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The functional decline in the immune response in the elderly, a phenomenon known as immunosenescence, is considered to be one potential trigger for disease processes that are associated with ageing. Two hormones are identified as key players in immunosenescence, namely cortisol and dehydroepiandrosterone (DHEA), with its sulphated form DHEA-S.
As individuals age, cortisol levels generally increase and DHEA secretion declines. The subsequent increase in the cortisol:DHEA ratio in an older individual is thought to impact the glucocorticoid axis significantly, such that it exposes lymphoid cells to a harmful process and leads to eventual compromise of the immune system.
Exercise as an intervention, can have a positive effect on the immune system, although the outcomes of different intensities of exercise are largely varied and alter the immune response in very different ways. It is the purpose of this review to identify the roles of cortisol and DHEA-S in the ageing individual and to explore the extent to which various exercise intensities affect these hormones. This is a necessary pre-requisite in identifying whether acute exercise has a positive effect on the immune response of an elderly individual.
Life expectancy is increasing globally without discrimination between the developed and developing worlds. Humans are living longer (Smith & Marmot, 1991), but this is synonymous with an increased prevalence of age associated diseases (Vellas et al, 1992). Ageing correlates with reduced efficiency in immunity. This process is known as immunosenescence (Phillips et al, 2007). These changes are only partially understood and are thought to be due to thymus involution, reduced numbers of helper T-cells and a decrease in DHEA secretion (Buford and Willoughby, 2008).
According to Bauer et al (2009), exercise has been found to increase immune function through increasing cardiovascular output. Strenuous exercise is associated with an absolute decrease in natural immunity (Hoffman-Goetz & Pedersen, 1994), where as regular, moderate aerobic exercise has been shown to improve health in the elderly by countering the processes that cause conditions such as osteoporosis, diabetes and heart disease (Mazzeo et al, 1998) although the mechanisms for this are multifactorial. To appreciate the effect of exercise on the immune system, we must understand firstly the roles that cortisol and DHEA-S play in this and secondly, understand the evolving interplay between them with age.
In recording the circulating levels of two adrenal hormones: cortisol and DHEA-S, we are able to assess the immune function in older adults, research has previously identified a change in cortisol and DHEA-S levels as humans age (Bauer et al, 2009; Luz et al, 2003; Kirschbaum & Hellhammer, 1989; Orentreich et al, 1984). An influential factor that can alter the immune response in ageing individuals is their activity level, as a result of altering the cortisol:DHEA ratio (Copeland et al, 2003).
Cortisol, DHEA-S and the immune system
The neuropeptide corticotrophin-releasing hormone (CRH) is secreted by the hypothalamus and stimulates the release of adrenocoticotrophic hormone (ACTH) from the pituitary gland into the blood (Pedersen et al, 2001). ACTH binds to receptors on adrenocortical cells and activates the release of cortisol from the "zona fasciculata" within the adrenal glands (Wu et al, 1995). This is one pathway within the hypothalamic-pituitary-adrenal (HPA) axis (Pedersen et al, 2001) and is a cascade that can be schematically represented by appendix 1. The HPA axis is pivotal in mounting a stress response, particularly following tissue damage, inflammation or infection. If the HPA axis is compromised, it will impact on the ability of an individual to mount an immune response and initiate recovery (Pedersen et al, 2001). Adams et al (2006) have identified that the HPA axis is activated by a 'cascade of signals from the limbic system to the hypothalamus and pituitary gland, where levels are maintained by negative feedback'.
Dehydroepiandrosterone (DHEA) and the sulphate ester, DHEA-S, are important adrenal steroids in humans (Orentreich et al, 1984). DHEA-S is a hormone that is secreted by the adrenal cortex into the blood in response to ACTH. It is the most abundant adrenal steroid which; according to Luz et al (2003), and reinforced by Dillon in 2005, has immunomodulatory properties.
Cortisol is a stress hormone and according to Buford and Willoughby (2008), can suppress immune function; this is in stark contrast to DHEA which can enhance it. The two hormones are essentially antagonistic in effect. This is a useful summary but it is vital that we understand the HPA axis in its entirety, as it is central in conducting a cascade of endocrinological variables that contribute to immune protection. It is an over simplification to look at the roles of DHEA and cortisol in isolation without consideration of the wider axis.
According to McEwen (1997), an individual's HPA axis activation increases as they age. This hyper activation is demonstrated in figure 1 and the increased synthesis of cortisol causes hippocampal damage, resulting in a feed-forward effect known as the 'glucocorticoid cascade hypothesis' (Pedersen et al, 2001). If the research from McEwen (1997) is true, in combination with Kohurt et al's research in 2005, we have contradicting attitudes on the role of the HPA axis, cortisol and immune system performance with ageing when comparing it to the research from Willoughby and Buford (2008). This represents how poorly understood the role of the HPA axis has been until recently. However, certainly the more recent evidence base is constructing a stronger case for HPA suppression as a means of improving immune function.
An individual's diurnal cortisol rhythm is one of the key performance indicators of the HPA axis. On average, a diurnal cortisol rhythm in an individual consists of high levels of cortisol upon waking, followed by an increase (50-60%) in the concentration thirty minutes after wakening. The latter increase is referred to as the cortisol awakening response (CAR) shown in appendix 2. Following this initial increase, there is a steady decline in cortisol levels across the day (Kirschbaum and Hellhammer, 1989). The area under the curve (AUC) is a way of assessing the effects of cortisol throughout the day; individuals with a low AUC and a high CAR suffer more chronic illness (Kudielka and Kirschbaum, 2003). Changes in the diurnal cortisol slope, such as a flattening may be an effect of chronic and acute psychosocial stress (Adam et al, 2006). Any change in the diurnal cortisol pattern can affect the endocrine function dramatically in older adults, and is associated with immunosenescence (Phillips et al, 2007).
Contrary to research by Kohut et al (2004) identifying a link between intense training and increased prevalence of respiratory tract infections; later studies identified that intense physical stress can enhance the immune system's defence against viral pathogens through the secretion of cortisol (Kohut et al, 2005).
Age and immune function
There are two components to the immune system: innate and adaptive. The former is usually the first line of defence to pathogenic organisms and triggers an immediate response. The latter can take days to stimulate but in doing so is more efficient due to its specificity (Gomez et al, 2005).
The attitudes towards immunosenescence are varied, some argue that it is the consequence of losses in the adaptive immune system (Mishto et al, 2003); whereas others argue that it is the result of decline in the innate immune system (Plackett et al, 2004).
A decline in innate immunity in older adults is largely attributed to a gradual decline in number and function of Natural Killer Cells (NK) cells. These are a type of cytotoxic T-lymphocyte whose primary role is to destroy pathogens as they penetrate the innate defences. They are bactericidal but extend their function to the destruction of a variety of parasitic, protozoal and fungal infections (Marketon and Glaser, 2008). In vitro NK cells from the spleens and lymph nodes of older rats show a decline in their ability to respond to infections when compared to the young (Castle, 2008). In addition, this research also identifies losses in the number of B-lymphocytes with age, thus causing a decline in essential antibody production. This impacts both the innate and adaptive systems to their detriment and contrary to earlier opinion; it appears immunosenescence is not discriminatory to either the innate or adaptive systems, it affects both.
According to Parham (2005), as individual's age, the ability of the thymus gland to produce new T-lymphocytes diminishes. By the age of fifty, there is a considerable reduction and by sixty years old, it is nearly impossible to produce new naÃ¯ve cells. However, Lord et al (2001) have identified that the elderly have a higher percentage of memory T-cells relative to a younger individual. The impact of this is that the elderly have very specific immunity for recognised infections i.e. those previously exposed to, but their immune systems lack any dynamic edge that allows them to adequately respond to new pathogens (Lord et al, 2001).
The effect of aging on cortisol and DHEA-S
The functional decline in a physiological system is not confined to the immune system. The endocrine system also becomes suboptimal with ageing, a phenomenon known as endocrinosenescence (Roshan et al, 1999). Endocrinosenescence causes a decrease in the secretion of Growth Hormone (GH), the sex hormones Follicular Stimulating Hormone and Luteinising Hormone (FSH, LH) and DHEA (Roshan et al, 1999). This is likened to a state of panhypopituitarism. Serum DHEA-S concentration decreases with age (Luz et al, 2003). This has a catalytic effect, causing a surplus of glucocorticoids and an increase in immune diseases (Kiecolt - Glaser et al, 1996). Sternberg (2000) agrees with this conclusion and argued that if the HPA axis is altered in this way, there would be an increased vulnerability to autoimmune inflammatory disease. Consequently, older adults have an increased susceptibility for both infectious and chronic diseases (Mishto et al, 2003). This is consistent with the earlier literature discussed, presented by Buford and Willoughby (2008), that cortisol suppresses the immune system. Cortisol by its nature dampens down the body's immune cascade through the inhibition of inflammatory cytokines such as the interleukins and TNF-alpha, so it is rather intuitive that its loss will lead to hypersensitivity and unregulated, excessive immune reactions.
Over an individual's lifespan DHEA serum levels decrease, and is at an optimum in young adults (19 to 25 years old), after which it steadily decreases. Research shows that when individuals are aged 70 to 80, they have circulating DHEA levels that are 10-20% compared to their peak (Orentreich et al, 1984). The age related decrease in DHEA has been termed 'adrenopause' and differs from other adrenocortical hormones, which do not demonstrate clear age related changes (Orentreich et al, 1984; Phillips et al, 2007). In earlier research, there was evidence suggesting that cortisol levels remain constant in healthy individuals (Kudielka et al, 2000); thus meaning that there will be a relative excess of cortisol in older adults (Ginaldi et al, 1999).
The diurnal rhythm of cortisol changes across different ages (figure 2) however the main pattern remains the same: being at its highest in the morning and lowest at night (Kirschbaum and Hellhammer 1989). Appendix 2 provides graphical data and shows that older adults compared to children and younger adults have a higher awakening and 30 minutes after wakening cortisol level. Salivary cortisol levels have been found to be significantly higher (45%) throughout the day in healthy older adults when compared to young adults (Luz et al 2003). Older adults exhibit a flatter DHEA secretion pattern throughout the day. This change in the DHEA levels explains immunosenescence, as DHEA has immune enhancing properties (Bauer et al, 2009). The consequence is a raised cortisol:DHEA ratio throughout the day.
Another cause for the high cortisol:DHEA ratio in older adults, is that cortisol is secreted after a trauma or stress (Butcher et al, 2005); but unlike the young who can counteract the surplus in cortisol by secreting the antiglucocorticoid hormone, DHEA, older adults create less DHEA (Orentreich et al, 1984). Trauma can cause the cortisol:DHEA to be seven times higher in older adults than the young trauma patients (Butcher et al, 2005). This difference in the ratio means that when comparing infection rates following injury, older adults have an increase glucocorticoid response to the stress compared to young adults. Glucocorticoids have strong immune suppressing actions, an example being their ability to cause death of lymphocytes in the thymus (Ginaldi et al, 1999). Butcher et al (2005) have found, in vitro, that ageing is accompanied by an exaggerated response to trauma; by producing a relative excess of cortisol which suppresses neutrophil bactericidal function when DHEA levels are decreased compared to younger age groups.
Conclusions can be made that increased cortisol and lower DHEA may contribute to changes in immune function with ageing. The decrease in DHEA is a key driver of immunosenescence, as DHEA-S is an androgenic hormone that has reported immune enhancing properties, in contrast to the immunosuppressive action of glucocorticoid's (GCs). The change in levels of these two hormones can result in lymphoid cells being exposed to the harmful effect of cortisol (Bauer et al, 2009).
The effect of exercise on immunity
Health benefits are appreciable with increasing exercise levels (Mazzeo et al, 1998). Compared to other research in the field of delaying or reversing the immunosenescence process, exercise has the advantage that it is non invasive and unrestricted to environmental situations, Buford and Willoughby (2008) agreed with this by hypothesising that 'exercise is highly recommended for older adults in conjunction with many health benefits' meaning that as one ages, exercise levels should be maintained to help improve immune function.
The theory of the "inverted J hypothesis" with immune function on the Y axis, against exercise intensity on the X axis (Woods et al, 1999), suggests that a moderate level of exercise improves immune function; whereas intense, strenuous exercise decreases immunity in older adults and increases susceptibility to disease (appendix 3). Kohurt et al (2004) performed a ten month moderate aerobic exercise intervention (3 days/week, 25-30 minutes at 65-75% of maximum heart rate). This concluded that the participants who subscribed to this exercise regime suffered fewer days with upper respiratory tract infections compared to their sedentary counterparts.
Other studies support the "inverted J hypothesis". Akimoto et al (2003) concluded that moderate exercise can cause an incline in salivary immunoglobulin A (sIgA). This is important as it neutralises toxins and viruses and limits the reproduction of pathogenic micro-organisms (Tomasi, 1992). However, "the inverted J hypothesis" is further reinforced by Gleeson et al (1999) who found a reduction in salivary IgA levels after intense exercise training.
There have been numerous studies researching the immune response in older adults who regularly participate in exercise compared to sedentary adults (Filaire & Lac, 2000; Flynn et al, 1999; Nieman et al, 2003; Tremblay et al, 2004;2005). For example, Nieman et al (1993) have shown that the trained athletes had a higher NK basal rate (54%); however Shinkai et al, 1995 concluded that there was no significant difference in NK cell activity in older adults who participated in exercise. However, exercise was found to increase T cell response by up to 40-50% in the physically active compared to the sedentary older adults (Nieman et al, 1993; Shinkai et al 1995). A plausible reason for the opposite findings where the level of activity of the athletes (elite vs. recreational), the length of time they had been physically active (5 years vs. 17 years) and the minimum amount per week (7 hours vs. 5 hours).
Cortisol is affected differently by exercise, although the evidence base lacks clarity. According to Flynn et al (1999) resistance exercise interventions cause a decline in cortisol levels immediately after and up to two hours post exercise. The study attributed this decline to 'elevated two hour post exercise NK cell activity'. However, research by Smilios et al (2007) contradicts this. Cortisol appears to increase following resistance exercise sessions when compared to the respective time points in the control session where decreases in cortisol were observed. These differences were explained to be the consequence of the 'circadian rhythm of the hormone'.
Cortisol and DHEA-S response in older adults with acute exercise
There is conflicting research into how acute exercise influences immunity in the elderly. Pedersen et al (1999) argue that immunity is maintained by acute exercise with age. Others, notably Ceddia et al (1999) argue that it slightly reduces immunity in older people.
Early research by Howlett (1987) identified that the cortisol response after acute exercise is dependent on intensity. During less acute intensity exercise, cortisol levels decrease, mirroring the diurnal rhythm. In contrast, higher intensity exercise increases the cortisol level (Davies & Few, 1973). To differentiate the two exercise intensities, Davies and Few (1973) go on to propose that a high intensity represented a VO2max of 60% or higher.
Kemmler et al (2003) conclude that cortisol levels decrease significantly during and after acute exercise; appendix 4.1 shows a 36% decline immediately after exercise and a further 14% reduction two hours post exertion. The study by Copeland et al (2002) displayed significantly decreased cortisol levels after endurance exercise (appendix 5.1). Supporting this, studies in older adults showed acute endurance exercise reduced cortisol level (appendix 6.1, quartile 5). Therefore, there seems to be much agreement and consistency between the studies, which suggest in general terms that cortisol decreases in response to acute exercise.
DHEA operates at higher plasma concentrations when an older adult exercises (Copeland et al, 2002; Filaire and Lac, 2000; Kemmler et al, 2003; Riechman et al, 2004). Kemmler et al (2003) quantified this and found a significant increase in DHEA-S (figure 4.2) by 10% immediately after and two hours post exercise. This is supported by findings from Johnson et al (1997) which concluded that that DHEA serum concentrations are significantly higher when compared to a control group after acute exercise (30 minutes of treadmill exercise at 90% of maximum heart rate). This evidence is further enhanced by Copeland et al (2002). As appendix 5.2 illustrates, DHEA levels after acute resistance exercise are significantly higher compared to the control group. Even in older adults, appendix 6.2 demonstrates an increase in DHEA post acute endurance and resistance exercise compared with the control group.
Tremblay et al (2004) compared the 'training status of the subjects' across varying intensities of acute exercise (resistance or endurance). The results from this study concluded that DHEA-S levels generally increased post exercise. This increase was more apparent in the resistance trained individuals compared to the endurance trained athletes. The findings from this study are consistent with research from Copeland et al (2002); Filaire and Lac (2000); Kemmler et al (2003); Riechman et al (2004). However, research from Keizer at al (1987) contradicts these findings and concluded that training status has opposite effects on DHEA-S post exercise. For example, they showed that marathon runners have a lower DHEA-S level compared to sedentary control subjects. Arguably this research is out dated, data recording and gathering have both subsequently improved, rendering older techniques obsolete. Nevertheless, it is important that we consider this evidence base years on, and identify how trends and attitudes have evolved. We have seen how the evidence base in this field remains largely inconsistent and it is this which makes further research in this field justified and fundamental.
An acute exercise bout can be classified as a duration of minutes or hours (Kemmler et al, 2003; Tremblay et al, 2005). Tremblay et al (2005), identified that 'there has been little research â€¦isolating the effect of exercise duration' and therefore proceeded to investigate the effects of three different durations of acute exercise: 40 minutes, 80 minutes and 120 minutes, on endurance trained males ranging between 19 and 49 years old. The hormonal response of DHEA-S is represented in appendix 7.1 and shows that after the 40 and 80 minute exercise durations, DHEA-S levels decrease immediately after the exercise. However, after 120 minutes of exercise, the levels remained significantly higher 1 hour after the run. Therefore, we can see why the evidence base has appeared contradictory, it is the likely result of a lack of standardisation in trials. Indeed, Tremblay et al (2005) have identified DHEA-S concentrations to be duration dependent. This is in stark contrast to the earlier research from Copeland et al (2002); Filaire and Lac (2000); Kemmler et al, (2003); Riechman et al (2004), which concluded that DHEA levels are directly proportional to the length of exercise. A plausible reason for this discrepancy could be that Tremblay et al (2005) investigated males of all ages; whereas the findings from Copeland et al (2002) were based on a study population consisting of females over 60 years old. It was identified earlier in this chapter how research by Orentreich et al (1984) which concluded a sex difference in DHEA-S levels, is highly relevant to the result interpretation. It provides a clear warning that we must interpret the evidence base with significant caution and carefully define study populations for further research in this field.
The duration of acute exercise also affects the level of circulating cortisol in the body. Research by Tremblay et al (2005) depicted in appendix 7.2, shows that at 40 and 80 minute exercise durations, post exercise cortisol levels decrease and this follows the trend identified by Kemmler et al (2003). However, at 120 minutes, cortisol levels were found to be significantly greater post exercise compared with levels whilst resting (Tremblay, 2005). This anomalous result was attributed to a 'threshold for adrenal activationâ€¦greater than 80 minutes at a low intensity'.
The level of exercise a person performs affects the adrenal hormones; Kemmler et al (2003) highlights that exercise may be partially responsible for a greater decline in cortisol levels in older female adults, and an increase in DHEA-S levels. The increase in DHEA-S and decrease in cortisol levels post exercise causes a decrease in the cortisol:DHEA ratio. Therefore, exercise is a highly recommended activity for older adults to help improve immunity in conjunction with the many other health benefits and physiological adaptations that are associated with exercise (Buford and Willoughby, 2008).
In summary the research shows circulating cortisol and DHEA levels in the blood and saliva in older adults to be affected by exercise (Copeland et al 2002; Kemmler et al, 2003; Tremblay et al 2004; Tremblay et al, 2005). Cortisol levels decrease significantly after acute exercise when the subjects are elite endurance trained (Copeland et al 2003; Kemmler et al 2003). Overall the circulating DHEA-S levels increase after acute exercise, appreciably more so in older adults (Copeland et al, 2002; Filaire and Lac, 2000 Johnson, Kemmler et al 2003; Riechman et al, 2004). The effects of moderate exercise on immune function in older adults are predominantly positive as DHEA-S can enhance immunity, whereas it is suppressed by cortisol (Butcher et al, 2005). Ageing correlates with a cortisol:DHEA-S ratio increase; however exercise has been proven to increase DHEA-S and decrease cortisol (Copeland et al, 2002; Johnson et al, 1997; Kemmler et al 2003). The consequence of this is a reduced cortisol:DHEAS ratio and a slow reversal of the immunosenescence process.
The hypothesis that ageing leads to a decline in immune function has been proposed by several authors (Graham et al, 2006; Phillips et al, 2007; Luz et al, 2003). This age related decline has been termed immunosenescence and is considered to be in part the result of a reduction in the ability of NK cells to respond to new pathogens (Castle, 2000). In parallel to the changes that occur to NK functioning at a cellular level, ageing is associated with an increase in frailty and it is this which correlates with low DHEA-S levels (Voznesensky et al, 2009).
The immune system can be stimulated by increasing exercise and much of the research presented has shown that as exercise intensity increases, immunity is enhanced, eventually reaching an optimum at a moderate intensity according to the 'inverted J hypothesis' by Woods et al (1999). This hypothesis has been supported by work from Kohut et al (1994) who suggested that moderate intensity exercise led to a reduction in days in which these participants suffered from upper respiratory tract infections.
Activity levels affect the cortisol and DHEA-S profile in the elderly and alter the cortisol: DHEAS ratio. Serum cortisol levels are reduced by different forms of exercise (Kemmler et al, 2004; Flynn et al, 1999). Exercise simultaneously increases DHEA-S levels by up to 10% according to Kemmler et al (2003). The current evidence base is in favour of exercise in the elderly. It supports an alteration in the cortisol:DHEA. More specifically, as older adults exercise, cortisol levels decrease and DHEA-S levels increase and this supports a slow reversal of the process of immunosenescence. However, a lack of standardisation in defining research populations has caused some confusion in the evidence base. At best it is contradictory and at worst unreliable and this has led the way for further research into the effect of acute exercise on immunity, in what is a rapidly expanding area of interest with ageing populations.
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Appendix 1: (Source: Adaptation from Pedersen et al, 2001)
Appendix 2: (An adaptation taken from the citation in Fries et al, 2009 from Pruessner et al, 1997)
The mean cortisol levels (Â±Â standard error) after awakening, Subjects studied: children aged 7-14 years, adolescents aged 19-37 years, and elderly adults aged 59-82 years
Appendix 3: (Source: adapted from Woods et al, 1999)
Appendix 4: (Source: Adapted from Kemmler et al. 2003)
Fig 4.2 - DHEAS
Fig 4.1 - Cortisol
Appendix 5: (Source: adapted from Copeland et al. 2002) combining all age groups
Fig 5.1: Cortisol
Fig 5.2 : DHEA
Appendix 6: (Source: adapted from Copeland et al. 2002) separating the age groups
Fig 6.2: DHEA
Fig 6.1: Cortisol