What is immunosenescence?
Immunosenescence is the process of physiological aging of the immune system in the elderly people. The immune cells (lymphocytes, monocytes, macrophages etc.) dramatically lose their quantity, diversity of subsets, capability to produce normal immune response and provide the immune defense against pathogens due to age-linked immune deterioration and immune dysregulation [1,2]. Increased susceptibility to infections may result from impaired activity of the aged immune system; moreover, inappropriate immunologic functions associated with aging can determine an insufficient response to vaccines. Immunosenescence of all components of adaptive (cellular and humoral) and innate immune systems in the elderly patients increases the higher incidence and severity of infectious diseases [3,4,7,8,12,14,16], cancer development [4,9,14,15,16], autoimmune diseases [4,6,14,16], neurodegenerative and neurological diseases [9,13,15], inflammatory conditions [4,8,9,13,16], decline in vaccine efficacy [6,12,14,16], chronic obstructive pulmonary disease [8], chronic cardiovascular diseases [8,13,15,16], metabolic diseases [8] etc. According to this, the immunosenescence may have a significant impact on the aging and elderly people [6,7,12,16].
How does aging affect innate and adaptive immunity?
Both parts of the immune system, the adaptive and innate immune cells, are impacted by the immunosenescence. However, T and B lymphocytes (T and B cells), which are major contributors of the adaptive cellular and humoral immunity respectively, are more sensitive and more vulnerable to these deteriorations of the immune system [1,2]. According to the same authors, “adaptive immunity is immature at birth, peaks at puberty and progressively declines thereafter” [1]. Before, it has been believed that the innate immune system presented by macrophages, monocytes, granular cells (neutrophils, basophiles and eosinophils) and natural killer cells, changes during aging of the body insignificantly or does not impacted by the immunosenescence [1]. However, in last fifteen-seventeen years, it has become obvious that the non-specific innate immunity experiences the immunosenescence as well; the innate immune cells undergo functional and phenotypical alterations just like the cells of the adaptive immune system [6].
What elements of the immune system decline?
As said above, the T and B lymphocytes of the adaptive immune system decline in the process of immunosenescence; they decrease their functions, activity, development, lifespan, quantity and variety of subsets [1,2]. The ratio of CD4+ / CD8+ cells (both cells are T lymphocytes or CD3+ cells) decreases due to the immunosenescence, there is also a loss of the co-stimulatory molecule CD28 [8]. Moreover, there is an imbalance between Th17 and regulatory T-cells [8].
Immune cells of the innate immune system, like macrophages, monocytes and natural killer (NK) cells, may undergo immune paralysis after a very long inflammatory process. For example, monocytes show defects of their major function, phagocytosis (the ingestion of bacteria, fungi etc.) during a half of year after a recovery from an inflammation [8, 17]. It has been reported, that the number of NK cells and their functional activity may decrease, resulting in the induction of the experimental polymicrobial sepsis [18]. Neutrophils show decreased phagocytosis, chemotaxis and apoptosis [8]. Additionally to the defective phagocytosis, macrophages show the impaired antigen presentation [8]. Natural killer cells have a reduced cytolytic potential (the potential to destroy cells). Dendritic cells show the reduced production of interferon, an important substance of antiviral immunity and immunoregulation [8]. Changes of the ratio of subsets of T follicular helper cells and T follicular regulatory cells may feature of immunosenescence in older adults and could be involved in atherosclerosis, cancer, and autoimmunity [16]. The mucosal immune system, which protects mucosal surfaces of the digestive and respiratory systems, experiences mucosal immunosenescence. It appears as a failure to induce secretory pathogen-specific IgA (SIgA), a major element secretory of mucosal immunity, and loss of ability to protect from the gut infections [7]. Alterations in the gut microbiome in the elderly patients probably affect mucosal immunity [7]. What are some proposed mechanisms? Increased inflammatory response, mediated by proinflammatory cytokines, may decrease the number and functional activity of immune cells and, therefore, may inhibit the immune activation of B cells, T cells, macrophages, monocytes, NK cells [10,17,18]. In this chronic inflammation and following immunosuppression in the course of immunosenescence, the role of molecules such as uric acid crystals, heat shock proteins and mitochondrial components has been recognized [20,21]. These molecules may induce the production and release of pro- and anti-inflammatory cytokines (IL-6, TNF-α, IL-1 etc.) in macrophages [22].
The situation is going to be more complicated, because the proinflammatory role of these molecules can be involved in other mechanisms of the immunosuppression and immunosenescence (like inflammasomes, toll-like receptors etc.)! On the other hand, mitochondria may also modulate (change) immune response due to its role in energy metabolism [10]. We know that activation of T lymphocytes makes a shift from oxidative phosphorylation (the production of ATP, an energy molecule, because of transfer of electrons from the molecule NADH or FADH2 to oxygen by special electron carriers) to aerobic glycolysis (the production of ATP from glucose in the presence of oxygen) [23]. Because functions of mitochondria significantly impaired in the elderly people with immunosenescence, such dysregulation can also impact the activity of T lymphocytes [20]. Indeed, the CD4+ T cells of the aged patients in comparison with young individuals have a much higher number of mitochondria with damaged functions. These mitochondria may stimulate inflammation in the aged patients, contributing to the immunosenescence and to decreasing the immune defense in those people [24]. On the molecular and biochemical level, the potential mechanism of immunosenescence is chronic oxidative stress, which is involved in many pathologic conditions of elderly patients [8]. The increased oxidative stress may contribute to aging though oxidative damaging effect on DNA, activation of mTOR signaling and shortening of telomeres [8]. Activated inflammatory immune cells (neutrophils and macrophages) may produce reactive oxygen species, a hallmark of oxidative stress. By the way, mitochondria are a major source of accumulation in the tissues of reactive oxygen species [25]. Reactive oxygen species may produce the oxidative damage of DNA, contributing to cellular senescence [8,25]. Increased mTOR signalling is suggested to play a central role in immunosenescence [8].Telomere shortening due to oxidative stress may also decrease a number of naïve T cells and B cells (8). Age-related atrophy or involution (shrinkage) of thymus, an organ of the immune system where T lymphocytes are formed and mature, contributes to the immunosenescence of T cell adaptive immunity at the cellular and molecular levels (including epigenetic regulation) [8,15,26]. Due to the atrophy of the thymus with age, the number of naïve T-cells and B-cells decreases, too [8].
Moreover, chronic inflammation can induce myeloid-derived suppressor cells, which also can induce immunosuppression; some tumor cells, secreting proinflammatory cytokine IL-1, may contribute to the immune suppression of T cell responses [19]. Anything else that is interesting and relevant. There are several potential drugs against the aging process and the immunosenescence (geroprotectors) have been developed: rapamycin, metformin, theophylline, spermidine, resveratrol, quercetin, sirtuin activating compounds and novel antioxidants [8]. They affect various potential mechanisms and targets of immunosenescence. While chemical geroprotectors are still on trials, lifestyle changes (such as diet and physical activity) may slow down aging and its consequences [3,5,8,14,28]. For example, daily intake of multivitamins [5], tryptophan, n-3 polyunsaturated fatty acids, and probiotics in the diet of elderly people provides significant benefits during aging of the immune system [14]. In another study, quantity of protective antibodies against influenza were greater in the active aging patients than in the moderately active people and especially in the inactive sitting subjects [5]. Proliferation of lymphocytes and monocytes was dramatically decreased in these inactive sedentary people [5]. Optimism and social activity of the aging people and the daily intake of multivitamins may provide them with beneficial increases of anti-inflammatory cytokines IL-10 and IL-2 [5]. Caloric restriction prolongs the lifespan and delays the immunosenescence by inhibition of inflammatory mTOR signaling [8]. Due to plenty of flavones, polyphenols and stilbenes, the Mediterranean diet may increase healthy lifespan and reduce incidence of neurodegenerative, cardiovascular and metabolic diseases and cancer in elderly patients [28]. Immunosenescence probably provides the higher mortality in the elderly patients during coronavirus disease Covid-19 pandemic [11]. We are not surprised, because T cells play a central role in controlling viral infections, while the reduction in thymic activity is one of features of immunosenescence [26]. However, according to these authors [11], the involvement of another virus (es) is required. It has been known, that the level of cytomegalovirus increases with age [27]. In the aged population, the virus causes the clonal proliferation of T cells and the reduction of naïve T cell diversity, and contributes to reduced capacity for immune responses to novel viral infections, like COVID-19 [11].
References
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