Age Exercise Effects

Introduction: Exercise and Aging

Physical activity can influence the development of disability in old age. Regular participation in physical activity has been shown to minimize the physiologic changes associated with aging, contribute to the overall health and well being of the individual and assist in the prevention and treatment of disability with increasing age. Planned exercise has been shown to improve immune system function, insulin sensitivity and glucose tolerance as well as counteract the functional decline of the musculoskeletal system. Overall, exercise in the aging population is said to prevent diseases such as cardiovascular disease, stroke, type 2 diabetes, obesity, hypertension, osteoarthritis, depression and osteoporosis.^Singh Exercise also affects the hormonal changes seen with aging. The effects of exercise on hormonal secretion is dependent on the type and duration of the activity. ^Hackney

Immune System

Exercise has been shown to enhance or suppress immune function depending on intensity and type of activity. ^Goodman Researchers are now studying how age can also be one of the depending variables. The role of exercise in attenuating immune dysregulation that accompanies aging has only recently become a popular topic in research. ^Kohut Exercise is quickly becoming the intervention of choice for many chronic diseases, as well as aging, primarily due to its low-cost, non-invasive nature that is easy to implement into many lifestyles and environments. ^Gueldner, ^Kohut However, due to the newness of these studies there is still more research needed to specifiy the most beneficial parameters of exercise for the aging population.

Innate Immune System 

Neutrophils

There have been few studies done regarding the effects of exercise on the innate immune system. The minimal data that is available has shown some benefit to phagocyte function and overall number of circulating cells. One study looked at the benfeits of exercise on neutrophils and found that in adults over the age of 60, neutrophil phagocytic function was enhanced in men who participated in regular exercise of moderate intensity when compared to age-matched controls. ^Yan The exercise consisted of any aerobic activity (swimming, running, cycling) lasting over an hour on 2 or more days of the week for 3 years. ^Yan Alternatively, studies looking at single bouts of exercise in the geriatric population have shown a possible increased number of circulating neutrophils. More research is needed to support this finding. ^{Cannon & Fiatarone}, ^{Cannon & Orencole}

Macrophages

Exercise may reverse the decline in macrophage function associated with aging. More studies are needed, however, in murine studies regular exercise of moderate intensity has been shown to enhance several functions of macrophages in mice. Older mice participating in a minimum of 9 weeks of moderate exercise consisting of 45 min/day, 5 days/week demonstrated increased macrophage antiviral resistance and  increased peritoneal macrophage production of TNF-alpha and capacity to kill tumour cells. ^{Kohut & Boehm},^{Kohut, Senchina & Madden}, ^Lu

NK cells & IL-2

NK cell function and cytotoxicity has been found to be preserved in elderly (>70 years old) individuals who participated in acute bouts of bicycling.^nieman, ^shinkai   Regular aerobic exercise such as running has also been shown to be just as beneficial  in elderly individuals as younger controls when comparing NK cell function and cytotoxicity. (fiatarone) Another study found that elderly woman in their 70's who participated in a 16-week maximal treadmill exercise programme exhibited similar results in NK cell function. ^Crist However, a study by Rincon et al. found NK cell activity to decline following a long-term exercise programme in frail older men (>70 years old at risk for falling ). ^Rincon

Interleukin 2 (IL-2), a paramount regulator in the immune system that's production has been shown to decline with aging, has recently been shown to be expressed greater on lymphocytes in elderly subjects (62-86 years old) that participated in regular aerobic exercise when compared to sedentary women of the same age and younger ^drela. This increased expression of IL-2 may preserve the activity of NK cells and the formation of cytotoxic lymphocytes by enhancing the “maintenance of lymphocyte homeostasis” ^Lin,^drela. Additional research with elderly male subjects has demonstrated that long-term endurance training can increase the production of IL-2 to comparable levels found in young male subjects. These findings strongly suggest chronic exercise could delay immunosenescence by IL-2's association with higher T cell proliferation. ^Arai

Acquired Immune System

T cells

Effects of physical activity and its role in improving the responsiveness of T cells is variable. ^Drela, ^kohut In a study by Woods et al., no significant changes in T cell reactivity and proliferation was found after a group of previously sedentary elderly subjects participated in 6 months of aerobic exercise three times/week.^Woods  Additionally, Nieman et al, found that 4 months of aerobic exercise five days/week resulted in no significant changes in circulating levels of T cells, when compared to sedentary, age-matched controls. ^Nieman  However, studies of older male and female athletes have found an increase in T cell proliferation in response to mitogen stimulation. ^Shinkai, ^Skinkai, ^Nieman These athletes performed aerobic exercise regularly for multiple years as opposed to a single bout or 6 months of exercise training, indicating that long-term exercise lasting greater than 6 months may be more beneficial. ^kohut One study evaluated elderly subjects who regularly participated in vigorous aerobic exercise and their lymphocyte proliferation response to immunization with influenza antigen. Two weeks post-immunization the participants demonstrated greater T cell proliferation compared to less active older subjects. ^{Kohut & Cooper}

Current evidence of exercise effects on the expression of CD3+, CD4+, CD8+, and CD 25 on T cells is variable possibly due to the heterogeneity of the available studies. Some studies have found a greater CD25 expression on T lymphocytes with active older individuals who performed an aerobic exercise intervention compared to sedentary or less active subjects.^Whisler, ^Lee However, flexibility and resistance training did not have the same beneficial effect. ^Lee Woods et al, revealed 6 months of aerobic exercise for three days/week was not sufficient in increasing the expression of CD3+, CD4+, CD8+ on T lymphocytes. ^Bruunsgaard Another study observed the effects of an acute bout of  “exhaustive endurance exercise” on younger subjects and found in increase in CD3+, CD4+, and CD8+ that decreased in the recovery stage below pre-exercise levels. ^Shek

Antibodies

It has been suggested that elderly adults who participate in regular exercise will produce a greater percentage of antibodies. This has been evaluated in many studies in elderly subjects after receiving influenza vaccine. Kohut et al. found that elderly adults that regularly participated in high intensity exercise showed an increase in immunoglobulin M (IgM) and immunoglobulin G (IgG)  two weeks post-immunization. ^{kohut & Cooper} Another study examined active and sedentary elderly adults response to novel antigens. An increase in IgM and IgG in the active subjects was observed when tested 21 days post-immunization. ^Smith These studies support the theory that older adults participating in regular activity will benefit from enhanced immune responsiveness to immunization. ^Senchina

Recommendations

After reviewing the literature, long-term exercise training (>6 months) is preferred for elderly adults seeking improved immune function. The most beneficial type of physical activity currently supported by recent research is aerobic exercise interventions compared to resistance training. ^kohut, ^Woods, ^Flynn, ^Rall A long-term exercise program including 30-40 minutes of aerobic exercise per session at 65-75% of heart rate reserve performed 5 days/week is recommended. ^Nieman, ^kohutAdditionally, the current health status of the patient population tended to have an affect on outcomes from exercise intervention as well. Subjects described as “frail elderly adults” repeatedly showed no change or a greater decline in immune function following a minimum of 3 months of aerobic exercise, and exercise interventions involving endurance and resistive training. ^Rincon, ^Kapasi One proposed theory is that these individuals may not be capable of achieving the level of intensity necessary to reverse or slow age related changes.

Endocrine System

Cortisol 

Cortisol is a steroid hormone that has important functions of metabolizing glucose/fats/proteins, increasing BP during a stress response, and reducing immune responses.  During high intensity exercise cortisol is essential in promoting gluconeogensis to maintain blood glucose level.  Typically, cortisol levels will increase during and immediately after a bout of exercise, and then will decrease to normal levels during a cool-down period.  Evidence regarding exercise effects on cortisol levels in the elderly is conflicting.  Vale et al examined the effects of 12 week strength training and 12 week aerobic training on basal cortisol levels and found no change from pre to post intervention.^Vale  This study looked at the chronic effects of exercise.  A study by Traustadottir et al. examined the acute effects of high intensity (15 min on treadmill: 50% VO2 max 5 min, 70% VO2 max 5 min, 90% VO2 max 5 min) treadmill exercise on cortisol and ACTH (link to endocrine) and found a prolonged recovery time in the older patients compared to the younger.^{Traustadottir}  No difference was found in cortisol recovery time between old and young.  However, when comparing the old-fit group to the old-nonfit group, there was an increased cortisol response during recovery.  Possibly, the old-fit women have a higher adrenal capacity/sensitivity to ACTH and thus have an increase in cortisol production/secretion.  The researchers postulate that this could be a beneficial adaptation, as an increase in cortisol (a stress hormone) could increase the likelihood of survival in the face of acute stress or high magnitude challenges.^{Traustadottir}

IGF-1  

Insulin-like growth factor (IGF-I) is one of the main catabolic agents in the human body having a strong correlation with muscle strength, maintenance of the skeletal muscle system, and metabolic rate.  In the aging human body IGF-I secretion is decreased, and bone/muscle sensitivity to IGF-1’s effects are diminished (link to cell bio part).  Physical training is a proposed mechanism for increasing circulating levels of IGF-1 in order to prevent muscle wasting and degeneration.  A recent study compared the effects of strength training, aquatic training, and a control group on the basal serum levels of IGF-1 in a population of elderly women. ^Vale Researchers found that strength training significantly increased levels of IGF-1 as compared to the aquatic training and control groups.^Vale The strength training group completed their program 3 days per week (alternating days) with a warm-up, main work, and cool down for a total of 50 minutes.  For the first four weeks, 8 strength exercises (targeting the main joints) were performed 2 sets of 15 repetitions (50% 1 rep-max).  For the next 8 weeks the subjects performed the same exercises with 2 sets of 8-10 repetitions (75-85% 1 rep-max).^Vale  Exercising at this intensity was also shown to improve IGF-1 levels in an elderly population by Lambert et al.  In this study they compared 12 weeks of low intensity strength training to 12 weeks of high intensity strength training.^Lambert 

Testosterone and Estrogen

Endurance trained men have abnormal concentrations of male reproductive hormones such as testosterone, luteinizing hormone (LH), and prolactin. A systematic review conducted by Anthony Hackney explored acute versus chronic exercise to determine if differences exist in reproductive hormone responses. One study showed short-term submaximal work caused an elevation in testosterone levels after 20 minutes. These levels returned to pre-exercise levels by 40 minutes into exercise recovery. LH (which stimulates testosterone production) levels were unaffected by this amount of exercise. When running to exhaustion, testosterone concentrations were found to increase proportionally to the intensity of the exercise with peak testosterone levels coinciding with maximal exercise intensity. LH levels were unchanged during exercise, but significantly decreased during the recovery period. These hormonal responses occur during activities such as weight lifting, rowing, swimming, and high-intensity sprinting ^Hackney.

Prolonged submaximal exercise (>60 min) showed an initial rise in testosterone levels followed by a decline as the activity continued. If the submaximal exercise lasted longer than 2 hours, testosterone concentrations were 25%-50% pre-exercise levels. Similar to other exercise levels, testosterone returned to pre-exercise levels within 24 to 72 hours into recovery. LH levels again showed significant declines during the recovery phase. Thus, duration of activity plays an important role in testosterone response to activity ^Hackney.

Hackney also aimed his literature search at comparing trained versus untrained men and found difference in resting state testosterone levels. Studies show significantly lower free (unbound) and total testosterone levels (60-85% the concentrations of age-matched, untrained men) in chronically endurance-trained men. Lower resting concentrations of prolactin also existed, but there was no difference in LH concentration. Excessively high or low levels of prolactin can suppress testosterone concentration in men. It is theorized that the absence of prolactin at the testicle alters the effectiveness of LH to stimulate testosterone secretion. The literature has conflicting evidence as to how long it takes for these chronic hormonal changes to occur. Several studies reported changes in resting testosterone levels after 1-6 months of intensive activity, while other studies found no change after 2-3 months of training. The implication of these hormonal reductions in trained men is the potential disruption in the sperm production process. For instance, analysis of distance runners (30-80 miles/wk) showed 20% had oligospermic conditions and ultralow testosterone concentrations. Similar conditions were found in resistance-trained males (weight-lifters), however the degree of alterations was more pronounced in the distance runners. Although these findings suggest that endurance-trained men might have fertility problems, this does not seem to be the case. The literature only demonstrates a small-likelihood for exercise-related sperm production deficiencies. The research is too premature to make causal associations between endurance training and fertility problems ^Hackney.

Age impacts the response of male reproductive hormone to exercise. Kraemer et al. conducted a study looking at the impact of age on hormonal response to exercise. Two study groups (young or 30 y.o. vs old or 62 years old) underwent a 10 week power strengthening protocol that entailed squats, knee extensions, low back extensions, lat pull downs, leg curls, calf raises, bench presses, seated rows, military presses, and arm curls. Results were the younger group demonstrated higher total and free testosterone levels at rest and with exercise than the older men. However, the older men did demonstrate significant increases in total testosterone response to exercise stress and a reduction in cortisol. Thus, older men do respond to enhanced resistance training with an enhanced hormone profile, but the response is different from that of younger men ^Kraemer.

Intensive exercise also has an impact on female reproductive hormones. Reproductive abnormalities seen in female athletes usually are caused by hypothalamic dysfunction and disturbance of the gonadotropin-releasing hormone (GnRH). GnRH is primarily affected by the ratio of energy intake versus output. For instance, menarche occurs in girls when body fat rises to 17% of body weight. Also, leptin, a protein secreted by adipose tissue is associated with menarche. Amenorrheic women often have low leptin levels. This explains the lack of menstruation in sports that emphasize lean female figures such as ballet and figure skating. Such athletes demonstrate decreased estrogen levels causing menstrual disturbance. However, even women who participate in sports emphasizing strength over leanness such as swimming and rowing are still susceptible to menstrual irregularities. This is because athletes engaged in these sports demonstrate elevated LH levels and mild hyperandogenism. Increased levels of androgens, particularly DHEA) impair follicular development and result in anovulation or amenorrhea ^Warren.  

The impact of intensive exercise levels on the endocrine system is different for various age groups. Malarkey et al. compared triathletes in their 20s to 50-74 year olds. Following the triathlon, the younger group displayed significantly higher levels of DHEA and thyroid stimulating hormone (TSH) than their older counterparts. The older group had higher norepinephrine, estradiol, and sex hormone binding globulin than the younger group. This study shows that all hormone levels increased after the triathlon and confirmed what previous research has found, that there is an exercise-induced release of estradiol in the elderly. Disruption in the female reproductive system does not occur with all activity levels. Estradiol levels elevate significantly after even a 5 minute warm-up and this elevation is maintained at 24 hours post-exercise. Growth hormone also elevates at relatively low exercise intensities. This is in contrast to prolactin and testosterone, which have higher thresholds for activation (Gray). GH response to exercise differs with age. A study comparing young (20s)  and middle aged (40s) competitive cyclists before and after 4 months of intensive training. In young athletes, GH concentrations increased 7-fold the resting values with a peak between the end of exercise and the 10th minute of recovery. In the middle aged, maximal GH response was delayed and significantly lower than the younger athletes ^Zaccaria.

Recommendation 

To optimize the effects of IGF-1, older patients should participate in moderate - high intensity resistance training.  Conflicting evidence exists regarding the HPA axis and cortisol release, but exercise has not been found to be detrimental at moderate intensities. Submaximal endurance training is beneficial in men of all ages, but there is a threshold where exercise causes reductions in testosterone. Research shows this threshold occurs at 60 minutes of endurance training. Thus, shorter bouts of endurance training is recommended. Estrogen release also has a threshold, but it is lower than testosterone’s. Even a 5 minute warm-up can affect estrodial release. This is critical to elderly women as estrogen is markedly decrease post-menopausally. There is exercised-induced estradiol release in the elderly, so it is important for elderly women to stay active. Further, endurance training benefits the elderly in that it promotes GH release.

Musculoskeletal

An initial emphasis on weight bearing and high impact activities in the youth, shift towards a resistive loading and balance enhanced exercise in old age. This seems to optimally address the needs and capacities of the musculoskeletal system throughout the lifespan.  It has been shown that progressive resistive exercise, aerobic exercise, and balance training result in significant improvements in bone mass, collagen elasticity, muscle strength and endurance, as well as overall aerobic capacity. Chronic aerobic exercise enables the individual to sustain higher sub maximal workloads with less fatigue and a decreased cardiovascular response (i.e. heart rate, blood pressure and dyspnea). There is decreased mortality associated with exercise in the elderly. Mortality decreased 30% with an exercise regimen for at least 1000kcal/week and there was a 50% reduction in mortality with a person who exercises at least 2000 kcals/week.^Singh  

Mitochondria

The effects of resistance training on muscle mass and strength involve the increase in motor unit recruitment, improved excitation-contraction coupling and an increase in the synthesis of contractile proteins. A progressive resistive training program lasting 3-6 months or more in duration has been shown to increase muscle strength by an average of 40-150% and an increase in muscle fiber area by 10-30%.^Singh Eight weeks of treadmill training at low intensity increased the BCL-2/Bax ratio in soleus muscle in rats thus improving a cell’s ability to resist apoptosis.^DirksMenshikova et al looked at the effects of exercise on skeletal muscle mitochondria in older men and women over the age of 65. A 12 week exercise training program (4-6 sessions per week) resulted in improved NADH oxidase activity therefore improving electron transport chain activity and decreasing the presence of reactive oxygen species. The subjects in this study exercises for 30 minutes at a heart rate corresponding to 50-60% of their maximal aerobic capacity. The findings of this article suggest that there is a significant improvement in skeletal muscle mitochondria content and function in elderly men and women in response to a moderate intensity exercise program.^MenshikovaExercise increased oxidant stress at a greater extent in aged muscle. With aging and strenuous exercise there is a high rate of electron leakage from the mitochondrial electron transport chain leading to increased reactive oxygen species.  Old Fischer rats (26 months) that ran on a treadmill at 15 m/min and 5% grade until exhaustion (75-80% maximum oxygen consumption) displayed an increase in reactive oxygen species that was 77% higher than in rested old rates. This study revealed evidence to support that intense exercise to exhaustion in old age results in increased oxidative damage to cells thus resulting in less efficient mitochondria and oxidative phosphorylation.^Bejma

PGC-1a

PGC-1a is a key factor in regulating adaptive responses to regular endurance exercise, leading to enhanced oxidative capacity of skeletal muscle causing an increased capacity for fat and carbohydrate utilization. With exercise, there is an over expression of PGC-1a which resulted in a conversion of glycolytic muscle fibers to oxidative muscle and a large upregulation of cytochrome c and cytochrome oxidase.^Pilegaard In an animal study by Calvo et al. looking at the effects of increased PGC-1a on exercise performance, saw that mice with muscle over expression of PGC-1a demonstrated improvements in exercise performance both during sub maximal exercise intensities and during graded exercises to exhaustion. The mice also exhibited a 20% peak in oxygen uptake compared to the wild type mice.^Calvo In a study by Baar et al, five bouts of swimming (10 minutes per day for 5 days) induced increases in mitochondrial enzymes in skeletal muscle in rats. There was a twofold increase in the PGC-1a protein that was evident up to 18 hours after exercise. These findings further support that increased in PGC-1a is a key in the regulation of mitochondrial biogenesis and function during exercise.^Baar Similar results have been found in human skeletal muscle with endurance training yielding a 2-6 fold increase in mitochondrial PGC-1a levels.^{Pilegaard,Saltin}

Bone: INF-a, IL-6, CRP, NFK-b, IFN-y

A study by Greiwe et al found that a 3 times a week progressive resistance exercise program for 3 months reduced TNF-a protein content and TNF-a mRNA by 34% and 46%, respectively, compared to no exercise in the elderly population (mean age 80).  It was also found that the rate of mixed muscle protein synthesis increased in the exercise group by 83%.  These finding suggest that resistance training decreased the inhibitory effects of TNF-a on the formation of new protein in the elderly.^Greiwe Lambert et al also found that a 12 week (3 times a week) exercise program for 65 year old adults (mean) consisting of stretching, balance, aerobic and resistance training reduced expression of TNF-a and IL-6 mRNAs by 50% compared to no reduction with a 12 week 500-750kcal/day deficit diet. It is important to note that serum level of TNF-a and IL-6 did not change with exercise.  This finding suggests that cytokine gene expression in muscle is derived in muscle, and chronic muscle contraction from exercise reduces these muscle inflammatory proteins.^Lambert A similar study by Singh et al. found that a 12 week (5 -7 hours per week) exercise program for adults over the age of 65 years consisting of aerobic and resistive training resulted in decreases in the total adipose tissue accumulation and visceral fat by >20%. With significant decreases in visceral fat composition and decreased adipose tissues, there is going to be a decreased amount of TNF-a released causing a lower amount of local inflammation.^Singh  TNF-a has been shown to be elevated during senesence possibly leading to osteoperosis by stimulating osteoclast activity and bone resorption.

In a study by Buford et al., it was found that a short bout of lower extremity exercise in post-menopausal women resulted in up-regulation in mRNA content of numerous cytokines (IL-1,IL-6,TNF-a) 3 hours post-exercise, without an increase in serum levels of the same cytokines.^Buford It has been shown that estrogen withdrawal during menopause increases pro-inflammatory (IL-1, IL-6, TNF-a) cytokines which can result in increased bone resorption and osteoclast activity, ultimately leading to osteoporosis.  Another study by Nicklas et al found that a 12 month moderate intensity exercise program for the elderly (70-89 y.o.) decreased systemic IL-6 levels by 16%, whereas a control group, which was given an aging education intervention had a 13% increase in IL-6 after 12 months.  It was also found that the physical activity did not result in decreased body mass index or weight loss, which suggests that fat loss is not necessary to decrease IL-6 levels, although adipose tissue is a significant source of IL-6.^Nicklas It has been previously noted that increased levels of IL-6 is a contributor to osteoporosis in the elderly.  This study suggests that IL-6 levels can be decreased with long term exercise, which can decrease bone turnover and osteoclast activation that is related to osteoporosis.  This study also found no significant difference in CRP between groups, suggesting the reduction of CRP with exercise may be associated with reduction in adipose and BMI.^Nicklas 

In a recent study, 60-80 year-old elderly subjects who underwent a 6 month moderate intensity training program showed increased fibrinogen levels secondary to a significant rise in C - reactive protein and significantly decreased fibrinolysis.^SchuitaA study by Shimizu et al. found that a 6 month (5 days/week) moderate endurance and resistance exercise program in the sedentary elderly (61-76 y.o.) resulted in a significant increase in peripheral circulating IFN-y compared to no exercise.^Shimizu As stated in the cellular biology page for aging, T-cell production of IFN-y decrease during senescence which can lead to osteoporosis.  IFN-y prevents uncontrolled bone loss during inflammatory T-cell response by blocking RANK-L induced osteoclast differentiation, which is activated by T-cells.

Recommendations

Short term exercise of high intensities negatively effects skeletal muscle in old age. Long term exercises of moderate to low intensities maintain positive adaptations that are observed in young age.  Regular physical activity should be implemented early in the human lifespan in order to fully take advantage of the benefits of muscle and bones.^BarShai In the aging population it is recommended that aerobic (treadmill or swimming activity) and progressive resistive exercise, in combination, at a low-to moderate intensity of at least 3 times a week, for a minimum of 12 weeks, results in positive musculoskeletal function in the elderly.

Depression

Depression is a serious, widespread condition in the elderly population (link to cell bio).  There has been extensive research done on the effects of exercise on depression in the elderly.  A recent meta-analysis done by Netz et al. examined the effects of physical activity on psychological well being in advanced age.  They found that exercise in general improved the psychological well-being of the elderly.^Netz Mode of exercise and intensity of exercise were analyzed.  They found that moderate intensity was the best, followed closely by high intensity exercise.  In treatment groups, aerobic exercise was found to be the best followed closely by resistance exercise.  The long term effects of exercise on depression have also shown positive results.  In a recent randomized controlled trial done by Singh et al, high intensity resistance training (3 sets X 8 repetitions of 8 main joint resistance exercicses) was shown to maintain an anti-depressive effect after supervised exercise was changed to unsupervised after 20 weeks.^Singh At 26 months follow-up, those that were randomized to the exercise group still had a significantly improved depressive symptom response.  Another important finding was that 33% of those in the exercise group reported continued weight training at the 26 month follow-up.  

Conclusion

Due to the varying cellular mechanisms from exercise on multiple organ systems, it is difficult to draw a distinct conclusion with a blanket statement as to which exercise type, duration and intensity is most beneficial for the overall aging population. The most beneficial types of exercise for the aging Immune system may not be the best exercise type for the Endocrine and/or Musculoskeletal system. For this reason, when attempting to direct an elderly person in an exercise program it is vitally important to examine both the proposed reasons for the initiation of exercise and the target goal. With this in mind, it will be easier to choose a specific exercise type that will provide the best direct effect on a particular body system.

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