avoidance of drug therapy in the elderly

LEADING ARTICLE Drugs & Aging 6 (1),1-8,1995 1170-229X/95/000HJOOI/S04.00/0

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Avoidance of Drug Therapy in the Elderly Exercise as a Preventative Prescription

Yoshiaki Fujita

Division of Physiological Aging Research, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, Japan

1. Interaction of Exercise and Nutrition

Evans and Campbell have mentioned that 'there is no pharmacological intervention that holds a greater promise of better health and greater independence in the elderly than does exercise' .tIJ

Appropriate and regular physical activity is an indispensable factor in the maintenance and promotion of health, the prevention of age-related diseases and recovery from disease. Moreover, adequate physical activity not only makes you feel refreshed but also stimulates your appetite, resulting in an increased intake of food. Therefore, through exercise, elderly people can more easily obtain essential nutrients without becoming overweight, and so have an improved nutritional status.

Exercise increases a person's requirement of energy and those vitamins that relate to energy metabolism, such as thiamine (B I) and riboflavin (B2). However, exercise itself does not increase the need for dietary protein, because exercise does not significantly increase the total amount of nitrogen and urea excreted in the urine.f2) Nonetheless, it seems that the effect of exercise on physical fitness is accelerated by supplementation with a balanced diet consisting of adequate amounts of individual essential nutrients (including amino acids) rather than by foods containing energy sources alone.

Meredith and colleagues have examined the effects of additional food on gains in strength and

muscle mass during heavy trammg by elderly menV) During the 12 weeks of knee extensor and flexor training, group S was given a daily supplement of 560 kcal/day consisting of a balanced diet, whereas group U received no supplement. The exercise resulted in mid-thigh muscle hypertrophy, which was significantly greater in group S than in group U. However, group S showed increased bodyweight, skinfold thickness and subcutaneous mid-thigh fat. Results of other studies demonstrated that in elderly people plasma glycerol levels during exercise significantly decreased by 50%, despite a normal increase in plasma norepinephrine (noradrenaline). This indicated an impaired lipolytic response of fat cells to catecholamine stimulation and to exercise in elderly people.[4,5)

1 .1 Degenerative Diseases

It is generally accepted that regular physical activity reduces the risk of degenerative diseases, such as coronary heart disease, diabetes, hypertension and osteoporosis, through increased muscle mass and/or improvement in physiological and metabolic functions. Furthermore, appropriate exercise plays an important part in the rehabilitation programmes for patients with such diseases, as do drug therapy and nutritional control. Australian Aborigines, after making the transition from a traditional lifestyle (characterised by a high level

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of physical activity and a diet low in fat and high in fibre) to a Western lifestyle (characterised by reduced physical activity and a diet high in refined carbohydrates and fat) develop a high prevalence rate for these kinds of degenerative diseases.(6)

1 .2 Body Composition

In general, body composition changes progressively with age. In particular, body protein, intracellular water and bone tissue decrease and body fat increases. The most prominent of these changes at the tissue level is an age-related loss in skeletal muscle mass, resulting in reduced physical performance. Consequently, a large number of elderly people live below or just above the thresholds of physical ability. Thus, an adequate exercise training programme that increases skeletal muscle mass is essential for enhanced muscle function. In fact, women who are physically active, compared with those who are inactive, tend to show better results for body weight, body mass index [bodyweight/height (kg/m2)] and physical fitness.l6) In addition, Fiatarone and coworkers showed that, even in very old people aged over 90 years, high intensity resistance training for 8 weeks resulted in increases in strength, mid-thigh muscle mass and tandem gait speed)?]

Individual variations in physiological and metabolic functions increase with age, therefore the optimal intensity, duration and frequency of physical activity required to produce benefits must be tailored for individual people. In addition, other studies have reported that people have different baseline levels of daily physical activity depending on their socioeconomic status and gender.l8,9]

Therefore, these factors require sufficient consideration when planning an appropriate exercise loading programme for individuals.

2. Skeletal Muscle

The skeletal muscle mass decreases physiologically with advancing age, with this decrease accelerated by reducing daily physical activity. The decrease in skeletal muscle mass is one of the most prominent age-related changes. Reduced muscle

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mass is linked not only to decreased strength and aerobic capacity, but also to age-related changes in the metabolic functions of muscles and consequent changes in other tissues. Zimmerman and colleagues examined the effect of exercise (daily treadmill running for 10 weeks) on age-related changes in collagen metabolism in fast-twitch (gastrocnemius) and slow-twitch (soleus) muscles in rats.l IO) When hydroxylysylpyridinoline (HP), the cross-linked substrate in muscle collagen, was used as an indicator for the flexibility of muscles in sedentary rats, both gastrocnemius- and soleusHP increased with age. Running training prevented increases in soleus-HP with age, but not in gastrocnemius-HP. This result indicates that regular exercise prevents an age-related decline in flexibility in skeletal muscles, particularly in slow-twitch muscles.

The benefits of regular exercise on muscle functions are associated with an alteration in the rates of muscle protein synthesis and breakdown. Yarasheski and colleagues found that exercise for 2 weeks significantly increased the fractional rates of protein synthesis in the quadriceps muscle of elderly people, from 0.030 ± 0.003 %/h before training to 0.076 ± 0.11 %/h, whereas muscle mass and the rate of whole body protein breakdown did not change after exercise.! II) Regular exercise also improves age-related decreases in glucose uptake in skeletal muscles. Ezaki and coworkers found that exercise (1 km/day of treadmill running for 4 weeks) significantly increased the amount of glucose transport protein (GLUT4) in rat muscles by 30% in the soleus, 33% in the plantaris, 41 % in the gastrocnemius and 27% in the quadriceps, as compared with sedentary rats.l I2] In addition, these benefits were more prominent in older rats (12 months old) than in younger rats (1 month old).

Decreases in muscle mass with age are also associated with a decline in the resting metabolic rate of elderly people. Poehlman and colleagues showed that in healthy old people, moderate exercise (300 kcal per session, 3 times per week) significantly increased energy intake by 17% and theirresting metabolic rate by 9%)13] However, no

Drugs & Aging 6 (l) 1995

Exercise as a Preventative Prescription

significant changes were observed during light exercise (150 kcal per session). On the other hand, Sasco and colleagues found that moderate exercise by young adults when at university is linked to a reduced subsequent risk of Parkinson's disease, but that this association disappears at higher intensity of physical expenditure) 14J These results indicate that, to improve age-related decreases in muscle mass, strength and metabolic function, a more intensive exercise regimen than that undertaken usually by most healthy elderly people is necessary.

3. Bone

The appearance and development of osteoporosis are associated with differences in genetic background, lifestyle, nutritional environment and aging. Some risk factors for osteoporosis are listed in table I.

Bone fracture is one of the leading causes of disability and subsequent confinement to bed, especially in postmenopausal women. Bone mass and mineral density increase with age in early life until about 20 years of age, then progressively decrease. This age-related decline in bone mineral density, given similar genetic backgrounds, lifestyle and nutritional conditions and the same gender, is primarily associated with age-related decreases in serum levels of estrogen and vitamin D3 (cholecalciferol), and an increase in parathyroid hormone levels. Such changes in hormone levels seem to be physiological rather than pathological. Therefore, the best way to maintain a sufficient level of bone mineral density in later life is to reserve as much bone minerals as possible during early life by ensuring an adequate nutritional intake, particularly of calcium and protein.

3.1 Hormone Replacement Therapy

For these reasons, in the medical treatment of the elderly, and in particular of postmenopausal women, vitamin D3 administration and estrogen replacement therapy have become widespread. N aessen and colleagues examined whether low-dose estrogen replacement therapy (estradiol


Table I. Risk factors for osteoporosis

Ethnicity (more common in Caucasians than in Black people)

Genetic background (more common in Caucasians than in Black people)

Female gender

Low bodyweight

Less physical activity

Less sunlight exposure

I ncreased stress

Smoking

Alcoholism

Diabetes

Antacid drugs (aluminium gel, etc.)

Decreased excretion of sex hormones, particularly estrogen

Increased dietary fibre

Increased phytate intake

Increased protein intake

Increased caffeine intake

Increased sodium chloride intake

Increased phosphate intake

Nulliparity

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20mg implanted subcutaneously every 6 months) has a beneficial effect on bone loss in elderly women of mean age 67 years,l15] Treatment resulted in significantly increased bone mineral density, up by 20 to 25% in the distal radius, lumbar vertebrae and femoral neck, while serum estradiol reached physiological levels.

3.2 Glucocorticosteroids

Within the range of physiological levels, glucocorticoids have a beneficial effect on bone collagen synthesis. However, increased levels produce bone resorption through enhanced parathyroid hormone activity. Mitchell and coworkers showed that short term administration of glucocorticoids (prednisone 40 mg/day administrated orally for 5 days) in healthy elderly men suppressed the production of osteocalcin [bone Gla (y-carboxyglutamic acid) protein], whereas when the treatment was stopped, the levels of osteocalcin reverted to baseline levels)16]

3.3 Exercise and Nutrition

On the other hand, physical activity and regular exercise have a great potential to reduce the risk of

Drugs & Aging 6 (1) 1995

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osteoporotic fractures. Exercise reduces the risk of bone fracture not only by preventing bone loss, but also by decreasing the risk of falling by improving muscle strength, flexibility, sense of balance and reaction time. Edelstein and Barrett-Connor examined the relationship between bone mineral density and 8 body measurements (total bodyweight, body mass index, waist-hip ratio, lean mass, fat mass, percentage fat mass and current and maximum adult height) in 1492 elderly peopleJ17J Based on these measurements, it was concluded that bone mineral density was closely associated with the mechanical effect of body weight, and that weightbearing exercise is more effective in preventing bone loss than nonweight-bearing exercise.

An early epidemiological study has shown that in a population consuming foods rich in calcium and protein, the frequency of bone fracture will be significantly lower in both genders.l 18] Nelson and colleagues examined the effects of a supervised I-year walking programme and dietary calcium supplementation (831 mg/day) on bone mineral density in 36 postmenopausal women aged 60.2 ± 6.5 yearsJ19] Compared with the initial values, exercise and high dietary calcium intake increased the bone mineral density by 0.5% at the trabecular of the lumbar spine (Ll-L3) and 2.0% at the femoral neck, but had no effect on the lumber spine (L2-L4), distal radius or on total body calcium levels. Therefore, this treatment may preferentially alter bone density at different skeletal sites.

Lau and coworkers examined the effects in elderly people of calcium supplementation (800 mg/day) and/or load-bearing exercise (4 times per week) for 10 months.f20] Whereas the parathyroid hormone levels, which enhances calcium release from the bone, decreased significantly in people receiving calcium supplements, irrespective of whether accompanied by exercise, exercise alone had no effect on decreasing parathyroid hormone levels. However, the results of 2-way analysis of variance showed that calcium supplementation in combination with exercise had a significant additive effect on bone mineral density at the femoral neck, but not at the other sites. These results


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suggest that the benefits of physical exercise on bone density are not uniform at different bone sites.

Immobilisation or a sedentary lifestyle are key causes of accelerated bone loss. A negative calcium balance and bone mineral loss in astronauts due to mechanical unloading during a spaceflight is a typical example of accelerated bone loss during weightlessness and immobilisationJ21,22] In contrast, amenorrhoea and the resulting low levels of plasma estrogen from excessive physical training and/or extreme slimming also result in substantial bone loss. In such instances, calcium supplementation in diets cannot improve the negative calcium balance.

3.3. 1 Hormonal Effects

The secretion of growth hormone has been reported to increase during vigorous exercise. However, in patients with overload exhaustion of bones due to physical activity, the levels of growth hormone and somatotrophic hormone, which are important mediators for osteogenesis, are reduced considerably.[23] Furthermore, the balance of thyroid hormones, which accelerate bone resorption, is disturbed,l24]

3.4 Summary of Effects on Bone

The appearance and the progression of bone loss with advancing age are primarily associated with age-related changes in hormonal environments in the body, which are influenced not only by the physiological aging process but also by overall nutritional conditions. Furthermore, even in the elderly, appropriate exercise and calcium supplementation decrease age-related bone loss, and the benefits are further accelerated by exercise coupled with calcium and vitamin D3 supplementation. However, differences in kind, intensity and duration of exercise result in different effects at different bone sites. It appears likely that most regimens that require vigorous aerobic strength enhance bone density, whereas light exercise, such as walking, particularly in the short term, is relatively ineffective in preventing postmenopausal bone loss. However, it must be remembered that excessive training enhances bone breakdown.



4. Effects on Other Diseases

4.1 Diabetes Mellitus

Insulin-dependent diabetes mellitus (IDDM; type I diabetes) is more common in younger people than in adults and elderly people. Since this type of diabetes is primarily caused by poor excretion of insulin, exogenous insulin administration is essential. If this treatment is accompanied by appropriate dietary control and a physical exercise programme, the efficiency of insulin treatment is further accelerated.f25]

On the other hand, non-insulin-dependent diabetes mellitus (NIDDM; type II diabetes) is associated with insulin resistance, hyperinsulinaemia, diminished islet ~-cell function and glucose intolerance. These effects have been closely associated with the aging process, and nearly 50% of patients with this type of diabetes are over the age of 65 years. Oral administration of hypoglycaemic agents such as sulphonylureas is a useful treatment in patients with NIDDM. However, since oral hypoglycaemic agents have no direct effect on the level of plasma glucose, individuals for whom plasma glucose levels cannot be controlled with diet and exercise must be treated with insulin. Moreover, in elderly patients, since administration of these drugs can produce marked hypoglycaemia, especially when the therapy is a combination of insulin with oral hypoglycaemic agents, caution must be exercised.

In contrast, controlled and appropriate exercise loading produces mild beneficial effects on blood glucose levels of elderly people. Hughes and colleagues trained glucose-intolerant 64-year-old people at 50 to 75% of their maximum heart rate for 12 weeks, then examined oral glucose tolerance and insulin action.[26] After training, glucose tolerance and plasma glucose concentration were significantly improved, although the plasma insulin response remained unchanged. Long term exercise training, without changes in body composition, improved peripheral insulin action in participants with impaired glucose tolerance. However, in glucose-intolerant individuals, aerobic exercise

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training without dietary control does not appear to decrease lipoprotein cholesterol and triglyceride levels in the serum)27]

4.2 Cardiovascular Diseases

The idea that adequate physical activity reduces the risk of coronary heart diseases is widely accepted, although the mechanisms remain obscure. Gordon and Scott have postulated that lower levels of physical activity corresponding to 14 to 20 kcal/kg/week reduce the risk of cardiorespiratory disease.l28 ] In the rehabilitation of myocardial infarction patients, also, exercise plays an important role as do patient education, counselling and nutritional guidance.

Squires and colleagues reviewed existing literature and concluded that appropriate exercise after myocardial infarction decreased mortality and major cardiac events by 20 to 25%.129] However, the beneficial effects of exercise on coronary heart disease seem to be mainly due to metabolic effects, which reduce the oxygen requirement of the myocardium, rather than as a result of haemodynamic factors. This fact suggests that exercise programmes that do not produce metabolic change may fail to produce a training effect on cardiovascular fitness. 130 ]

Poehlman and colleagues showed that in healthy elderly people, moderate exercise (300 kcal per session, 3 times a week) significantly increased energy intake by 17% and resting metabolic rate by 9%. However, no significant changes were observed after light exercise (150 kcal per session).13l] Goran and Poehlman showed that short term endurance training significantly increased maximum oxygen consumption by 9% and resting metabolic rate by II % in healthy elderly people.l32] However, there was no significant change in total energy expenditure before and during the last 10 days of endurance training because of a 62% reduction in the energy expenditure during physical activity. This fact suggests enhanced cardiovascular fitness.


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5. Animal Studies

Laboratory rats are usually confined to cages that markedly restrict their physical activity, and are provided with food ad libitum. Goodrick showed that, in aging rats, voluntary wheel running prolonged survival, as compared with sedentary rats)33] Another report found that exercise and daily physical activity had a favourable effect on physiological and metabolic functions.f 34] However, most such investigations involved moderate or heavy exercise with a higher consumption of oxygen over a shorter period of time.

In laboratory rats housed in cages, basal metabolism accounts for about 90% of their daily energy expenditure, and daily physical activities for the remaining 1O%.l35] This profile of daily energy expenditure of laboratory rats is similar to those of bedridden or housebound elderly persons.l361

On the other hand, studies have found that rats and mice on a restricted diet showed prolonged longevity, reductions in the prevalence and the progression of age-related diseases, as well as reductions in the age-related declines in physiological and metabolic functionsJ37-401 Few studies have examined the beneficial effects of long term, light exercise throughout life, which is almost equivalent to regular physical activity in day-today life, on age-related changes in physiological and metabolic functions.

5.1 Effects of Exercise and Dietary Restrictions

In our study, we fed male Wistar rats a 20% casein diet ad libitum until maturity (100 days old), then divided them into 2 groups. The rats in one group (the RS group) received 10 g/day of a 20% casein diet, which is about 60% of the daily food consumption of rats fed ad libitum, and were maintained under sedentary conditions until 900 days old. Those in the other group (the RE group) were fed 11 g/day of the same diet and simultaneously underwent running exercise (3000m daily). From a preliminary study, the energy expenditure for this


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exercise loading was determined to be equivalent to about 1.0 g/day of the 20% casein diet used. The RE group rats were housed individually in a structure that consisted of a housing area, a running wheel and an automatic feeding device interlocked electrically with the running wheel. The animals received a constant amount of food and exercise throughout the test period.

s. 1. 1 Metabolic Rate We carried out metabolic studies at intervals of

100 days, then measured HP and lysylpyridinoline (LP) levels to determine bone collagen breakdown, and the amount of calcium and total nitrogen in the urine. In the energy metabolic study, we continuously measured the oxygen and carbon dioxide in the expired air for 24 hours with an automatic analyser. We calculated the basal metabolic rate (BMR) on the basis of the lowest value of oxygen consumption per hour. On day 900, we measured the bone mineral density of the femur by dual photon absorptiometry. All rats in both groups consumed all their food throughout the test period. The mean running distance was 2800 to 3000m daily.

The idea that the BMR decreases with age is widely accepted. But in our rats, who consumed a constant amount of food throughout life, the BMR remained almost constant irrespective of exercise, then increased slightly with advancing age. At 900 days, the BMR in the exercised rats was significantly higher than that in the sedentary rats. When the BMR is expressed on the basis of urinary creatinine levels, it decreased with age, and the decrease was greater in exercised rats than sedentary rats. This was because the exercised rats had greater amounts of skeletal muscle mass.

s. 1.2 Nitrogen Balance The mean nitrogen balance also showed signif

icantly higher positive values in exercised rats than sedentary rats, irrespective of the ages of the rats examined. The results in nitrogen balances accorded well with the results from the carcass analysis. At 900 days of age, while sedentary rats showed almost the same body composition as when 100 days old, the exercised rats had significantly



decreased body fat and increased body protein. Long term, light exercise produced significantly increased mass of the omohyoideus and gastrocnemius muscles, but caused no significant changes in the other muscles and viscera organs such as the liver, kidney, heart, gastrointestinal tract and lung.

5.1.3 Age-Related Diseases Compared with ad libitum feeding, restricted

feeding reduces the occurrence and progression of age-related diseases. Long term, light exercise in combination with a restricted diet further depressed the age-related pathological changes in the kidney and the liver. Also, exercise significantly increased the serum levels of protein and decreased plasma levels of insulin. However, under restricted feeding conditions, exercise did not result in significant decreases in total cholesterol and triglyceride levels in the serum.

As described in section 3, adequate daily physical activity or exercise loading is an effective method of preventing and remedying age-related osteoporosis. We examined the effect on bone metabolism of light exercise for a prolonged period of time in rats on a restricted diet. We measured HP and LP excretions in the urine, which are metabolites of bone collagen [types I and II, respectively (unpublished data)]. When we switched the diet from ad libitum feeding to restricted feeding, the urinary excretions of HP and LP decreased significantly in both groups, indicating decreased breakdown of bone collagen. However, subsequently there were no significant differences between the groups throughout the test period. In contrast, the exercised rats had higher urinary calci urn excretion throughout. At 900 days, while the length and weight of the femur bone showed no significant difference between the groups, the bone surface area was significantly greater in the exercised rats than sedentary rats, resulting in decreased bone mineral density in the exercised rats, particularly in the proximal area.

From these results, we concluded that the beneficial effects of restricted feeding on age-related changes in nitrogen and energy metabolism were further enhanced by long term, light exercise. In


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rats receiving only maintenance levels of protein, calcium and other essential nutrients under restricted feeding, long term, light exercise showed few beneficial effects on age-related changes in bone metabolism. This indicates that the benefits of long term, light exercise on bone tissues can be obtained during an adequate supply of essential nutrients, such as protein and calcium, that are required for osteogenesis.

6. Conclusion

Well controlled drug therapy may produce beneficial effects on diseases. However, there are many issues relating to the pharmacokinetics and pharmacodynamics of drugs in the elderly that remain to be solved. Moreover, drug therapy is not useful for preventing age-related diseases, except in such cases as estrogen replacement therapy for the prevention of bone loss in postmenopausal women. In contrast, appropriate physical activity enhances medical treatment as wel1 as disease prevention through increased muscle mass and enhanced physiological and metabolic conditions of the body. To obtain successful results by exercise loading, the careful coordination of drug therapy, exercise loading and nutritional control is essential.

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3. Meredith CN, Frontera WR, O'Reilly KP, et al. Body composition in elderly men: effect of dietary modification during strength training. 1 Am Geriatr Soc 1992; 40: 155-62

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8. Ford ES, Merritt RK, Heath GW, et al. Physical activity behaviors in lower and higher socioeconomic status populations. AmlEpidemiol1991; 133: 1246-56

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11. Yarasheski KE, Zachwieja JJ, Bier DM. Acute effects of resistance exercise on muscle protein synthesis rate in young and elderly men and women. Am J Physiol 1993; 265 (2 Pt I): E21O-E214

12. Ezaki 0, Higuchi M, Nakatsuka H, et al. Exercise training increases glucose transporter content in skeletal muscles more efficiently from aged obese rats than young lean rats. Diabetes 1992; 41: 920-6

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14. Sasco AJ, Paffenbarger Jr RS, Gendre I, et al. The role of physical exercise in the occurrence of Parkinson's disease. Arch Neurol 1992; 49: 360-5

15. Naessen T, Persson I, Thor L, et al. Maintained bone density at advanced ages after long term treatment with low dose estradiol implants. Br J Obstet Gynaecol 1993; 100: 454-9

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and Education Diabetic Practice Group. J Am Diet Assoc 1993;93: 309-14

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27. Hughes VA, Fistarone MA, Ferrara CM, et al. Lipoprotein response to exercise training and a low-fat diet in older subjects with glucose intolerance. Am J Clin Nutr 1994; 59: 820-56

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34. Tobin BW, Beard JL. Interaction of deficiency and exercise training to tissue norepinephrine turnover, triiodothyronine production and metabolic rate in rats. J Nutr 1990; 120: 900-8

35. Ichikawa M, Fujita Y. Effects of nitrogen and energy metabolism on body weight in later life of male Wi star rats consuming a constant amount of food. J Nutr 1987; 117: 1751-8

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Correspondence and reprints: Yoshiaki Fujita, Department of Nutrition, Division of Physiological Aging Research, Tokyo Metropolitan Institute of Gerontology, 35-2 Sakaecho, Itabashi-ku, Tokyo 173, Japan.


avoidance of drug therapy in the elderly

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