Old age and inflammation

It has been clearly established that baseline biochemical markers of inflammation, such as IL-1, TNF-alpha and CRP, are frequently raised 2- to 4-fold in the blood of elderly people, particularly those above the age of 80 years, compared with younger adults. ^{Reference Woods, Wilund, Martin and Kistler11,Reference Bruunsgaard and Pedersen12} In many individuals this can be explained by the presence of a clinically obvious chronic inflammatory disorder such as chronic obstructive pulmonary disease (COPD) or rheumatoid arthritis (RA). ^{Reference Chung, Cesari and Anton13} Similar levels of biochemical inflammation are often observed in elderly people with other disorders that are now known to have a pro-inflammatory effect, such as central obesity, ^{Reference Caspersen, Pereira and Curran14} cardiovascular disease, ^{Reference Driver, Djousse, Logroscino, Gaziano and Kurth15} or type 2 diabetes mellitus. ^{Reference Cowie, Rust and Byrd-Holt16} It is often present as a persisting abnormality after an acute inflammatory event, such as pneumonia. ^{Reference Starr and Saito17,Reference Boyd and Orihuela18} Raised pro-inflammatory biomarkers have also been associated with Alzheimer's disease, ^{Reference Kalaria, Maestre and Arizaga19} physical inactivity, ^{Reference Caspersen, Pereira and Curran14} chronic kidney disease ^{Reference Coresh, Selvin and Stevens20} and osteoarthritis. ^{Reference Dagenais, Garbedian and Wai21} In some clinically well elderly people raised biochemical inflammatory markers appear to occur with no demonstrable cause, and age itself appears to be associated with chronic inflammation, ^{Reference Ballou, Lozanski and Hodder22–Reference Wei, Xu, Davies and Hemmings24} though not all studies have confirmed this observation in healthy older people. ^{Reference Ahluwalia, Mastro, Ball, Miles, Rajendra and Handte25,Reference Beharka, Meydani, Wu, Leka, Meydani and Meydani26}

Persisting low-amplitude inflammation is associated with increased all-cause mortality, ^{Reference Kabagambe, Judd and Howard27,Reference DeMartinis, Franceschi, Monti and Ginaldi28} reduced muscle strength, ^{Reference Jensen29} impaired instrumental function ^{Reference Penninx, Kritchevsky and Newman30} and lower self-reported health status. ^{Reference Christian, Glaser, Porter, Malarkey, Beversdorf and Kiecolt-Glaser31} There is evidence that chronic disease progression is at least partly due to chronic inflammation and not merely indicated by it, ^{Reference Michaud, Balardy and Moulis32} so there is a complex interaction between cause and effect. The endothelial inflammation that occurs in atheromatous vascular disease is probably the best-described example. ^{Reference Golbidi and Laher33} It also appears that in many elderly people, the biochemical pro-inflammatory response to acute illnesses such as infection or injury does not resolve as quickly as it does in younger adults. ^{Reference Starr and Saito17,Reference Boyd and Orihuela18} The rises in IL-1, IL-6 and TNF-alpha persist longer and the rise in anti-inflammatory IL-10 is delayed and slower. This effect has been quantified for pneumococcal and endotoxin antigens, ^{Reference Bruunsgaard, Skinhoj, Qvist and Pedersen34,Reference Krabbe, Bruunsgaard and Hansen35} indicating an approximate 2-fold difference in the time to return to baseline between young and older subjects. This suggests an impairment of regulatory anti-inflammatory function that might be one of the reasons for the delayed rates of clinical recovery and chronic low-level inflammation often seen in old age.

There are, however, other purported mechanisms for chronic age-associated inflammation, including a decline in anti-oxidant capacity with consequent increased oxidative stress, ^{Reference Wu, Xia, Kalonis, Wan and Sun36} which appears to contribute to pro-inflammatory activity through stimulation of toll-like receptors on various immune cells. ^{Reference McFarlin, Flynn and Campbell37} A teleological argument can also be proposed that links raised baseline inflammation in old age to enhanced anti-neoplastic immune surveillance and subclinical auto-immune states. It is also not clear whether the tendency for cortisol and catecholamine levels to remain higher for longer after acute damage in old age ^{Reference Rotman-Pikielny, Roash, Chen, Limor, Stern and Gur38} is entirely due to higher pro-inflammatory cytokine levels or partly due to non-cytokine mechanisms governed by the pituitary–adrenal axis. Nevertheless, the evidence for cytokines playing a central role in age-associated inflammation is now substantial.

Clinical impact

The disturbance of inflammatory modulation described above appears to play an important part in the genesis and perpetuation of a number of common and clinically significant conditions in old age. These include cardiovascular and cerebrovascular disease, metabolic syndrome, loss of muscle bulk and strength (sarcopenia), some malignancies and neuronal dysfunction. ^{Reference Woods, Wilund, Martin and Kistler11} The last is particularly subtle and poorly understood, but there is evidence that pro-inflammatory over-activity and inadequate or incomplete anti-inflammatory activity contributes to cognitive impairment, low mood, illness behaviour and autonomic dysfunction. ^{Reference Woods, Wilund, Martin and Kistler11} The neuronal effects will be considered in more detail below as they represent the core of the problem from the perspective of geriatric clinical practice.

Chronic low-level elevation of CRP and SAA, released from hepatocytes mainly in response to raised IL-6 and TNF-alpha, is associated with enhanced risk of vascular disease. ^{Reference Golbidi and Laher33,Reference Johnson, Kip and Marroquin39} The CRP in such cases is probably a marker for the presence of the pro-inflammatory cytokines that are more directly involved in the pathogenesis of vascular disease through their promotion of insulin resistance, dyslipidaemia and macrophage activity. IL-1, IL-6 and TNF-alpha are consistently associated with these mediators of vascular pathology. ^{Reference Beavers, Brinkley and Nicklas40} More recently the pro-inflammatory cytokines interleukin-15 (IL-15), interleukin-18 (IL-18) and interleukin-8 (IL-8) have been found to be more specific risk factors for coronary artery disease, diabetes and some cancers. ^{Reference Everett, Bansal, Rifai, Buring and Ridker41–Reference Caruso, Carmack, Lockeshwar, Duncan, Soloway and Lockeshwar43} IL-1 and TNF-alpha also have a suppressive effect on some hepatocyte synthetic functions. ^{Reference Gauldie, Saunder, McAdam and Dinarello44,Reference Mahesh45} The main manifestation of this in clinical practice is a reduction of the serum albumin concentration, which is a useful indicator of systemic inflammation and rarely due to protein malnutrition or a protein-losing state. The mechanisms at molecular level are uncertain.

Receptors for pro-inflammatory cytokines are found on the surface of various types of neurons. ^{Reference Mahesh46} The evidence is building for a role of pro-inflammatory cytokines, and other substances involved in inflammation such as cortisol and adrenaline, in the modulation of neuronal function. ^{Reference Erta, Quintana and Hildago46–Reference Sparkman and Johnson48} Most research attention has been given to dementia, particularly Alzheimer's disease (AD), and there is no doubt that the cytokine milieu is altered in AD. ^{Reference Kalaria, Maestre and Arizaga19,Reference Zotova, Nicoll, Kalaria, Holmes and Bocke49} What is less clear is the role of cytokines in the initiation and progression of the AD pathogenesis; are the measured cytokine changes merely a reactive consequence or a key pathogenic component? The apparent protective effect of regular exercise on cognitive function suggests the latter. ^{Reference Ohman, Savikko, Strandberg and Pitkala50} It can be hypothesized that the autonomic dysfunction observed during and after acute inflammatory illnesses such as pneumonia might be mediated by pro-inflammatory cytokines. ^{Reference Erta, Quintana and Hildago46} The impairment of cardiovascular autonomic reflexes, an important contributory cause of the orthostatic hypotension often found in older patients after acute illnesses, is probably in part a result of cytokine-mediated autonomic down-regulation and is of considerable clinical importance. ^{Reference Vinik, Erbas and Casellini51} The same or a similar mechanism is likely to be the reason for the persistent cardiovascular autonomic dysfunction observed in chronic inflammatory conditions. The role of inflammatory chemistry in sensory, motor and co-ordination dysfunction is much less clear and therefore an attractive target for future research.

The adverse influence of pro-inflammatory conditions on the structure and function of skeletal muscle appears closely bound with IL-6, which is dealt with in a separate paragraph below.

Skeletal muscle and the particular role of IL-6

IL-6 has been mainly considered to be a pro-inflammatory cytokine with a broad range of effects including promotion of IL-1 and TNF-alpha, and as an inducer of obesity-related insulin resistance in inactive subjects. However, the main source of IL-6 is contracting skeletal muscle and it is therefore often subclassified as a myokine. ^{Reference Pal, Febbraio and Whitham52} In the context of exercise it has been shown to have paracrine and endocrine functions that mediate the insulin-sensitizing effects of exercise, and in that metabolic context it promotes the release of anti-inflammatory cytokines such as IL-10. ^{Reference Pedersen and Febbraio53} The full metabolic action of IL-6 is unknown and it seems to have an effect on inflammatory chemistry that is conditional upon prevailing stimuli in a pleiotropic manner. ^{Reference Pal, Febbraio and Whitham52,Reference Pedersen and Febbraio53} Therefore, during sepsis IL-1 promotes IL-6 and TNF-alpha, whereas after exercise IL-6 promotes IL-10 and IL-1ra. This apparent orchestrating function of a cytokine produced and released by active skeletal muscle puts it in a central position when considering the effects of exercise on inflammation, and it also raises the question as to whether IL-6 is not only an inflammatory cytokine but also a hormone. ^{Reference Kishimoto54} The apparent pleiotropic behaviour of IL-6 also indicates the possibility that another, as yet unidentified, substance is a more proximal controller. However, for this review IL-6 will be positioned as an inflammatory cytokine with an apparently key modulating role in immune responses, which is its best-defined function according to the prevailing evidence.

The rise in IL-6 during and immediately after exercise occurs at all ages. ^{Reference Golbidi and Laher33,Reference Mikkelsen, Couppe and Karlsen55,Reference Pedersen, Steensberg and Fischer56} Though most clearly demonstrated during rhythmic concentric exercise, such as cycling, IL-6 is also released during eccentric and isometric exercise. ^{Reference Pedersen and Pedersen57} Of course, general physical activity tends to be a variable mix of all three patterns of muscle use. The clearest studies have been performed on young adults undergoing vigorous exercise. Rises of IL-6 in peripheral blood of 100-fold or greater above baseline have been shown in young adults after prolonged exercise at high work rates, such as competitive long-distance running. ^{Reference Pedersen, Steenberg and Schjerling58} A dose–response relationship has been observed with work rate and duration, particularly the latter. Measurable rises have been shown after moderate exercise, such as cycling or brisk walking for 10–20 minutes, including in old age. ^{Reference Fischer59} However, there are no studies of the IL-6 response to very mild exercise, such as slow walking for a few minutes, that often represents the maximum achievable work rate of frail elderly people.

The IL-6 response to exercise is further complicated by an apparent reduction in baseline levels between episodes of recurrent exercise. ^{Reference Woods, Veira and Keylock60} In those who exercise regularly it can be argued that the fall in baseline IL-6 between bouts of exercise might be the key anti-inflammatory consequence of muscle activity, rather than the insulin-sensitizing effect of peak post-exercise levels. ^{Reference Pedersen61} The autocrine effects of IL-6 on myocytes also appear to depend on the pattern and context of IL-6 release so that the acute peaks that occur with vigorous exercise play a role in building muscle bulk, contractile strength and endurance, whereas chronically elevated baseline IL-6 levels play a part in the degenerative changes that lead to sarcopenia. ^{Reference Mikkelsen, Couppe and Karlsen55,Reference Woods, Veira and Keylock60–Reference Brandt and Pedersen62} A reasonable interpretation might therefore be that the IL-6-mediated benefits of exercise are due to at least three mechanisms: firstly, a general anti-inflammatory effect through the stimulation of IL-10 and IL-1ra that could have a positive influence on, for example, endothelial function, insulin sensitivity and hepatic synthetic function; secondly, two paracrine mechanisms whereby high peak exercise-induced levels improve muscle structure and performance and lower baseline levels reduce the tendency to sarcopenia.

The observed benefits of exercise

A number of large scale studies have established the beneficial effects of regular moderate aerobic exercise, such as walking and cycling, both from an epidemiological perspective based on self-reported exercise habits and during supervised intervention studies. The methodologies and approaches to data analysis vary across the published literature but the overall findings show an independent effect of exercise in reducing the risk of all-cause mortality, ^{Reference Ekelund, Ward and Norat63} stroke, cardiovascular disease and type 2 diabetes. ^{Reference Pedersen10,Reference Tuomilehto, Lindstrom and Eriksson64} There is also evidence of a reduced risk of some cancers, ^{Reference Arem, Moore and Park65} dementia, depression and physical dependency. ^{Reference Woods, Wilund, Martin and Kistler11,Reference Allison and Ditor47,Reference Angevaren, Aufdemkampe, Verhaar, Aleman and Vanhees66} People who take regular exercise report higher levels of wellbeing in intervention studies. ^{Reference Windle, Hughes, Linck, Russell and Woods67} Further, more specific exercise-based interventions are of proven value in COPD ⁶⁸ and after myocardial infarction. ⁶⁹ Though some benefits are dependent on the intensity of an exercise programme, for example building cardiovascular endurance, it has recently been shown that brief, low-intensity, exercise such as 20 minutes walking per day has a positive effect on all-cause mortality, particularly in individuals with obesity, ^{Reference Ekelund, Ward and Norat63} a known pro-inflammatory state. Relatively few exercise studies have focused specifically on elderly people but the evidence as it stands indicates positive effects on mobility, function and dependency, and probably a reduction in stroke and all-cause mortality. ^{Reference Woods, Wilund, Martin and Kistler11,Reference Golbidi and Laher33} Of course, some of the described benefits of exercise are likely to be mediated by non-cytokine mechanisms, including psychological effects, neuro-humoral changes and through the release of other hormone-like substances such as endorphins.

Having established a beneficial effect of exercise on a number of health indicators and outcomes, and given the association and probable mechanistic relationship between those indicators and a chronic pro-inflammatory state, the review will now consider the effect of exercise on the chemistry of inflammation.

The effects of exercise on blood markers of inflammation in old age

Several adequately powered observational studies of the effect of exercise on various biochemical blood markers of inflammation in older adults have been published. Most of the data pertain to the 60–79 year age range. Overall, a consistent inverse dose-related correlation between physical activity and inflammatory biomarkers was found, with some variation related to gender, use of supplements and body composition. ^{Reference Woods, Wilund, Martin and Kistler11,Reference Colbert, Visser and Simonsick70,Reference Taaffe, Harris, Ferrucci, Rowe and Seeman71}

The Cardiovascular Health Study ^{Reference Geffken, Cushman, Burke, Polak, Sakkinen and Tracey72} and the British Regional Heart Study ^{Reference Wannamethee, Lowe, Whincup, Rumley, Walker and Lennon73} included a total of more than 10,000 people over the age of 60 years. These studies showed an inverse relationship between CRP and self-reported physical activity that persisted after adjustment for multiple risk factors. The relationship held even at estimated exercise-related energy consumption levels as low as 368–1050 kcal/week. Of other studies, most but not all, showed a fall in TNF-alpha, IL-1 and baseline IL-6, when measured, ^{Reference Colbert, Visser and Simonsick70,Reference Taaffe, Harris, Ferrucci, Rowe and Seeman71} though the effects on cytokines were more consistently associated with relatively vigorous exercise, ^{Reference Taaffe, Harris, Ferrucci, Rowe and Seeman71,Reference Elosua, Bartali, Ordovas, Corsi, Laurentian and Ferrucci74} while light exercise, such as slow walking and intermittent housework, were only clearly associated with a fall in CRP. ^{Reference Hamer, Sabia and Batty75} At lower exercise levels, the fall in CRP was more consistent in elderly men, even after adjustment for body mass index (BMI), though the magnitude of the change was small and similar to that seen after treatment with statins. ^{Reference Woods, Wilund, Martin and Kistler11,Reference Elosua, Bartali, Ordovas, Corsi, Laurentian and Ferrucci74} Adiposity has been shown to correlate positively with baseline CRP, ^{Reference Nicklas, Ambrosius and Messier76} and some studies have found no inverse relationship to mild exercise once changes in body composition are factored in. ^{Reference Woods, Wilund, Martin and Kistler11,Reference Hamer and Steptoe77} Of course, adipose tissue has a pro-inflammatory effect, so such an observation must allow for a possible indirect anti-inflammatory effect of exercise.

There are few data concerning exercise performance or measures of aerobic fitness and inflammatory biomarkers in older adults, and none that used objective laboratory measures of cardiorespiratory capacity such as anaerobic threshold or maximum oxygen uptake. The findings in old age have been mixed, and difficult to compare due to different methodologies. One study found an inverse relationship between maximum walking speed and baseline IL-6 and CRP, ^{Reference Taaffe, Harris, Ferrucci, Rowe and Seeman71} while another found that the relationship disappeared when adjustment was made for adiposity. ^{Reference Valentine, Vieira, Woods and Evans78}

Healthy old age

The available data suggest that older people who are able to perform regular moderate exercise as part of a lifestyle habit can reduce their risk of a number of adverse health outcomes. This benefit is probably, at least partly, due to the anti-inflammatory and hormone-like effects of IL-6 released from skeletal muscle and other cytokine-mediated mechanisms. The benefits probably include improved endothelial-cardiovascular function, reduced risk of certain cancers, conservation of skeletal muscle strength, independent function, cognition and mood. The optimal dose of exercise in older age is not known and there is certainly no evidence to justify recommending regimens with very demanding work rates or prolonged duration. Perhaps Aristotle's intuition remains apposite: moderate exercise is best for the ordinary citizen.

The future

There is, of course, huge potential for research across the whole field of cytokine chemistry and the pathophysiology of inflammation. This might eventually translate into clinically useful pharmacological interventions to suppress the apparently deleterious effects of chronic, and slowly resolving acute, states of inflammation with conceivable benefits for vascular health, bone marrow function, hepatic synthetic function, strength, mobility, cognition, mood and the functional integrity of many other organ systems. However, there is also a need to demonstrate whether or not the very low levels of exercise that can be realistically expected of frail or very aged people result in a biochemically consistent anti-inflammatory effect, and more importantly, whether there are clinical outcome benefits as a consequence. In other words, does the anti-inflammatory dose–response effect hold true at very low work rates in frail old age? Further, if the dose–response has a lower limit, what is the threshold? A clearer understanding of these issues will help clinicians to be better able to inform their patients about the possible benefits of exercise programmes.

Conflicts of interest

None