1. Introduction
Epidemiological shreds of evidence indicate that regular physical activity reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as cancer and chronic inflammatory disorders [
1,
2], a very special condition during the Sars-Cov-2 infection due to the very high susceptibility of older. Despite the apparent health benefits achieved by leading an active lifestyle, which implies that regular physical activity and frequent exercise enhance immune competency and regulation, the effect of a single bout of exercise on immune function remains a controversial topic which a vigorous bout of exercise has been implicated in temporary suppression of immune function [
3] which can be undesirable.
Otherwise, prolonged, and intense exercises have been related to negative changes such as the immediate reduction of defenses against viral infections and increased risk of diseases [
4,
5] resulting in an increased incidence of infections [
2], probably, including COVID-19. Additionally, about high-intensity exercises authors state that there may be an increased risk of upper respiratory tract infections possibly due to a high response of cytokines of the Th1 and Th2 profile, which causes significant stress on the immune system decreasing its ability to fight antigens and pathogens [
6]. Furthermore, high-intensity exercises, e.g. High-intensity interval training (HIIT), may promote a transient decrease in the INF-γ/IL-4 ratio creates a possible immunological window for infections [
7] demonstrating the clinical importance of this discussion. However, this immunological window hypothesis does not present scientific support due to the various methodological flaws in the studies that fail to show robust and consistent results on the subject [
3].
Aging is also associated with an increase in inflammatory proteins in the circulation such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP), with the underlying development of chronic diseases [
8,
9]. Previous research has shown that chronic and well-structured exercises can produce chronic anti-inflammatory effects [
10] mainly mediated by IL-6, however in an anti-inflammatory environment with interleukin 10 (IL-10) [
11,
12]. However, the effects of HIIT on the immune system of the elderly are little explored due to the intensity of this type of exercise, which often hinders its application in an elderly population leaving an important gap in this field of study.
The pandemic is a complicated situation, and many doubts, like if we can, or cannot begin a physical exercise program. In especial, the high-intensity interval training remains without robust evidence. Previously, our group displayed that the HIIT causes acute inflammation like another kind of exercise in the early stages of the program in young adults, however, the inflammation decreases from seven to fifteen days, which allows us to suppose the hypothesis that at the end of acute inflammation the subjects could be submitted for a new overload [
13]. This notion became more relevant due to the pandemic of COVID-19 because it seems correct to state that previous physical exercise may play a role in infection and disease progression [
14,
15], however, beginning a physical exercise program during the pandemic can weaken the older adult and expose them to the risk of infection with unfavorable outcomes?
The hypothesis that guided or investigation states that the high-intensity, however, short time exercise is safe to sedentary older adults. Thus, the present study aims to investigate the acute effects of an exhaustive intermittent exercise session on the immunological parameters of the elderly and the subsequent incidence of upper respiratory tract infections and compare with the moderate-intensity.
4. Discussion
The hypothesis that guided or investigation states that the high-intensity, however, short time exercise is safe to sedentary older adults, so, to challenge this hypothesis we analyzed of the acute response of white blood cells, and cytokine kinetics in two exercise models, high-intensity interval training, and moderate-intensity interval training and compare both.
To do so sixty-three seniors started the study in the same condition: not previous physical exercise practicing and not having any health impairments identified in clinical examinations and laboratorial parameters. With that, to explore the hypothesis here established, blood collections were acquired before the experimental situation, and immediately, 2h, 24h, and 48h after promoting a time course overview. So, the biochemical tests, exhibited in
Table 1 demonstrate that all groups were equal between then. The main results presented showed that the physical exercises modify the leukogram cell count and the cytokine kinetics of the Th1, and Th2 profile as expected, but, the Th17 cytokine expression was an unexpected finding because the literature on the relationship of the IL-7a cytokine with exercise is very poor. Nonetheless, the clinical important about this is that the HIIT or MICT produced a short term transitory immunologic stress in older adults. Together, we revisited the importance of IL-6 and IL-10 importance as previously showed [
26,
27].
Here stood evident that both exercise regimes induced to an stress of the immune system, already demonstrated by different authors [
26,
27], including, as previously demonstrated for our group or HIIT [
28]. Even more recently, a Th-17 immune response profile, also pro-inflammatory, may be important for the long-term effects achieved by people who achieved HIIT[
29,
30,
31], however, we did not considered this stress so wide as to cause the classic effects related to strenuous exercise where the immune system has difficulty recovering, which causes the phenomenon of the immunological window with a pronounced J curve of the immunological parameters which, at least momentarily, leaves the subjects more susceptible to opportunistic infections as provoked by marathon, triathlon of long term high-intensity athletic proves[
32]. However, the classical strenuous exercise beyond high-intensity has long term of exposition, which is a fundamental difference to the approach here tested.
Following the logic rational before displayed, the infections, and diseases in older adults, in many cases, are mediated for a subclinical pro inflammatory state[
10,
33,
34]. This affirmation could contribute against our data in a non-contextualized view, however, here, we discuss that the one acute high-intensity stimulus led to a transient inflammatory state fast and non-prevalent, which is the a desirable stimulus for beneficial adaptations. This same situation if repeated for several time, will chronically provoke an anti-inflammatory state, and also a faster and more potent reaction of immunological agents such as macrophages, neutrophils and natural killer cells[
35], which has already been demonstrated to be considerably beneficial such as demonstrated several times in literature[
7]. This considerations, allow us affirm that to start one exercise program even in a pandemic state could be safe because the exercise to not injure the immune system of older adults.
Specifically, the white blood cells of older adults showed a classical response to exercise challenge here tested with a fast leukocytosis and lymphocytosis, however, the magnitude of this reactions did not impact the immunity availability for the immune vigilance performed for this type of cells[
36], and the effect here observed were lost after 24h for lymphocyte, and basophil, but although we had seemed a normalization in 2h and new increasing in the leucocyte levels in 24h, after 48h all come back to baseline levels. This kind of response to exercise was previously reported[
37] and do not compound a inedited data.
In regards to the explication the mechanisms under the immune response here observed, a conjunct of Th1, Th2 and Th17 cytokines were investigated in response to both exercises models here tested. The data presented here show that physical exercises modify the leukogram cell count and the cytokine kinetics of the Th1, Th2, and Th17 profile, including correlations between the cytokine results. The importance of IL-6 and IL-10 has already been revisited[
26,
27]. This stress on the immune system, already demonstrated by different authors [
26,
27], was also demonstrated in our study. Even more recently, a Th-17 immune response profile, also pro-inflammatory, may be important for the long-term effects achieved by HIIT [
29,
30,
31].
Is important to remember that sometimes the inflammatory process are a necessary stimulus to generate adaptations, for example, an important signal for muscle hypertrophy is mediated for inflammation[
38,
39], many immunologic battle against intracellular parasitic disease[
40] and intracellular microorganisms has participation of pro inflammatory cytokines [
41,
42], as well as many medicines effects are mediated for Th1 cytokine profile[
40]. In another hand, an incontrollable inflammation could be catastrophic to human body, for example, very recently in human history, the most important effects of COVIV-19 is linked to an exacerbated inflammatory[
43], state that lead to tissue destruction and organ impairments[
44]. We highlight that even in COVID-19, the physical exercise shown to be a valuable tool against the disease consequence[
45], where, was proved that the previous physical exercise practice confer protection[
15]. Additionally, the this same approach could help the fast recovery after the disease[
45,
46,
47].
Our data suggest that exercise program, for the elderly population, produces an acute inflammatory profile, with emphasis on the first hours of HIIT, suggesting that they would be able to have a similar profile to other people who were experienced in terms of exercise, such as women, healthy young men, and men managing opioid disorders[
31]. We observed that IL-6 was expressed in a behavior similar to that demonstrated for TNF-α, with a significant correlation, suggesting an inflammatory process initiated by TNF-α. A recent study demonstrated that the cytokines IL-6 and TNF-α are indeed increased during exercise[
48] but suggest that the role of TNF-α may be related to an inflammation related to cell growth and proliferation[
48].
Interestingly, we also emphasize that the correlation analysis, performed mainly with IL-10, suggests a non-classical pro-inflammatory role for this cytokine mediated AMPK/STAT3 pathway as displayed Islam and Cols.[
27], which may help us to explain how immune system influences the health success of the elderly.
It is noteworthy that all the results presented here demonstrated transience and immediate recovery of baseline values quickly, however, demonstrating that there was stress in the immune system of the elderly, although these system data suggest adequate immunocompetence. This discussion is extremely timely given the situation in which the world has witnessed COVID-19, as it is evident that this disease affects the cardiovascular, blood, and immune systems, all of which can be affected by exercise at various stages of a training program. Here, the idea of immune inflammation takes time was contested, which is pertinent at this point because exercise increases the cytokine profile almost immediately.
Following this rationale, we challenge the idea about the upper respiratory tract infections (URTI) in older adults in response to on HIIT session. Our data display that no improvement in prevalence of URTI debunking the idea that the intensity of exercise is the most important factor to development of opportunistic infections, but, we argue that the combination between the intensity and volume can produce an unrecovered stress and expose older adults to diseases.
These results corroborate previous data that affirm that the intensity alone do not is the villain in this context[
3]. Evidence pointed to the existence of a protective effect as observed in another study
8,17,32,33, but the impossibility of making a direct relationship between the immunological modifications of the exercise with the protection of the upper respiratory tract is our main limitation. Therefore, it is prudent to pursue the data with caution and to avoid further exposure to infections during the first two weeks of the exercise program. Another factor to be considered is our study was performed in a cohort with no presence of comorbidities or chronic diseases, so the subjects showed good immunological competence to produce cytokines, which may not be the rule in this cohort.
Investigations with elderly people with immunodeficiency and inflammatory diseases such as diabetes and obesity may be important and represent another limitation of our study. The control of medications, daily sleep schedule, eating habits, and other daily behaviors was not carried out, however, the random composition of the group and the control group reduced the influence of this variable in our data. We cannot investigate the expression of RNA, enzymes, or proteins involved in many pathways that could help us explain the results observed here, and only cell counts and cytokine kinetics support our discussion. Another limitation example, is about the mechanisms under the observations that do not were explored.
But, what does this article add and what is the clinical significance? First, we put into the discussion that the laboratory tests related to good health did not change in a few hours, proving that the groups formed were elderly people without pre-existing clinical conditions, it is a big limitations of previous studies, however, in the acute phase it is already possible to detect that there are significant differences between the cytokines that modulate the Th1/Th2/Th1 pattern and that these cytokines are correlated with an inflammatory pattern. Studies suggest that the elderly population may benefit from significant increases in IL-10, IL-6, and TNF-α, however, no important alterations on white blood cells were noted despite the interleukin. That the presence of IFN-ϒ may also suggest an improvement in susceptibility to tolerated in the upper administered tract, as well as the increased presence of IL-17 may be something desirable [
49].
Therefore, regardless of the patient's age, starting a physical exercise program, whether intense and short-term or moderate for longer, seems to be safe and even desirable, as do other studies that evaluated the benefits of exercise in other children. Finally, it is important to think about future studies that use intense physical exercise in people who use anti-inflammatory drugs for long periods to find out if the cytokines and inflammations released.
Author Contributions
Conceptualization, DASS, LDFN and JRVS; DASS, LDFN and JRVS; methodology, DASS, LDFN and JRVS; formal analysis, ACG, BDCM, ES, FNS, DLF, DMS, CSP, RNMS, ECL, AMML; investigation. DASS, LDFN and JRVS; data curation, DASS, LDFN, ES and JRVS; writing—original draft preparation, ACG, BDCM, ES, FNS, DLF, DMS, CSP, RNMS, ECL, AMML, JRVS; writing—review and editing, SASS, JRVS; supervision, JRVS; project administration. All authors have read and agreed to the published version of the manuscript.” Authorship must be limited to those who have contributed substantially to the work reported.