Clinical Section / Short Communication

Gerontology 2020;66:431–438 Received: April 20, 2020

Accepted: June 6, 2020
DOI: 10.1159/000509216 Published online: June 25, 2020

Immunological Implications of Physical

Inactivity among Older Adults during the
COVID-19 Pandemic
Anthony Damiot a Ana Jéssica Pinto a James E. Turner b Bruno Gualano a, c
       

a Applied
Physiology and Nutrition Research Group, School of Physical Education and Sport, Rheumatology Division,
Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil; b Department for Health, University of
 

Bath, Bath, UK; c Food Research Center, University of São Paulo, São Paulo, Brazil
 

Keywords direct evidence that physical activity can prevent or treat

Older adults · Health · Immunology · Inflammation · ­COVID-19, promoting an active lifestyle is a key intervention
Coronavirus to counteract the effects of social isolation, especially in old-
er adults and other at-risk individuals, such as those living
with chronic diseases associated with ageing and lifestyle.
Abstract © 2020 S. Karger AG, Basel
Social distancing has been adopted worldwide to control se-
vere acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
transmission. Social isolation is likely to lead to a decline in Introduction
physical activity, which could result in immune system dys-
function, thereby increasing infection susceptibility and ex- The emergence of severe acute respiratory syndrome
acerbating the pathophysiology of conditions that are com- coronavirus 2 (SARS-CoV-2) and the complications
mon among older adults, including cardiovascular disease, caused by coronavirus disease 2019 (COVID-19) are a
cancer, and inflammatory disorders. Older adults and people global public health challenge. The pathophysiology of
living with these comorbidities are at a greater risk for com- SARS-CoV-2 infection closely resembles cases from the
plications during coronavirus disease 2019 (COVID-19). In 2002–2003 epidemic of SARS-CoV, with aggressive in-
this review, we discuss the negative impact of physical inac- flammatory responses resulting in damage to the lungs
tivity on immune function and showcase evidence that reg- [1]. Disease severity is not only due to viral infection but
ular physical activity may be an effective strategy to counter it is strongly influenced by the characteristics of the host
some of the deleterious effects of social isolation. Further- immune response. Indeed, SARS-CoV-2 infection and
more, we briefly highlight key research questions in exercise the destruction of lung cells trigger a local immune re-
immunology, with a focus on older adults in the context of sponse. Innate immune cells including local macro-
COVID-19. Although it is worth emphasizing that there is no phages, and monocytes recruited from blood, respond to

karger@karger.com © 2020 S. Karger AG, Basel Prof. Dr. Bruno Gualano

www.karger.com/ger Applied Physiology and Nutrition Research Group, Rheumatology Division
Faculdade de Medicina FMUSP, Universidade de São Paulo
Ave. Dr. Arnaldo, 455, 3º andar, Sao Paulo, SP 01246-903 (Brazil)
gualano @ usp.br
 Aging
a
Risk of chronic age-related diseases
Risk of all-cause mortality
Less effective vaccine responses
Immune function Viral and bacterial infection
Cognitive decline
Frailty
Habitual physical activity level

b
Reduced risk of chronic age-related diseases
Reduced risk of all-cause mortality
Exercise Lower cardiometabolic risk factors Ameliorated
Improved muscle mass and function age-related
Lower systemic inflammation disturbances in
Physical activity the immune system
Anti-inflammatory profile
Improved vaccine responses

Fig. 1. Impact of aging (a) and physical activity (b) on immune function and morbimortality.

the infection releasing cytokines, priming an adaptive im- disease pathogenesis. In this brief review, we discuss the
mune response from T cells and B cells [1]. In most cases, negative impact of physical inactivity on immune func-
this immune response is capable of resolving the infec- tion and showcase evidence that regular physical activity
tion. However, in some cases, an exaggerated production may be an effective strategy to counter some of the delete-
of cytokines, also known as a “cytokine storm,” can lead rious effects of social isolation. Furthermore, we highlight
to sepsis, which is responsible for 28% of the total fatal key research questions in exercise immunology, with a
cases of COVID-19. In such cases, exacerbated inflamma- focus on older adults in the context of COVID-19.
tion leads to multi-organ damage, affecting mostly pul-
monary, cardiac, hepatic, vascular, and renal systems [1].
In the absence of evidence-based treatments or vac- Physical Inactivity and the Immune System
cines to counter SARS-CoV-2, social distancing has been
adopted worldwide to control virus transmission; how- The majority of research conducted over the past cen-
ever, isolation measures are not without adverse effects. tury has investigated how being physically active affects
Periods of confinement can lead to physical dysfunction the immune system [6] (Fig. 1b). However, evidence is
and mental distress, partially attributed to reductions in beginning to accumulate that physical inactivity, and its
habitual physical activity [2]. Physical inactivity accumu- consequences, such as adipose tissue accumulation and
lated over weeks and months can lead to immune system muscle dysfunction, deleteriously affect both innate and
dysfunction, which could, in principle, increase infection adaptive immunity. For example, physical inactivity ac-
susceptibility and exacerbate the pathophysiology of con- cumulated over weeks, months, and years is associated
ditions that are common among older adults, including with increased systemic inflammation (e.g., increased
cardiovascular disease, cancer and inflammatory disor- TNF-α, IFN-γ, and CRP), impaired natural killer cell cy-
ders [3]. Older adults and people living with these comor- tolytic activity [7], and reduced T-cell proliferation and
bidities are at a greater risk for complications during CO- cytokine production [8, 9], all of which can result in a loss
VID-19 disease. Given that ageing is also associated with of viral control [10, 11]. It is important to emphasize that
a decline in physical activity and alterations in immune some understanding of how physical inactivity affects im-
function [4, 5], it is plausible that there is an interaction mune function comes from experiments conducted in
between these age-associated changes and COVID-19 space, so the effects of microgravity, radiation exposure,

432 Gerontology 2020;66:431–438 Damiot/Pinto/Turner/Gualano

DOI: 10.1159/000509216
and psychological stress need to be considered. However, ing circulation concomitantly with the release of cate-
other studies have been conducted using space-flight an- cholamines and glucocorticoids, following the activation
alogs on Earth, consisting of head-down tilt bed rest in of the sympathetic nervous system and the hypothalamic-
humans, or in animal models, using hind-limb unloading pituitary-adrenal axis [11]. This orchestrated response
[9, 10, 12]. For example, in rodents, hind-limb unloading induces a striking 2- to 4-fold increase in total leukocytes
resulted in decreased responses of bone marrow cells to (leukocytosis) and a redistribution of so-called effector
colony-stimulating factors, resulting in an alteration of cells between the blood compartment and the lymphoid
leukocyte differentiation and activation following anti- and peripheral tissues [11]. Indeed, exercise preferential-
genic stimulation [13]. Other studies have shown that ly mobilizes leukocyte subtypes with tissue-migrating
hind-limb unloading results in failure to generate long- characteristics and the capacity for rapid effector func-
term memory responses among T cells leading to a loss of tion, such as natural killer cells, CD8+ T cells, and neu-
resistance to bacterial pathogens [14]. Human bed rest trophils [11]. The rapid redistribution of immune cells
studies have also reported increases in systemic inflam- with every exercise bout most likely enhances immune
mation, alterations in leukocyte subset distribution, im- surveillance, reducing the chance of pathogens gaining a
paired T-cell IFN-γ production, and impaired natural foothold and causing overt disease in regular exercisers.
killer cell functions [13]. These immune system distur- Many of the immunoenhancing effects of exercise are di-
bances are thought to contribute to the development of rect, including “priming” of the cells mobilized by exer-
urinary tract infections and reactivation of latent herpes- cise, improving their tissue migration capacity, cytotoxic
viruses in astronauts during missions [13] or mild reacti- function, and the ability to recognize antigens [11]. Other
vation of Epstein-Barr virus and varicella zoster virus [15] effects of exercise include immune cell metabolic repro-
during prolonged periods of physical inactivity. Further gramming, anti-inflammatory signaling [11], and effects
research that could be interpreted as supporting the con- on the lymphatic system [25]. For example, although
cept that physical inactivity leads to impaired immune lymph is thought to primarily circulate due to intrinsic
function comes from other settings, such as studies re- lymphatic pumping, extrinsic compression caused by
cruiting overweight or obese participants who are often skeletal muscle contraction, respiratory activity, and
physically inactive too. For example, people who are bodily movement also contribute [25]. Thus, being phys-
obese exhibit poor antibody responses to vaccination ically active may facilitate the circulation of lymph within
[16–18] and impaired lymphocyte proliferation follow- the lymphatic vessels, further enhancing the ability of the
ing mitogenic stimulation [19]. These immunological ef- immune system to respond to antigens [25].
fects likely lead to a greater risk of viral and bacterial in- Although the immune system responds to single bouts
fections and longer stays in hospital due to more frequent of exercise in a transitory way, it is likely that these effects
and prolonged complications following surgery [20, 21]. accumulate over time and produce the immunological
adaptations that happen with long-term exercise training
[11] (Fig.  1b). For example, regular exercise has been
Physical Activity and the Immune System shown to reduce chronic low-grade inflammation and
has been linked to increased T-cell proliferation and cy-
Research over the past century has determined that be- tokine production following antigenic stimulation, in-
ing regularly physically active and undertaking bouts of creased neutrophil phagocytic activity, and increased nat-
exercise has a profound effect on the immune system [6]. ural killer cell cytolytic activity [11]. These changes indi-
Although since the 1980s there has been a debate over cate that regular, moderate-intensity exercise might be
whether very large volumes or high intensities of exercise capable of improving, or at least maintaining, immunity
can suppress the immune system [22, 23], it is now gener- across the life span [26]. Indeed, exercise training is ca-
ally agreed upon that most forms of moderate- to vigor- pable of improving immune responses to influenza and
ous-intensity exercise is beneficial for immune function pneumococcal vaccines, hastening the recovery following
[24]. Indeed, it is now accepted that bouts of exercise en- experimental rhinovirus infection [11], and reducing the
hance immune surveillance. This is because exercise incidence and the number and severity of symptoms as-
causes substantial hemodynamic changes (e.g., increases sociated with acute respiratory infections (e.g., upper re-
in cardiac output, vasodilation, and blood flow), which spiratory tract infection) [24]. Long-term regular exercise
impose mechanical forces on the endothelium [11]. This training can also reduce the expression of Toll-like-recep-
causes leukocytes to demarginate and enter the free-flow- tors (especially TLR-4) on the surface of monocytes, pro-

Physical Inactivity, Aging, and COVID-19 Gerontology 2020;66:431–438 433

DOI: 10.1159/000509216
moting switching of the proinflammatory M1-like mac- Immunosenescence as a Modifiable Risk Factor for
rophages to the anti-inflammatory M2-like, a response COVID-19?
that mitigates the monocyte-downstream inflammatory
signaling cascades, resulting in anti-inflammatory ac- Immunosenescence is the decline in immune function
tions [27]. Other longer-term but indirect effects of exer- that takes place with biological aging (Fig. 1a), which is
cise on the immune system are largely attributable to influenced by environmental factors, such as viral infec-
changes in body composition and metabolism [11]. Re- tion, in particular cytomegalovirus, but probably also life-
ducing fat mass reduces inflammatory macrophage accu- style [5, 26, 30]. Immunosenescence is characterized by
mulation in adipose tissue, chronic low-grade inflamma- particularly marked changes in the adaptive immune sys-
tion, and inflammatory signaling cascades [28]. Reducing tem, especially among T cells and B cells [31]. Within the
cholesterol content of cell membranes that accompanies T-cell compartment, there is a diminished thymic output
changes in body composition may improve T-cell recep- of naive T cells from adolescence and continued differen-
tor signaling for antigen presentation, while improve- tiation into memory T cells with infections [31]. Some
ments in cardiovascular and endothelial function with studies show that, overall, T cells exhibit a reduced pro-
exercise may facilitate immune cell recirculation between liferative capacity and cytokine production in response to
the blood, the lymphoid, and peripheral tissues [11]. Fi- stimulation by mitogens [30]. Other cells are also affect-
nally, evidence that regular physical activity over a life- ed, including a decreased production of proinflammatory
time might prevent, delay, or limit the age-associated cytokines in response to Toll-like receptor agonists in
­deterioration of immune competency – referred to as myeloid dendritic cells [31]. Within the B-cell compart-
­immunosenescence – is now beginning to accumulate ment, naive B cells decline, memory B cells accumulate,
[5, 26]. and there is a diminished diversity of the B-cell repertoire
It is unknown how bouts of physical activity and ex- [31]. These effects on the cellular composition and func-
ercise might influence the immune response to SARS- tion of the immune system lead to a greater incidence and
CoV-2 infection, which could be a moot point given severity of viral and bacterial infections among older
that individuals self-isolate and typically rest when an adults [32, 33] and less effective vaccine responses [34]
infection is suspected. However, there remains a possi- when compared to younger individuals. Importantly, im-
bility that individuals may undertake physical activity munosenescence has been linked to a higher risk of
or exercise when unknowingly infected, especially if ini- chronic diseases, frailty, and all-cause mortality [35]. Im-
tially asymptomatic. Following SARS-CoV-2 infection, portantly, individuals exhibiting signs of immunosenes-
active replication, and release of virus causes the host cence may have poor control over the initial inflamma-
cells to undergo pyroptosis and release “danger signals” tory response to infection and may have a poor ability to
recognized by neighboring epithelial cells, endothelial generate an efficient and robust adaptive immune re-
cells, and alveolar macrophages, which produce proin- sponse by effector T cells and B cells [31, 35]. This may
flammatory cytokines and chemokines. Additional tis- partially explain the suboptimal responses to infection
sue-resident macrophages are recruited, and monocytes and vaccination exhibited by older adults compared to
and T cells extravasate from blood and other tissues, younger counterparts [34]. Thus, it could be argued that
contributing to the inflammatory response. Thus, it is immunosenescence predisposes older adults to a greater
conceivable that this immune surveillance response risk of complications caused by COVID-19 [36].
might be enhanced by bouts of physical activity or ex- Encouragingly, evidence is beginning to accumulate
ercise, facilitating the detection and elimination of showing that people who have been regularly active for the
SARS-CoV-2 infected cells and potentially limiting dis- majority of their lifetime exhibit less pronounced features
ease severity. For example, animal experiments using of immunosenescence. For example, one study compared
labelled cells have shown that the lungs are a site of im- 125 adults (55–79 years) who had maintained a high level
mune cell extravasation following exercise [29]. How- of physical activity for much of their adult lives to less-
ever, if SARS-CoV-2 infection is suspected, resting active 75 age-matched controls [4]. The frequency of B
would be the most cautious approach, given that it is the cells, naive T cells, and recent thymic emigrants were
excessive accumulation of immune cells in the lungs, higher in active compared to inactive older adults. Some
and an overproduction of proinflammatory cytokines, of these effects were thought to be driven by higher serum
which leads to complications in the most severe cases of levels of the thymoprotective cytokine IL-7 and lower IL-6
COVID-19 [1]. among active older adults [4]. In addition, there is evi-

434 Gerontology 2020;66:431–438 Damiot/Pinto/Turner/Gualano

DOI: 10.1159/000509216
dence that regular exercise training can improve influenza the blood from contracting skeletal muscle, independent-
vaccine responses among older individuals [11]. For ex- ly of TNF-α or NF-κB activation (e.g., as opposed to sep-
ample, antibody titers to the H1N1 and H3N2 strains of sis) and induces a subsequent increase in the production
the influenza A virus were enhanced in older adults im- of IL-1ra and IL-10 by various immune cells. In addition
munized with a trivalent influenza vaccine after a to the acute effects brought about by stimulating the
10-month aerobic exercise training intervention [11]. “myokinome,” regular physical activity also modulates
Likewise, community-dwelling older adults engaged in a the properties of subcutaneous and visceral adipose tis-
10-month, cardiovascular exercise training program had sue, reducing systemic inflammation [28]. Thus, partly
increased seroprotection rates compared to nonexercising due to these mechanisms, physical activity is associated
age-matched controls up to 24 weeks after receiving an with a reduced incidence of chronic age-related condi-
influenza vaccine [11]. Studies showing improvements in tions, such as cardiovascular, metabolic and pulmonary
vaccine responses following exercise training are consid- diseases, and cancer [44]. In addition, these anti-inflam-
ered to be robust evidence showcasing how the immune matory mechanisms provide a nonpharmacological ther-
system can be positively affected by exercise [37]. Al- apeutic intervention that can influence the disease patho-
though it might be expected for very active people to ex- genesis and disease trajectory in a number of clinical con-
hibit slower immunological ageing compared to inactive ditions [45, 46]. Taken together, these data emphasize the
people, interaction between physical activity or exercise importance of maintaining optimal levels of physical ac-
with individual components or drivers of immunosenes- tivity in older adults in order to ameliorate (or perhaps
cence – such as cytomegalovirus – are more nuanced [38]. prevent) age-related disturbances in the immune system
For example, individuals latently infected with cytomega- and minimize complications caused by chronic disease.
lovirus exhibit exaggerated exercise-induced T-cell im- Given the very recent emergence of SARS-CoV-2 and
mune surveillance, which might improve the detection of COVID-19, future studies should investigate whether be-
infections and damaged cells but could also amplify in- ing physically active is a protective factor for reducing the
flammatory responses [38]. Not all immune responses to risk of complications caused by COVID-19. This hypoth-
exercise are affected in the same way by cytomegalovirus, esis is supported by a recent cohort study that calculated
however. Exercise-induced immune surveillance by natu- the population attributable fraction to show that physical
ral killer cells is impaired, whereas exercise-induced B-cell inactivity accounted for up to 8.6% of hospitalized cases
responses remain unaffected, among people latently in- of COVID-19, and obesity – a condition potentially pre-
fected with cytomegalovirus [38]. ventable by physical activity – contributed to 29.5% of the
Further justification for promoting a physically active cases [47]. Interventional studies are necessary to confirm
lifestyle among older adults is that habitual physical activ- these findings. In addition, it should be examined wheth-
ity declines with aging, due to an increase in time spent er people who are regularly physically active exhibit faster
undertaking sedentary behaviors and decreasing time recovery times and are less likely to have poor outcomes.
spent undertaking moderate-to-vigorous physical activ- Considering that single bouts of aerobic and resistance ex-
ity [39], leading to muscle wasting and weakness [40]. ercise have been shown to improve vaccine responses
Skeletal muscle is a major immunoregulatory organ and [26], if older adults exhibiting signs of immunosenescence
produces a range of soluble factors, which have anti-in- generate poor antibody responses to vaccines developed
flammatory and immunoprotective effects [41]. Indeed, for SARS-CoV-2 [36], then exercise could be prescribed at
regular exercise improves physical capacity and muscle the time of vaccine administration to boost antibody re-
mass and function and reduces cardiometabolic risk fac- sponses as a form of “behavioral adjuvant,” i.e., the so-
tors and systemic inflammation in older adults [42]. called immune-enhancement hypothesis [48], which re-
Physically active older adults have lower concentrations mains to be tested in the context of COVID-19.
of circulating proinflammatory biomarkers, and higher
concentrations of anti-inflammatory cytokines, com-
pared to physically inactive individuals, and this is partly Summary and Conclusions: the Benefits of
due to muscle physiology [42]. Indeed, muscle contrac- Remaining Active during Isolation
tion triggers an anti-inflammatory response by releasing
so-called “myokines” – muscle-secreted factors that in- Social isolation is likely to lead to a decline in physi-
fluence almost all aspects of physiology and metabolism cal activity, which could result in immune dysregula-
[43]. During exercise, predominantly IL-6 is released into tion but more broadly also impairments in glucose and

Physical Inactivity, Aging, and COVID-19 Gerontology 2020;66:431–438 435

DOI: 10.1159/000509216
 Isolation due to COVID-19 Isolation due to COVID-19
without physical activity with physical activity

Increased inactivity and sedentary behavior Maintaining/increasing physical activity level

+ +
Increased physical dysfunction and mental distress Reduced physical dysfunction and mental distress
infarction

Altered/dysfunctional innate and adaptive Maintained/enhanced innate and adaptive

immune function immune function

Less effective Maintained/enhanced

immunosurveillance immunosurveillance

Pro-inflammatory profile Anti-inflammatory profile

Impaired function and Effective anti-viral and

activation of immune cells anti-bacterial responses
Frequent reactivation of Infrequent reactivation of
latent viruses latent viruses

Higher infection risk Lower infection risk

Fig. 2. Potential impact of isolation throughout the COVID-19 pandemic on immune function, with or without
physical activity.

lipid metabolism, physical dysfunction, and mental dis- Thus, healthcare professionals and public health policy
tress [49]. In this scenario, the maintenance of physical makers should promote physical activity to everyone,
activity levels become of paramount relevance for im- but especially older adults and other at-risk individuals,
proving immune function for the general population such as those living with chronic diseases associated
(Fig.  2). Physical activity is particularly important for with aging and lifestyle.
older adults and those with chronic disease not only be-
cause these individuals may exhibit impaired immune
function [26] but also because these people will gain al- Conflict of Interest Statement
most immediate benefits related to cardiometabolic
The authors declare no conflict of interests.
health, muscle function, and overall wellbeing [12, 49].
Of clinical relevance, social isolation has been associ-
ated with heart disease, depression, anxiety, and mental
Funding Sources
distress [50]. Some studies have shown that stress, de-
pression symptoms, and social isolation can impair im- A.D., A.J.P., and B.G. are supported by grants from the Funda-
mune defenses, which can make an individual more ção de Amparo à Pesquisa do Estado de São Paulo (FAPESP;
susceptible to a potential viral infection [13, 27]. In this 2019/22160-6; 2015/26937-4 and 2018/19418-9; and 2017/13552-
context, promoting a physically active lifestyle could 2).
help individuals to cope with the psychological distress
and the dramatic lifestyle changes during social isola-
tion. Although it is worth emphasizing that there is no Author Contributions
direct evidence that physical activity can prevent or A.D., A.J.P., and B.G. drafted this paper with critical revision
treat COVID-19, promoting an active lifestyle is a key from J.E.T. All of the authors have seen and approved the final ver-
intervention to counteract the effects of social isolation. sion of this papers for publication.

436 Gerontology 2020;66:431–438 Damiot/Pinto/Turner/Gualano

DOI: 10.1159/000509216
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