Preventing or Reversing Immunosenescence

Can Exercise Be an Immunotherapy?

Adriana L de Araújo; Léia CR Silva; Juliana Ruiz Fernandes; Gil Benard


Immunotherapy. 2013;5(8):879-893. 

In This Article

Abstract and Introduction


There is now a strong body of evidence demonstrating that aging is accompanied by severe alterations in the immune system, a process known as immunosenescence. Among these changes are alterations in T-cell subpopulation size, cytokine secretion pattern, cell replicative capacity and antibody production, all of which culminate in a proinflammatory state called 'inflammaging' and a diminished capacity to respond to new antigens. These alterations are closely related to the increased mortality and morbidity rates observed in this population. However, the role of exercise on the prevention or treatment of immunosenescence is virtually unknown. Data gathered from the literature regarding the effects of physical activity on immune system aging are still limited and conflicting, with existing reports either advocating benefits or asserting a lack of evidence. Exercise as part of a healthy lifestyle has already been shown to provide long-term benefits with regard to cardiovascular, cognitive, psychosocial and other aspects of the elderly. If positive effects are also observed for immunosenescence, exercise could be a highly cost-effective measure to improve human quality of life compared with other strategies currently being pursued.


The progressive increase in life expectancy documented in the last decades represents a new burden on medical intervention as this increase is correlated with a higher prevalence of neoplasia and age-related diseases.[1] Furthermore, infections in the elderly are associated with higher morbidity and mortality rates compared with other age groups. According to Arnold et al. in 2011, the assurance of longevity and healthy aging occurs by maintaining the integrity of immunity.[2] However, this is not always possible because deleterious changes occur with aging in the composition, physiological function and competence of the immune system. The alterations that occur with aging that compromise the competence of the immune system are defined as immunosenescence. Comfort in 1979 defined senescence as the incapacity to maintain homeostasis under conditions of functional overload.[3]

The etiology of immunosenescence is multifactorial and reflects the lifelong exposure to pathogenic agents and viral infections, contributing to increased early morbidity and mortality.[4] Of note are gastrointestinal infections, increased susceptibility of developing autoimmune diseases and cancer, and decreased response to vaccines.[5,6] These inflammatory and infectious processes, in turn, accelerate immunological exhaustion, particularly of the T-cell compartment of adaptive immunity,[1] although the functionality of B cells[7] and innate immunity[8] are also affected to a lesser degree.

Many cell types are affected during immunosenescence, such as hematopoietic stem cells, lymphoid progenitors, mature lymphocytes of secondary lymphoid organs and peripheral blood.[9] The main feature of immunosenescence is the change in the cellular composition of the T-cell compartment, including a decrease in the number of naive phenotype cells in association with an increase in the number of memory phenotype cells. Thymic involution is directly related to a reduction in precursor cell number and the decline of hematopoietic stem cell function. The innate immune system also suffers with aging from functional defects in APCs, an increased number of NK cells, and an increase in the inflammatory background. The alterations that compromise adaptive immunity include changes in some cell populations, decreases in the function of these cells, reduced telomere length and a higher apoptosis rate. Regarding the humoral immune response, a decrease in the B-cell population, deficiency in isotype switching and reduced ability of specific antibody production are observed.[10,11] Additionally, as pathogens can accelerate the changes caused by immunosenescence, latent CMV infections have been widely studied within this context.[12]

In this review, we describe the main changes that occur in the immunological system of elderly people, highlighting the main changes that occur in the T-cell compartment of adaptive immunity (Figure 1). Furthermore, we discuss the effects of exercising on the elderly immune system and its potential to prevent or reverse the consequences of immunosenescence.

Figure 1.

Immunological changes that occur with aging and affect immunocompetence.
Chronic viral infections (e.g., CMV), obesity and physical and psychological stress, among other events, potentially contribute to immunosenescence. The most notable features of immunosenescence are (A) the imbalance of naive and memory T-cell subpopulations related to the thymic involution, which results in diminution of the repertoire of T-cells and the reactivity to new antigens; (B) the low-grade systemic inflammation (inflammaging), which consists of persistently high serum levels of IL-6, TNF-α and C-reactive protein, but reduced IL-10 levels; (C) the accumulation of circulating senescent T cells, phenotypically characterized by loss of CD28 expression and acquisition of CD57 and KLRG1 expression; and (D) genotypically characterized by telomere shortening, in consequence to the successive replicative cycles that occur during the life span of the elderly. Telomere shortening, on the other hand, may be associated with increased resistance to apoptosis, favoring inflammation. All of these alterations contribute to the development of illnesses, including cancer and autoimmune and cardiovascular diseases, worsening of the severity of the infections, and decreased responsiveness to vaccines, increasing the morbidity and mortality of the elderly.