Acute–chronic–intense physical activity

Previous studies have reported an immune–physiologic adaptation to an acute bout of exercise leading to an increase of neutrophils together with a decrease of eosinophils, most probably influenced by plasma volume changes⁽Reference MacKinnon^21–Reference Romeo, Jiménez-Pavón and Cervantes-Borunda²⁵⁾. The possible mechanism seems to be associated with the migration of cells from endothelial tissues, as well as a phagocytic and inflammatory response to exercise-induced tissue damage⁽Reference Pyne²⁶⁾. Nevertheless, which different subsets of leucocytes migrate differentially into different tissues after exercise seems to be dependent on other factors such as the duration and intensity of the exercise⁽Reference Nieman and Pedersen²⁷⁾. A suppression of the respiratory burst and/or phagocytic capacity from neutrophils immediately after acute exercise has also been observed⁽Reference Pyne²⁶⁾.

Although the global health significance of transient changes in innate immunity cells such as natural killer cell subsets remains unclear⁽Reference Timmons and Cieslak¹¹⁾. After high-intensity exercise periods, a period of natural killer cell function depression has been described to be partly responsible of an increased susceptibility to the infection stage⁽Reference Pedersen and Ullum²⁸⁾. Some in vitro cross-sectional studies of the immune function have suggested enhanced natural killer cell cytotoxicity⁽Reference Nieman, Henson and Gusewitch^29, Reference Starkie, Hargreaves and Rolland³⁰⁾ and T-lymphocyte proliferation among highly trained athletes v. untrained subjects⁽Reference MacKinnon^19, Reference MacKinnon^21, Reference Pedersen and Nieman^22, Reference Kusaka, Kondou and Morimoto^31, Reference Fehrenbach and Schneider³²⁾. With regard to immune cell counts, the results are less consistent⁽Reference Pedersen^33–Reference Gleeson³⁵⁾.

Acute and chronic intense exercise are also known to impair cell-mediated immunity by decreasing the expression of toll-like receptors and increasing cortisol and IL-6 production, leading to a state of inflammation, via a decreased macrophage and T-helper (Th) 1 cell cytokine production⁽Reference Gleeson³⁵⁾. Furthermore, intense training seems to be associated with an imbalanced immunity response by an enhanced release of pro-inflammatory cytokines such as TNFα, IL-1β and IL-6, followed by anti-inflammatory cytokines release, such as IL-10 and IL-1ra⁽Reference Castell, Poortmans and Leclercq^36, Reference Nieman, Henson and Smith³⁷⁾, and also suppressing cellular immunity, leading to an increased infections risk susceptibility⁽Reference Suzuki, Nakaji and Yamada³⁸⁾.

A number of factors including exercise duration and intensity, and sex and age seem to influence the changes produced in the immune response and further studies are needed to identify additional moderating factors (e.g. training and nutritional status) to understand the mechanisms⁽Reference Timmons and Cieslak¹¹⁾.

Immune-senescence

Ageing is a continuous multi-dimensional process of physiological changes including several immunological alterations characterized by increased susceptibility to infectious and autoimmune diseases that are collectively called immune-senescence⁽Reference Castle^55, Reference Bauer, Jeckel and Luz⁵⁶⁾. Older adults have been shown to exhibit an increased incidence of infections as compared with young or middle-aged adults⁽Reference Malaguarnera, Cristaldi and Vinci^39, Reference Malaguarnera, Cristaldi and Vinci^57–Reference High, Bradley and Loeb⁵⁹⁾. This clinical evidence enhances morbidity and mortality risk in this population group. Alternatively, the elderly population also frequently presents a higher risk of developing nutritional disorders caused by the ageing process, which may modify the dietary habits as well as physical activity habits⁽Reference Meunier, Feillet-Coudray and Rambeau^60–Reference Unkiewicz-Winiarczyk, Bagniuk and Gromysz-Kałkowska⁶²⁾.

With regard to immune alterations associated with increased infectious risk, ageing is associated with declines in T-cell subset counts as well as their function⁽Reference Solana and Pawelec^63–Reference Linton and Thoman⁶⁵⁾. The factors leading to this T-cell imbalance include a decrease in naive T-cells or Th0 cells⁽Reference Franceschi, Bonafe and Valensin^64–Reference Naylor, Li and Vallejo⁶⁸⁾, age-associated changes in surface molecule expression⁽Reference Schwab, Russo and Weksler^69, Reference Xu, Beckman and Dimopoulos⁷⁰⁾, alterations in intracellular signalling⁽Reference Miller, Jacobson and Weil^71, Reference Ohkusu, Du and Isobe⁷²⁾, increased rates of apoptosis⁽Reference Gupta^73, Reference McLeod⁷⁴⁾ and decreased proliferative capacity⁽Reference Froelich, Burkett and Guiffaut^75, Reference Castle, Uyemara and Crawford⁷⁶⁾.

Ageing has also been associated with alterations in the Th1–Th2 balance⁽Reference MacKinnon¹⁹⁾, but with contradictory outcomes. While some studies have documented an age-associated shift towards Th2 cytokine as IL-4, IL-6 and IL-10 production in human subjects⁽Reference Castle, Uyemara and Wong^77, Reference Rink, Cakman and Kirchner⁷⁸⁾, others have reported a trend towards increased Th1 (IL-2 and interferon-γ)⁽Reference Fagiolo, Cossarizza and Scala^79, Reference Riancho, Zarrabeitia and Amado⁸⁰⁾. These conflicting findings are probably due to experimental factors such as techniques and in vitro stimulus used⁽Reference Gardner and Murasko⁸¹⁾.

A decrease in B-cell numbers and function has also been observed in the elderly population⁽Reference Whisler and Newhouse^82–Reference Frasca, Riley and Blomberg⁸⁴⁾. An incomplete stimulation from other immune cells and a diminished differentiation capacity has been suggested as possible biological mechanisms to explain the age-related immunodepression⁽Reference Ennist, Jones and St Pierre^85–Reference Whisler and Grants⁸⁷⁾.

Physical activity counteracting age-induced immunodepression

Since the decline in immune response with age is well documented, the interest of the impact of physical activity on immune competence among the elderly has increased. On the other hand, sedentary habits seem to be associated with increased infection risk in ageing. Leveille et al. observed that physical inactivity in women aged 55–80 (followed for a period of 6 years) was associated with an increased risk of hospitalization largely due to infections⁽Reference Leveille, Gray and LaCroix⁸⁸⁾.

Other studies addressing the impact of physical activity in elderly populations have suggested that moderate exercise may counteract the effects of immune senescence⁽Reference Malaguarnera, Cristaldi and Vinci^39, Reference Bruunsgaard and Pedersen^89–Reference Kohut and Senchina⁹¹⁾. Some studies have also suggested that exercise may reduce low-grade inflammation by reduced levels of C-reactive protein (CRP)⁽Reference McFarlin, Flynn and Campbell⁹²⁾. A decrease in lipopolysaccharide-stimulated IL-6, IL-1β and TNFα production in the active elderly have also been shown when compared with the sedentary elderly⁽Reference McFarlin, Flynn and Campbell⁹²⁾. According to a retrospective and prospective study carried out to examine the relationship between physical activity and URTI in elderly subjects (aged 66–84 years), the greatest protection from URTI seems to be associated with a specific level of physical activity (equivalent to jogging 7 km/d or walking 90 min/d at a speed of about 19–20 min/mile)⁽Reference Kostka, Berthouze and Lacour⁹³⁾.

Besides, the duration of the intervention studies seems to be a determining factor to debate about the final outcome. While a 10-week moderate-to-vigorous exercise trial was not associated with decreased URTI in older women⁽Reference Fahlman, Boardley and Flynn⁹⁴⁾, longer intervention trials (10 months) have reported a decrease of URTI symptoms after regular moderate intensity exercise intervention⁽Reference Kohut and Senchina⁹¹⁾. These different effects could be partially due to the relatively small number of subjects and the short exercise intervention of the former study⁽Reference Fahlman, Boardley and Flynn⁹⁴⁾.

The intensity of the activity is also important. Moderate exercise training has been associated with the improvement of expression of CD28 on Th cells and Th1–Th2 balances in the elderly. Exercise training could up-regulate Th cell-mediated immune functions and be helpful for a decrease in the risk of infections and autoimmune diseases in elderly people⁽Reference Shimizu, Kimura and Akimoto⁴⁶⁾. Nevertheless, a 12-month moderate resistance training programme has been reported to increase the muscle strength of previously sedentary, clinically healthy, elderly women, although no changes were found on immune phenotypic or functional parameters, such as natural killer cell cytotoxic activity, lymphoproliferative response to the mitogen phytohemaglutinin, CD3, CD4, CD8, CD19, CD56 cell counts, as well as CD25, CD28, CD45RA, CD45RO, CD69, CD95, human leucocyte antigen (HLA)-DR cellular expression⁽Reference Raso, Benard and Da Silva Duarte⁹⁵⁾.

Finally, it seems important to highlight that the combination of physical activity programmes added to diet interventions may be promising. Several studies on middle-aged adults have found that physical activity and diet interventions resulting in weight loss reduced serum CRP, IL-6 and IL-18, whereas exercise training alone reduced serum CRP, IL-6, and blood mononuclear cell production of TNFα and IL-1α in patients at risk for heart disease⁽Reference Raso, Benard and Da Silva Duarte^95–Reference Goldhammer, Tanchilevitch and Maor⁹⁸⁾.

The mechanisms by which different levels and duration of physical activity programmes affect numerous cell types and responses remain unclear. But there is enough evidence supporting the regular physical activity benefits counteracting the immune-senescence and the infection risk of elderly populations (Fig. 2).

Fig. 2. Proposed model of the relationships between ageing, infection risk and physical activity.

Further studies of how physical activity impacts on immunosenescence in older adults are warranted and very promising in order to improve the healthcare of geriatric populations.

Endurance athletes

Considerable evidence indicates that inadequate nutrition and psychological stress increase the negative effects of exertion (i.e. exercise periods) upon the immune system⁽Reference Marcos, Nova and Montero¹⁰⁴⁾. A number of non-systematic review articles have recommended that athletes consume a balanced diet ensuring energy and nutrient requirements⁽Reference Gleeson^108, Reference Gleeson, Nieman and Pedersen¹⁰⁹⁾. In this sense, several studies have evaluated the efficacy of nutritional supplements on the incidence infection risk after exercise periods. We briefly describe the main studies reporting effects on nutritional supplements used in physical activity performance.

Several studies have pointed to the benefits of carbohydrate (CHO) ingestion before and during exercise for maintaining immune competence (attenuated reduction in functional responses in a number of immune cells and mediators including lymphocytes, neutrophils and inflammatory cytokines)⁽Reference Bishop, Blannin and Robson^110–Reference Starkie, Arkinstall and Koukoulas¹²⁰⁾. In fact, several studies have reported larger stress hormones (cortisol and adrenaline) and plasma cytokine (IL-1ra, IL-6 and IL-10) responses in subjects performing exercise on diets with less than 10% of energy intake from CHO, as compared to those on normal or high CHO diets⁽Reference Bishop, Blannin and Armstrong^114, Reference Mitchell, Pizza and Paquet¹²¹⁾.

The amount of CHO consumed in the pre-exercise meal has recently been suggested to probably be the most important influencing factor rather than the type of CHO in modifying the immune response to prolonged exercise (approximately 112 min at 70% VO_2max for the first hour and 76% VO_2max for the last 52 min) reflected in less perturbation of the circulating numbers of leucocytes, neutrophils and T lymphocyte subsets and in decreased elevation of the plasma IL-6 concentrations immediately after exercise⁽Reference Chen, Wong and Wong¹²²⁾. Bishop et al. showed that ingestion of CHO-rich sports drink by cyclists undertaking 2 h of moderate intensity exercise decreased the salivary IgA concentration, with no overall effect on the salivary IgA secretion rate⁽Reference Bishop, Blannin and Armstrong¹¹⁴⁾. Other studies have suggested that CHO beverage supplementation (about 1 litre/h of 6% CHO) may attenuate the serum cortisol increases in both runners and cyclists⁽Reference Bishop, Blannin and Robson^110, Reference Nieman, Henson and Garner^116–Reference Nieman, Davis and Brown^118, Reference Koch, Potteiger and Chan^123–Reference Chan, Koch and Benedict¹²⁶⁾. Summarizing, besides the number of studies supporting the effects of CHO supplementation on the maintenance of the immune response after exercise, further studies are needed to understand the clinical significance.

High-intensity physical exercise disrupts the balance between oxidants and antioxidant defences contributing to free radical generation⁽Reference Packer, Cadenas and Davies¹²⁷⁾. Thus, although the cellular antioxidant mechanism adapts efficiently to exercise, extreme physical exercise causes oxidative damage to athletes, which may be associated with immune alterations⁽Reference Mena, Maynar and Gutierrez^128–Reference Radak, Pucsuk and Boros¹³⁰⁾.

Vitamin C supplementation (≥1000 mg/d) augmented the increase in lymphocyte counts after exercise, attenuated the serum cortisol increase in ultramarathon runners and attenuated the increase of inflammatory cytokines⁽Reference Nieman, Henson and Butterworth^131–Reference Peters, Anderson and Theron¹³⁵⁾. No significant differences in the self-reported incidence of URTI after exercise have been found when the subjects consumed 1000 mg vitamin C daily for 2 months prior to and 1 month after the marathon⁽Reference Himmelstein, Robergs and Koehler¹³⁶⁾.

An inhibitory effect of combined vitamin C and vitamin E supplementation (for 4 weeks) on plasma IL-6 and cortisol responses to prolonged exercise has been reported in physically active non-athletes⁽Reference Fischer, Hiscock and Penkowa¹³⁷⁾. Acute supplementation with Zn and vitamin E did not have an effect on the cortisol response to exercise in eumenorrheic runners⁽Reference Singh, Papanicolaou and Lawrence¹³⁸⁾.

Restoring glutamine levels after prolonged exercise to physiological levels have been reported to be useful in immune response recovery⁽Reference Moreira, Kekkonen and Delgado¹⁷⁾. However, a large number of studies evaluating the glutamine supplementation effect have not found consistent effects on the immune response (lymphocyte and neutrophil counts, salivary IgA levels, oxidative burst activity, or plasma IL-6 concentrations) after exercise⁽Reference Castell, Poortmans and Leclercq^36, Reference Peters, Anderson and Nieman^134, Reference Krzywkowski, Petersen and Ostrowski^139–Reference Hiscock, Petersen and Krzywkowski¹⁴²⁾. Consequently, the available literature does not provide evidence to support the beneficial effect of glutamine supplementation during exercise.

The fact of increasing the dietary fat intake of athletes to 42%, while maintaining energy intake equal to expenditure, has been reported to improve endurance exercise performance at 60–80% of VO_2max in cyclists, soldiers and runners⁽Reference Venkatraman, Leddy and Pendergast¹⁴³⁾. Other studies have found no effects on immunity after supplementation of n-3 PUFA⁽Reference Toft, Thorn and Ostrowski¹⁴⁴⁾. Further studies are needed to determine whether the beneficial effects of higher fat diets or fatty acid supplementation in athletes are able to reduce their rate of infections.

Soyabean supplementation with moderate-intensity endurance exercise in rats may be useful in the prevention of the impairment of T-cell immunity caused by soyabean supplementation through increases in interferon-γ production and changes to the CD4+:CD8+ ratio⁽Reference Kwon, Hwang and Kim¹⁴⁵⁾.

Probiotics could positively affect athletic performance through enhanced recovery from fatigue, an improved immune function, and maintenance of a healthy gastrointestinal tract function⁽Reference Nichols¹⁴⁶⁾. There is emerging evidence of the humoral and cell-mediated immune systems with probiotic enhancement⁽Reference Erickson and Hubbard¹⁴⁷⁾, although the effects of probiotics on the immune function in highly trained athletes remain unclear⁽Reference Moreira, Kekkonen and Delgado^17, Reference Kekkonen, Vasankari and Vuorimaa¹⁴⁸⁾.

Increased salivary IgA levels have been observed among a cohort of athletes (35 distance runners; 15 female, 20 male; 35–58 years) following colostrum supplementation for 12 weeks⁽Reference Crooks, Wall and Cross¹⁴⁹⁾.

Ginseng (1125 mg/d) consumption has also been evaluated in 10 healthy sedentary males for 35 d after a moderate-exercise protocol. No effects were found in the total leucocyte, neutrophil, monocyte, or lymphocyte (CD3+, CD4+, CD16+ and CD20+) counts, lymphocyte proliferation or neutrophil oxidative burst⁽Reference Biondo, Robbins and Walsh¹⁵⁰⁾.

Ageing

Nutrition supplementation in ageing has unclear benefits. In middle-aged adults, several studies have reported weight loss and reduced serum CRP, IL-6 and IL-18, whereas exercise training alone is able to reduce serum CRP, IL-6, and blood mononuclear cell production of TNFα and IL-1α in patients at risk for heart disease⁽Reference Smith, Dykes and Douglas^96–Reference Goldhammer, Tanchilevitch and Maor⁹⁸⁾.

Hammett et al. performed a randomized controlled trial to assess the effects of 6 months' regular exercise training on serum CRP levels in a healthy elderly population (60–85 years). The training intensity was increased gradually so that by the fourth month, participants were training for 45 min at a heart rate of 80% of their current estimated VO_2max. Although an improvement of the cardiorespiratory fitness of these subjects was reported, no significant reduction was found in their serum CRP levels⁽Reference Hammett, Oxenham and Baldi¹⁵¹⁾.

Anyway, since a longer-term intervention (10 months) in older adults found that aerobic exercise training reduced serum IL-6, CRP, IL-18 and aerobic exercise plus flexibility–balance–resistance exercise training were associated with reduced TNFα⁽Reference Kohut, McCann and Russell¹⁵²⁾, the type and intensity of exercise may be an important determinant in reducing inflammatory markers.

The effects of 17 weeks physical exercise and micronutrient enriched foods were evaluated on cellular immune response in the elderly population of 112 independently living, frail elderly men and women (mean age 79·2 (sd 5·9)). While the authors found that exercise may prevent or slow the age-related decline in the immune response measured by the delayed-type hypersensitivity skin test response and micronutrient enriched foods showed no effect⁽Reference Chin, Paw and de Jong¹⁵³⁾.