Immunosenescence


Immunosenescence is the process of physiological aging of the immune system. The quantity of immune cells (lymphocytes, monocytes, macrophages etc.) declines as a person ages. The diversity of immune cells also declines. Age-linked immune deterioration and immune dysregulation [1,2] results in the body becoming less able to respond to pathogens and less able to adapt to vaccines. Immunosenescence of adaptive (cellular and humoral) and innate immune systems increases incidence and severity of infectious diseases in the elderly, including [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], and metabolic diseases [8].

Both the innate and adaptive immune systems suffer 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 deterioration of the immune system [1,2]. The innate system is less affected by age. In a landmark paper, Linton and Thoman state "adaptive immunity is immature at birth, peaks at puberty and progressively declines thereafter" [1]. Decades ago scientists thought that the innate immune system - characterized by macrophages, monocytes, granular cells (neutrophils, basophils and eosinophils) and natural killer cells - suffers little or no decline with age [1]. However, in the last fifteen-seventeen years, it has become obvious that non-specific innate immunity experiences immunosenescence as well; the innate immune cells undergo functional and phenotypical alterations just like the cells of the adaptive immune system [6].

The biochemical process of immunosenescence involves a multi-faceted decline in the body’s T and B lymphocytes of the adaptive immune system - a decline in 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, there is also a loss of the co-stimulatory molecule CD28 [8]. Moreover, there is an imbalance between Th17 and regulatory T-cells [8].

Cells of the innate immune system, like macrophages, monocytes and natural killer (NK) cells, may decline after a long period of inducing inflammation. For example, monocytes show defects in 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 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 in older adults could be involved in atherosclerosis, cancer, and autoimmune disorders [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].

Mechanisms

Increased inflammatory response, mediated by proinflammatory cytokines, decreases 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 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-a, 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.)

Mitochondria may also modulate (change) immune response due to their 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 the functions of mitochondria are 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 have a much higher number of mitochondria with damaged functions than the same cells in young adults. These mitochondria may stimulate inflammation in the aged patients, contributing to the immunosenescence and to decreasing immune defense[24].

On the molecular and biochemical level, the mechanism behind immunosenescence appears to be chronic oxidative stress, which is involved in many pathologic conditions of elderly people [8]. The oxidative stress may damage DNA, activate mTOR signaling, and shorten telomeres [8]. Activated inflammatory immune cells (neutrophils and macrophages) may produce reactive oxygen species, a hallmark of oxidative stress. Reactive oxygen species may produce the oxidative damage of DNA, contributing to cellular senescence [8,25]. Researcher Peter Barnes suggests that increased mTOR signalling plays 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]. Atrophy of the thymus results in a decline in 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 secrete proinflammatory cytokine IL-1, contributing to the immune suppression of T cell responses [19].

Slowing Immunosenescence

Several potential drugs have been developed to forestall the aging process, including immunosenescence: rapamycin, metformin, theophylline, spermidine, resveratrol, quercetin, sirtuin-activating compounds and novel antioxidants [8]. The term geroprotectors is sometimes used to classify these medicines. They affect various potential mechanisms and targets of immunosenescence.

While chemical geroprotectors are still in development, lifestyle changes (such as diet and physical activity) may slow down aging and lessen its consequences [3,5,8,14,28]. For example, daily intake of multivitamins [5], tryptophan, n-3 polyunsaturated fatty acids (aka omega-3 oils), and probiotics in the diet of elderly people yields significant benefits to the immune system [14]. In another study, the quantity of protective antibodies against influenza was greater in the active aging patients than in the moderately active people and substantially more than in inactive sedentary subjects [5]. Proliferation of lymphocytes and monocytes dramatically declines in inactive sedentary people[5].

mTOR Inhibitors

Can we reverse or retard immunoscensense? Scientists are trying to do that. The mTOR class of medicines, in particular the TORC1 inhibitors have attracted interest.

A drug called RTB101 similar to rapamycin made it through the development process to clinical trials. Scientists hope it will make the immune system stronger.

How will a stronger immune system manifest itself? The person will be less susceptible to disease, but a stronger immune system even makes other medical intervention easier. For instance, it is thought that when the immune system is improved, the patient will respond better to a flu shot.

Rapamycin is used to help facilitate organ transplants. As we get older, the mTOR system becomes overactive in parts of the body, and while the rapamycin protocol may turn off mTOR operations in transplant patients, a strategy to fight aging will be to lower mTOR activity to levels seen in younger people rather than turning it off.

The RTB101 drug proved unsafe in a Phase III trial, but research in this area continues.

Lifestyle

Optimism and social activity may provide elderly folks 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]. Because it delivers 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 is a major cause of higher mortality among the elderly during the coronavirus disease Covid-19 pandemic [11]. T cells play a central role in controlling viral infections, while reduction in thymic activity is one of features of immunosenescence [26]. However, researchers at the Oxford Vaccine Group feel the involvement of another virus (es) is required. It has been known that the level of cytomegalovirus increases with age [27]. This cytomegalovirus 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].

Related: Cell Senescence
Recommended Vaccines for Older People
Biomarkers of Aging

References

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