrelin is “the hunger hormone” – produced by the stomach, ghrelin signals hunger to the brain
  • Adiponectin – produced by fat, improves insulin sensitivity and promotes fat breakdown. Low levels are associated with obesity

Hormone-Balancing Tips

So, what can you do to take care of your hormonal health and achieve a hormone balance that favors optimal health and your healthiest weight? What works for each of our bodies will be different, so a personalized approach is key. As a starting point, here are some tips:

  • Eat a blood-sugar balancing diet to improve insulin sensitivity — this means eating balanced meals that work best for your unique biology, containing adequate protein, fat, and fiber
  • Incorporate resistance training using your body’s largest muscles to improve insulin sensitivity as well as cardiovascular exercise to mobilize fat stores
  • Address high cortisol by getting enough sleep, actively managing stress levels, and avoiding extremes when it comes to diet or exercise
  • Make sure your thyroid hormones and sex hormones are within a normal range
  • Work with a practitioner who specializes in hormones if you need more help!

Let's Recap

  • Several hormones can have an impact on weight. Imbalances in insulin, cortisol, thyroid hormones, sex hormones, and others may be impacting your ability to lose weight
  • Balancing your hormones is crucial to achieving and maintaining a healthy weight
  • By focusing on balancing your blood-sugar with nutrition guidance tailored to your unique biology, lowering your stress levels, hormone imbalances can be overcome!

About the author

This post was written by Melissa Groves Azzaro, RDN, LD, an award-winning integrative registered dietitian and owner of The Hormone Dietitian LLC. She helps busy women with hormone imbalances, PCOS, and fertility issues regain regular periods and get pregnant naturally. She uses a functional medicine, food-first approach that combines holistic lifestyle changes with evidence-based medicine.

She works virtually with clients one-on-one and in group programs, has a self-study course on PCOS called the PCOS Root Cause Roadmap, and is the author of A Balanced Approach to PCOS. Melissa currently serves as Chair-Elect for the Dietitians in Integrative and Functional Medicine Dietetic Practice Group, and has contributed to several online publications, including Healthline.


The Deadliest Sin

From survival of the fittest to staying fit just to survive: scientists probe the benefits of exercise -- and the dangers of sloth.

Sidebars:

The first formal epidemiologic study linking activity to better health took place in the late 1940s, when a researcher in London, Jeremy Morris.

Fuel for an Active Lifestyle Everyone should eat a balanced diet, but exercisers in particular should pay attention to the following advice.

Genetic endowments aside, an elite endurance athlete and the average daily walker are, in their adaptations to exercise, different less in kind.

In the bottle before you is a pill, a marvel of modern medicine that will regulate gene transcription throughout your body, helping prevent heart disease, stroke, diabetes, obesity, and 12 kinds of cancer — plus gallstones and diverticulitis. Expect the pill to improve your strength and balance as well as your blood lipid profile. Your bones will become stronger. You'll grow new capillaries in your heart, your skeletal muscles, and your brain, improving blood flow and the delivery of oxygen and nutrients. Your attention span will increase. If you have arthritis, your symptoms will improve. The pill will help you regulate your appetite and you'll probably find you prefer healthier foods. You'll feel better, younger even, and you will test younger according to a variety of physiologic measures. Your blood volume will increase, and you'll burn fats better. Even your immune system will be stimulated. There is just one catch.

There's no such pill. The prescription is exercise.

"We've spent years studying numerous nutritional and lifestyle factors," says Frank Hu, associate professor of nutrition and epidemiology at the Harvard School of Public Health (SPH). "Good nutrition is essential for health," but once-promising discoveries, including antioxidant supplements like beta-carotene, have turned out not to be magic pills. "The single thing that comes close to a magic bullet, in terms of its strong and universal benefits, is exercise."

During the last 10 years, epidemiologists like Hu have clearly demonstrated exercise's protective effects against many serious diseases. And yet, as one medical researcher studying exercise in elderly populations put it, "Exercise is often overlooked." Though a large body of epidemiological research shows its protective effects against numerous maladies, there has been less research into how these effects actually take place. Exercise can change virtually every tissue in the body, but because it works by many different pathways — metabolic, hormonal, neurological, and mechanical — understanding why and how it works, in an integrated way, is not easy. We know exercise is good for us. But why?

The Sedentary American

Seventy-five percent of the population of the United States fails to meet even the minimum government recommendation for daily exercise: 30 minutes of walking or its equivalent, accumulated in bouts as short as 8 to 10 minutes. The recommendations have in some ways become easier over the last three decades (see "Exercise: A Changing Prescription"), but we have given up physical activity of any kind even faster.

"America loves to think of itself as a youthful nation focused on fitness, but behind the vivid media images of robust runners, Olympic Dream Teams, and rugged mountain bikers is the troubling reality of a generation of young people that is, in large measure, inactive, unfit, and increasingly overweight." So begins Promoting Better Health, a Centers for Disease Control (CDC) report. "Walking and bicycling by children aged 5 to 15 dropped 40 percent between 1977 and 1995," it continues. Even in schools, budget constraints have led to suspension of physical education classes. Steven Gortmaker, professor of society, human development, and health at SPH, and colleagues recently used a tracking device to measure the minute-by minute physical activity of school-age children throughout the day. The highest levels of activity, he told a group of public-health professionals at an October 2003 seminar on the "Worldwide Childhood Obesity Epidemic," occur during the hours when children travel to and from school. Since 1980, the percentage of American children who are overweight has doubled.

In 2003, the CDC declared obesity the most important public-health issue in the United States. Obesity increases the risk for type 2 diabetes, cardiovascular disease, and some cancers. Two-thirds of Americans are now overweight or obese. In Michigan, half the men are overweight — 34 pounds on average — and the problem has been steadily growing for more than 25 years. Children and teenagers are contracting "adult-onset" diabetes at a rapidly increasing pace. As Dr. Kenneth Cooper, M.P.H. '62, one of the country's foremost experts on physical activity (he coined the word aerobics) puts it, "In Texas, we may have the first generation in which the parents will outlive their kids," as obese children who develop diabetes before 14 years of age can expect their lifespan to be reduced by 17 to 29 years.

This epidemic is not confined to any particular region of the United States. It is ubiquitous, Gortmaker says, in rural and urban communities, among both the wealthy and the poor.

The cause? Epidemiologists call it an energy imbalance: too much food and too little activity.

The imbalance is small, equivalent to the caloric content of one sugar-sweetened drink per day, Gortmaker says, suggesting that giving that up, or forgoing a few bites at dinner, could prevent further weight gain. Soda, fast food, and the super-sizing of portions are frequently cited as culprits on the intake side of the equation, because a typical fast-food meal (double cheeseburger, soda, fries, and a dessert) can contain, at 2,200 kilocalories, enough energy to power a 120-pound person through an entire marathon. Even so, by some estimates, this country's per capita caloric intake in the last 20 years has not increased enough to account for the increased body mass in the same period. For that, we have to look to other changes in lifestyle.

"Obviously, there is no longer any need for physical activity for transportation, food-seeking, or daily survival," says JoAnn Manson, M.D., chief of preventive medicine at Brigham and Women's Hospital in Boston and a professor at SPH and Harvard Medical School (HMS). "We have labor-saving devices everywhere. You can get through the day expending virtually no energy, doing virtually no physical activity. Many people do choose that lifestyle."

The modern lifestyle is a radical departure from the one in which we evolved. Though scholars disagree on the relative amount of time that our hunter-gatherer ancestors spent running versus walking, the evidence suggests that they covered a lot of ground either way: 10 to 20 kilometers a day walking among men, says professor of biological anthropology Richard Wrangham, "and about half that for women. Chimpanzees, by comparison, walk only 2 to 4 kilometers a day, and all other apes walk even less. The ordinary thought," he says, "is that women would have done this every day, because they would have been the providers of the staple foods." Activity levels were probably more variable with men: "[They] would have been bringing in the more chancy foods as well as relaxing after a particularly heavy day the day before." Wrangham's colleague, professor of anthropology Daniel Lieberman, thinks running has long played an important role in human societies. He points not only to anthropological evidence (the running traditions of Native Americans, for example), but also to a host of musculoskeletal adaptations that he says can only be explained as adaptations for running, such as the Achilles tendon, which "has no function in walking, is absent in chimpanzees, and first appears in the genus Homo." Either way, the human record tells a story of frequent, long distance, aerobic exercise.

Epidemiologists debate the merits of walking versus running, but agree that studies link increasing activity levels to better health along a continuum ranging from extreme sedentary behaviors to the "vigorous exercise" of subjects who run more than 20 miles a week. Hu believes that in discussions of the benefits of exercise, the extreme low end of the spectrum — sedentary behavior — is too often neglected. Being sedentary is an independent risk factor for coronary heart disease (CHD), notes Manson, even among people who do exercise. "We found in the Women's Health Initiative [a study of more than 160,000 postmenopausal women aged 50 to 79] that the longer you sit each day, the greater your risk of cardiovascular disease, even after you adjust for time spent in recreational activity." She tells her patients to get up and walk around as much as possible, and to reduce screen time (TV, video games, working at the computer). "The key is to minimize sitting," she says. Hu agrees. Given that the average American spends 4 to 5 hours a day watching television, he says, "For most people, it is not sufficient to address only the exercise side of the coin. Equally important is the sedentary side of the coin."

One sedentary behavior in particular has drawn the attention of public-health researchers. In a landmark study that compared watching TV to reading, sitting at a desk, and driving, Hu found that TV watching is far more likely to lead to obesity and diabetes than any of the other sedentary behaviors. First, Hu explains, "when people watch TV, they eat." Second, they tend to make bad food choices: TV watchers eat more junk food and fast food. And when people watch TV, their metabolic rate (the rate at which energy is burned) drops lower than when they sit and read or work on a computer. "The reason is that TV watching is completely passive," says Hu. "It is almost like sleeping — sit back and relax — that's the message." People who watch TV also tend to spend a lot of time at it (women watch at least an hour more per day than men). And so prolonged TV watching — Hu calls it "a major public-health hazard" — displaces other activities that would be better for people's health. Gortmaker, who pioneered studies of television watching among American children (60 percent of whom have a television in the room where they sleep), notes that among youth, time spent watching television is the one behavioral variable most predictive of obesity.

The Case for Physical Activity

An estimated 18 million Americans now have diabetes, a leading cause of heart disease, stroke, blindness, kidney disease, and nerve damage. If current trends continue, the CDC estimates, more than one in three children born in the year 200o will develop diabetes during their lifetime. This is shocking, but not surprising given the American lifestyle. When researchers want to model the disease, they feed mice a high-fat or high-sugar diet and don't let them exercise. "Within a few weeks or months," says Hu, "they will become obese and they will become diabetic." Modern society has put us in almost the same environment, he says, "with an unlimited amount of calories and foods and also very little physical activity."

Diabetes is a metabolic disorder that leads to excess sugar in the blood. More than 90 percent of diabetes is the type 2, or "adult-onset," form of the disease that can be prevented or delayed by exercise. In type 2 diabetes, cells that normally take up sugar in response to the body's secretion of insulin become "insulin resistant," causing blood-sugar levels to spike. (People with type 1 diabetes are sensitive to insulin, but require injections of the hormone because they have lost the ability to make enough for themselves.) In the Nurse's Health Study (a large study of female registered nurses begun in 1976 and based at Channing Laboratory, Brigham and Women's Hospital), Hu found that even walking — a moderate-intensity activity — for 30 to 45 minutes per day lowered the risk of developing type 2 diabetes by 30 to 40 percent. "This reduction is remarkable," he says. "There is nothing else that has stronger and quicker effects than physical activity for preventing diabetes."

"We know that if you get diabetes, there is no cure," Hu continues. "You will live with the disease for the rest of your life." Exercise can help manage diabetes in several ways. Because 75 percent of people with diabetes will die of cardiovascular disease, it is extremely important to prevent or delay the onset of the disease among this population. Walking a half hour to an hour a day lowers a diabetic's risk of dying from heart disease by 40 to 50 percent. A number of drugs are good at controlling blood pressure, he says, "but none of them is as effective as exercise in delaying or preventing cardiovascular complications and preventing deaths among people with diabetes."

Among healthy people, exercise can raise levels of HDL, or "good" cholesterol, improve clotting factors, lower blood pressure, and decrease inflammation. All of these factors, says Hu, reduce the risk of cardiovascular disease: "We have found that both vigorous exercise and walking can substantially reduce the risk of heart attacks and — this was somewhat of a surprise — both kinds of stroke." (Ischemic stroke, caused by insufficient blood flows in the arteries of the brain, is very similar to heart disease. Hemorrhagic stroke occurs when vessels in the brain rupture and bleed.) "Even though their pathophysiology is very different," says Hu, "exercise can decrease the risk of both." Long-term exercise causes the endothelial cells lining the blood vessels to synthesize nitric oxide, a relaxing factor that increases blood flow. People with insufficient nitric oxide in their system are more likely to have stiff blood vessels, hypertension, and other inflammatory factors, he explains. "That's the common pathway leading to both kinds of strokes, and that is why exercise is beneficial in each case."

For similar reasons, exercise has been shown to help fight erectile dysfunction, says Eric Rimm, SPH associate professor of epidemiology and nutrition and assistant professor of medicine at HMS. In a study of older men, Rimm found that exercise enhances the relaxation response necessary for an erection and improves vascular reactivity to stimulation. Nitric oxide again plays a key role, but all the other improvements in circulation associated with exercise can also contribute to improved function. In a German study comparing the effects of exercise to Viagra (sildenafil) and a placebo treatment, men with erectile dysfunction and mild to moderate circulation problems engaged in a two-year program of squatting exercises and pelvic and leg lifts designed to improve blood flow to the pelvis, buttocks, and upper leg muscles. Eighty percent of the exercisers reported better erections, compared with 74 percent taking sildenafil and 18 percent on the placebo.

How much exercise is enough? Some controversy remains about the optimal amount and intensity of exercise required to reap protective benefits against cardiovascular disease. "Some people say you need to do vigorous exercise in order to achieve the benefits," explains Hu. "Others have said that, no matter what kind of exercise you do, if you have the same amount of energy expenditure, you will get the same benefit." Hu thinks that both are probably right. "For the majority of Americans, it is probably not very useful to distinguish moderate- from vigorous-intensity exercise the highest priority is simply to increase their energy expenditure. No matter what they do," he says, "it is better than sitting on the couch."

But people who already exercise can probably reap additional benefit by increasing the intensity of their activity. "We have found that among men, the intensity itself can give you additional cardiovascular protection above and beyond the total amount of exercise you do," Hu says. Vigorous aerobic exercise may be best at burning visceral fat, the metabolically active intra-abdominal adipose tissue that the liver draws on for energy when other fuel sources run low. Fat is not just an energy reserve, researchers have learned in recent years. It can produce and regulate hormones that cause inflammation of the cardiovascular system. Any exercise that gets rid of visceral fat will improve health.

And the optimal amount of exercise? Early studies suggested that when you reached a certain amount of activity, your benefit would plateau. "Our data so far don't support this assumption or hypothesis," says Hu. "Basically, the more the better. There is a straight dose-response relationship in both men and women. For preventing heart disease and stroke," he says, "there is no limit to the benefits of exercise."

But changes in blood pressure and vascular relaxation are not the only effects of exercise on the cardiovascular system, Hu says. Exercise increases the stability of the heart beat, reduces important markers for inflammation in the blood like C-reactive protein, and causes changes in blood lipids (like the size of cholesterol particles) that are still being characterized and understood. It also reduces the coagulability of the blood, by changing the secretion of thrombogenic factors (hormones that control clotting), so that blood can flow more easily to working muscles. This prevents the formation of clots in the blood, further reducing the risk of heart attack and stroke.

Smart Muscle and Cellular Fuel Sensors

When you eat carbohydrates, either simple sugars or starch, both are converted to glucose and your blood-glucose levels rise quickly. Because long-term high blood-sugar levels are not good for your body, brain, or heart, the pancreas immediately responds by secreting the hormone insulin to counter the surge. Insulin decreases blood sugar by signaling skeletal muscles (as opposed to muscles like the heart) to increase their uptake of glucose from the blood, and helps to inhibit the production of new glucose by the liver. In this way, insulin plays an important role in maintaining the proper blood-sugar level.

If you are physically active and lean, your tissues are very sensitive to the effects of insulin, so you need only a small amount to be effective at controlling blood glucose. But if you are obese or sedentary, the muscles and liver are less sensitive to insulin, so that glucose uptake by muscle is reduced and the liver may continue to produce glucose even when your body doesn't need it. Such people are termed "insulin resistant" and tend to have higher blood sugar. Insulin resistance, a component of metabolic syndrome or syndrome X, is present in nearly a quarter of all Americans older than 20, and in 40 percent of those over the age of 60. Many people live with the condition for years without knowing it, until they develop diabetes.

Even for a person with type 2 diabetes, however, a single bout of exercise sends glucose "right into the muscle, and you have increases in glucose uptake that are normal or near normal," says the Joslin Diabetes Center's Dr. Laurie Goodyear, who studies molecular effects of exercise. This suggested to Goodyear and others in the field that even though exercise and insulin can both increase glucose uptake by the muscle, they must work by different mechanisms.

Insulin circulating in the blood normally works by attaching to insulin receptors on the surface of a muscle cell. This activates a complex series of signaling proteins that instruct glucose transporters within the cell to come to the cell membrane, where they pick up blood glucose and carry it into the cell, where it is either stored as glycogen or undergoes numerous reactions that result in the generation of energy.

If you exercise every day, the number of glucose transporters in your muscles increases, making the muscles themselves even more susceptible to the actions of insulin. "This allows less insulin secretion," says Goodyear, "and a better overall regulation of glucose levels in the body." That effect, depending on the type of exercise and the way you eat "could last for 24 to 48 hours after the exercise bout," says Goodyear. "I think this is the fundamental way that exercise can reduce the risk of developing diabetes and can delay the development of diabetes."

A major factor that controls the sensitivity of muscles to the insulin signal is the level of glycogen (stored fuel), she says: "The more you deplete glycogen levels, the more sensitive the muscles will become." Thus, longer and more vigorous activity — jogging for 60 minutes, for example — will have longer-lasting effects on glucose uptake than a short walk.

But the reason exercise works so well in treating people who already have type 2 diabetes has nothing to do with insulin: they already have insulin in the bloodstream, but the muscles don't respond. The current challenge in Goodyear's field, therefore, is to figure out how this separate exercise effect works.

When a muscle contracts, glucose transporters move to the cell membrane — just as they do in the presence of insulin. This suggested to researchers that perhaps exercise activates the same protein-signaling pathways as insulin. Not so, says Goodyear. She and other scientists have since discovered that a molecule called AMP kinase may be a key to the regulation of glucose transport by exercise. The molecule, which is already known to regulate fatty acid oxidation, is now the subject of an "explosion of research," Goodyear says. "It turns out that AMP kinase is probably doing lots of things in the cell besides regulating glucose transport." It may even regulate PGC-1, a gene transcription protein that HMS professor of cell biology Bruce Spiegelman has shown can increase the number of mitochondria (energy-producing structures) in muscle cells, increase fatty acid oxidation, and even induce switches in muscle fiber type — all adaptations to endurance exercise, says Goodyear. For the purposes of glucose transport, AMP kinase acts as a kind of cellular fuel sensor. Pharmaceutical companies are interested in the molecule as a possible drug target — perhaps a first for the field of exercise research.

Despite the possibility of AMP kinase-based medicines for people with diabetes, Goodyear's research has led her to conclude that it is not the only molecule involved in exercise-induced glucose transport. Her laboratory is now searching for another "mystery" signaling protein that may complete our understanding of how exercise improves glucose transport.

Goodyear emphasizes that she is describing just one of the beneficial effects of exercise. "In addition to the metabolic effects," she says, "exercise changes the phenotype [or pattern of gene expression and hence structure] of the muscle in a positive way." When muscle contracts, she says, "It sends some sort of signal to turn on the transcriptional machinery that will increase the expression of proteins promoting better oxidation of fuels, better glucose transport, and decreased muscle fatigue. We all know that when you train, your muscles perform better. Protein synthesis is enhanced. We are trying to find the signals that lead to these beneficial changes in muscle," she says, "but of course there are changes going on throughout the whole body. All the different cells and tissues are affected in some way."

The Cancer Connection

Increasing evidence suggests that exercise's effects on insulin sensitivity and glucose uptake may be important not only for people with diabetes, but also for those at risk for certain cancers.

What is it that makes high levels of insulin so unhealthy? Insulin is a growth hormone, and to the extent it is oversecreted, it may lead some cells to the uncontrolled proliferation seen in cancer tumors. Alternatively, its detrimental effects may be linked to its role in fat metabolism. Even though insulin and exercise work similarly in triggering glucose uptake by the muscles, they are radically different in their effects on fat. While exercise promotes fatty-acid uptake into the muscle, where it is burned, insulin promotes fat storage. Fat, as already mentioned, does more than just store calories. It can produce and regulate hormones with detrimental effects on health.

Several types of cancer whose incidence is dramatically reduced in people who exercise seem to have a connection to insulin sensitivity and glucose metabolism. "There are now 60 studies or so showing that people who walk briskly as little as three or four hours a week have about a 40 percent reduction in their risk of developing colorectal cancer," says SPH and HMS associate professor Edward Giovannucci. Even that surprising figure probably underestimates the maximum protection we can get. Exercise levels among Americans are so low that in large epidemiological studies of what people actually do, "Even the top exercisers are doing very little," says Giovannucci, "compared to the levels of activity seen in pre-industrialized societies, where rates of colon cancer are 90 to 95 percent lower than in the U.S." Some 147,500 Americans get colorectal cancer each year, and 57,000 die of the disease insulin has been implicated in its pathogenesis.

Pancreatic cancer, which is nearly always fatal, may also have an insulin connection. "Diabetics are at higher risk for pancreatic cancer," says Giovannucci, "and at the same time, people who exercise seem protected. It hasn't been studied a lot," he cautions, "but it looks very promising." Two other cancers that are connected to obesity — uterine and kidney cancer — have not yet been studied in relation to exercise, Giovannucci says, "but we have frequently found that in diseases where obesity is a risk factor, exercise is protective."

Exercise does not seem to reduce one's risk of developing prostate cancer — but vigorous exercisers may reduce their risk of dying from the cancer once they get it, either by reducing the growth of the tumor or enhancing their ability to withstand it. In the Health Professionals Follow-Up Study (which followed 51,529 men in the health professions), Giovannucci found a 50 percent reduction in the risk of dying from prostate cancer among men at the top end of vigorous exercisers.

In Outer Space and on Earth

"A lot of the epidemiological effects [of exercise] that have been uncovered were unexpected," says HMS professor of cell biology Alfred Goldberg, who studies the atrophy of muscle and bone. "They're related to indirect effects — for example, [the effects] of exercise on lipid metabolism, as in atherosclerosis. But we are still far from understanding exactly how it works." Better understood is what is happening with muscle and bone during exercise. Goldberg approaches this subject from a unique perspective: he is an adviser to NASA's space biomedical research program. "One of the big problems for astronauts is tremendous loss of bone and muscle," he reports. When you lose bone mass, what's left becomes brittle and susceptible to fracture. It also releases calcium phosphate and organic components that can make you much more sensitive to renal stones. That is why the loss of bone that takes place with extreme disuse — whether in space, in wasting diseases, as part of aging, or during extreme bedrest — can lead to kidney disease.

Goldberg is co-leader of a team trying to prevent the loss of muscle, which he says, is "absolutely necessary for a long-term space program." The rate of muscle loss — including heart muscle loss — during spaceflight is so great, he says, that "unless this problem is solved, by the time an astronaut got to Mars he wouldn't be strong enough to walk around or even to go out to repair the space vehicle if necessary."

Goldberg's group has discovered that, at the cellular level, the muscular response to disuse is very similar to what is seen in fasting, cancer, AIDS, and renal failure. He says, "We've identified a whole group of genes that are turned on, according to a specific program, whenever a tissue atrophies. Sometimes this program is turned on by disease, and sometimes it is turned on by disuse." His group has dubbed the most critical of these genes atrogin. It tags proteins for destruction — without destroying cells — by a process that is still not fully understood.

Goldberg and his colleagues hope to find a biochemical way to turn off this genetically controlled program of atrophy. Exercise turns it off by causing release of a growth factor called IGF-1 (insulin-like growth factor-1) which stimulates the production of new proteins while reducing the breakdown of old ones (except during fasting). But exercise is not easy in a space capsule under zero-gravity conditions.

The Physical Response to Training

"Muscles adapt to the kind of work that they do," says Goldberg. We all possess a mix of muscle fibers, some better for short bursts of activity, some superior for endurance. "The dark meat of a chicken or a turkey or a fish is muscle that is continually active." These muscles have a large blood flow and lots of mitochondria in their cells, and they burn fats and glucose all the time. The meat is dark because it is full of iron, which carries oxygen and is used by the mitochondria to burn fuels. These are the type of muscle fibers found in greater abundance in the legs of marathoners. In contrast, "The big muscles you see in a weightlifter," says Goldberg, "are the pale white muscles used for maximum strength in a short time."

But exercise is more than just a problem of the muscles working, Goldberg points out. A marathoner will have more dark muscle fibers that are fatigue resistant, but will also exhibit many other kinds of specialized adaptations. The body has to mobilize enough energy to keep the muscles working by delivering oxygen, fats, and glucose. That means the circulatory system has to work well. The heart has to adapt to pump more blood and the red cells need to be able to carry oxygen better. The circulation has to be able to carry away waste, like carbon dioxide and lactic acid circulating hormones need to mobilize the energy, whether from blood glucose or fats, to keep the muscles working. The circulatory system must also redistribute the heat generated in working muscles by delivering it to the heart, where it is pumped to the surface and radiated (when you turn red) or spread by the evaporation of sweat. "A person who is trained," says Goldberg, "has to have all these systems working pretty well."

People who engage regularly in vigorous aerobic exercise undergo some remarkable adaptations. Not only will they develop more mitochondria, glucose transporters, and oxidative enzymes in their muscles, they will grow new capillaries in the skeletal muscles, the heart, and the brain. The left ventricle of the heart will grow larger, and pump even more effectively as total blood plasma volume increases. The number of circulating red blood cells will also rise, improving the ability to carry oxygen. Blood pressure will go down, as will the heart rate at rest.

Peak bone density in the young will improve, and in adults, the rate of bone mass loss will slow with exercise, says anthropologist Daniel Lieberman, who recently completed an experiment providing the first definitive proof of this effect. Even the joints change, he says, as "mechanical loading leads to enormous and prevalent effects throughout the skeleton."

Muscles will quickly become much stronger, even without getting bigger. This is thought to be the result of improved muscle fiber "recruitment patterns," as the neuromuscular system learns to contract just the right combination of fibers within a muscle in order to complete a particular task efficiently. Strength gains may also come from improved synchronization, the coordinated firing of individual motor neurons that control muscle fiber. Muscles and liver will learn to store more fuel in the form of glycogen, further improving endurance. Circulating levels of cortisol, an anti-inflammatory hormone and mood enhancer, will go up, as will epinephrine and norepinephrine, hormones that regulate, among other things, the burning of adipose tissue.

Many of these positive adaptations involve common physiological markers of aging, including blood pressure, cardiac output, cholesterol levels, endurance, and strength, says SPH and HMS associate professor I-Min Lee. "Almost everything that declines physiologically as you grow older improves with exercise."

Staying Young by Keeping Fit

Jennifer Sacheck is a postdoctoral fellow in Alfred Goldberg's laboratory. She likes to run marathons, row in the Head of the Charles Regatta, and race to the top of Mount Washington (not all in one day, of course). A former national-level rower, Sacheck has a master's degree in exercise physiology and a Ph.D. in nutritional biochemistry. Now she is studying the biochemical basis of use and disuse in muscle tissue in order to understand both what is lost with age and what exercise can do to prevent or reverse that.

Not all changes from aging can be reversed, she explains. The maximum heart rate goes down about one beat per year. The number of motor neurons decreases. And the ability to increase muscle mass declines.

But her work with older populations has convinced her that there are lifelong benefits to both strength and aerobic training. "Don't tell me that someone is old when they are 50," she says. "I've had 90-year-olds lifting weights, still reaping the benefits. Resistance training helps with balance, stability, and the strength of the core muscles" that girdle the back and the abdomen. This reduces the risk of falls and hip fractures. "Strength training also helps maintain muscle mass," she continues. In an aging person, muscle mass helps keep the resting metabolic rate from falling. (Muscle mass is the most important determinant of energy needs at rest.) Resistance training can also help people who are dieting — which can actually lower the metabolic rate, through mechanisms very like the atrophy that Goldberg and Sacheck study — by increasing or maintaining muscle mass. When muscle mass is lost, the body's energy requirements go down, requiring even further reductions in caloric intake in order to lose weight. (Physicians like JoAnn Manson — who will actually write an exercise prescription for her patients — usually recommend starting with easy or moderate-intensity exercise and then practicing caloric restriction). Resistance exercise also helps prevent osteoporosis, a condition that ultimately affects 50 percent of all American women, and is increasingly common among men as they, too, live longer lives.

"Older patients with rheumatoid arthritis can also benefit from exercise," says Maura Iversen, S.D. '96, a clinical researcher at Brigham and Women's Hospital and instructor in medicine at HMS. "The concern," she says, "has been whether weight-bearing activity on a joint with minimal cartilage would benefit the joint or wear it out." With the advent of magnetic resonance imaging, it is now possible to measure changes in cartilage and the joint surface itself. This is an area of new and growing exploration. What researchers have found is that in healthy joints, "when you move, you actually improve the lubrication of the joint," she says. "Movement leads to better cellular turnover in the synovial fluid, which provides nutrition to the cartilage and maintains cartilage health. We know that exercise can improve physical function and now have the capability to examine its impact on cartilage."

Iversen recently completed a pilot study of chronic low-back pain in elderly patients and found that a 12-week program of endurance exercise on a stationary bicycle led to modest improvements in patients' ability to perform the activities of daily living. The exercise program also led to enhancements in mood.

Exercise, it turns out, is particularly useful in treating the mild depression often experienced by elders due to declining function and increasing isolation. "Keeping your heart and body in shape is just a side benefit to exercise's major effects on the brain," asserts John Ratey, an HMS associate clinical professor of psychiatry. "The brain is where all the action is." During exercise, "the increase in cerebral blood flow creates more capillaries, more conduits for blood to flow in the brain. So you are building a reservoir and protecting the brain, in a way, from strokes in the future."

The increase in cerebral blood flow causes many interesting things to happen. Exercise increases production of a growth factor called BDNF, or brain-derived neurotrophic factor. "I call it Miracle-Gro, brain fertilizer," Ratey says, "because it keeps the neurons young and healthy and makes them more ready to connect with each other. It also encourages neurogenesis — the creation of new nerve cells." This may have a cognitive benefit. Studies have shown that older adults with higher levels of cardiorespiratory fitness experience a slower rate of cognitive decline over time.

But exercise does more than just maintain the health of the brain. "In a way, exercise can be thought of as a psychiatrist's dream treatment," says Ratey. "It works on anxiety, on panic disorder, and on stress in general, which has a lot to do with depression. And it generates the release of neurotransmitters — norepinephrine, serotonin, and dopamine — that are very similar to our most important psychiatric medicines. Having a bout of exercise is like taking a little bit of Prozac [an antidepressant and anti-anxiety agent] and a little bit of Ritalin [which boosts the attention system], right where it is supposed to go." He says there are now many studies which show that "exercise is as good or better than some of our antidepressants."

Why? When we move, we have a sense of purpose, of competence, and of accomplishment. "People don't get the fact that our frontal cortex evolved to make us better movers," Ratey points out. "The higher functions — the executive function, thinking, abstraction, and philosophy — all evolved from the moving brain."

"We're animals," he says. "We should be moving."

Jonathan Shaw '89, managing editor of this magazine, once ran a marathon, but is now a long-distance cross-country skier.


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