The Role of Immune Cells in Oxi-Inflamm-Aging

Irene Martínez de Toda, Noemi Ceprián, Estefanía Díaz-Del Cerro, Mónica De la Fuente, Irene Martínez de Toda, Noemi Ceprián, Estefanía Díaz-Del Cerro, Mónica De la Fuente

Abstract

Aging is the result of the deterioration of the homeostatic systems (nervous, endocrine, and immune systems), which preserve the organism's health. We propose that the age-related impairment of these systems is due to the establishment of a chronic oxidative stress situation that leads to low-grade chronic inflammation throughout the immune system's activity. It is known that the immune system weakens with age, which increases morbidity and mortality. In this context, we describe how the function of immune cells can be used as an indicator of the rate of aging of an individual. In addition to this passive role as a marker, we describe how the immune system can work as a driver of aging by amplifying the oxidative-inflammatory stress associated with aging (oxi-inflamm-aging) and inducing senescence in far tissue cells. Further supporting our theory, we discuss how certain lifestyle conditions (such as social environment, nutrition, or exercise) can have an impact on longevity by affecting the oxidative and inflammatory state of immune cells, regulating immunosenescence and its contribution to oxi-inflamm-aging.

Keywords: aging; biological age; immune cells; inflammatory stress; oxidative stress.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Influence of immunosenescence in the accumulation of senescent cells. Oxidative compounds come mainly from two sources, the mitochondria and NOX-2, located in the membrane of immune cells, especially in phagocytes. These oxidative compounds lead to senescent and apoptotic cells. However, senescence can be transient and homeostatic or chronic and damaging depending on the efficiency of immune cells in removing them. Thus, from the fetal stage to adulthood, the senescent cells that appear are transitory thanks to the adequate function of immune cells. Thus, immune cells remove these cells, promoting regeneration and repair processes, which are crucial for proper development. However, from adulthood to death, chronic exposure to ROS produces oxidative tissue damage and deterioration of the function of immune cells (immunosenescence), which causes accumulation of senescent and apoptotic cells, leading to accelerated aging and, consequently, increased morbidity and mortality.
Figure 2
Figure 2
Effects of immunosenescence in oxi-inflamm-aging. 1. Aging starts with the leakage of reactive oxygen species (ROS) that happens in the mitochondria, that react with the mitochondrial DNA (mtDNA) and cause mitochondrial dysfunction, which increases ROS production and generation of mtDNA fragments. These fragments travel to the nucleus and insert into nDNA generating DNA damage and genomic instability. These ROS beyond a threshold cause the cell to enter senescence and develop a senescence-associated secretory phenotype (SASP), which happens in both immune and non-immune cell types. 2. ROS impact the expression of cadherins and integrins, causing a higher adherence and lower migration capacity of immune cells. 3. DNA damage results in a lower lymphoproliferative response. 4. ROS decrease the cytotoxic activity of immune cells that is responsible for the accumulation of chronic senescent cells in other tissues. 5. Uncontrolled ROS balance also leads to inefficient phagocytosis, which results in the increased concentration of several molecules from both immune and non-immune cells that behave as damage-associated molecular patterns (DAMPs) and that can bind to immune cells and throughout inflammasome and nuclear factor kappa B (NF-κB) activation induce the production of inflammatory mediators (cytokines, CKs) causing inflamm-aging. The accumulation of chronic senescent cells, together with the increased pro-inflammatory mediators at the systemic level, causes excessive production of ROS by immune cells, mainly phagocytes through NADPH-oxidase (NOX-2), to destroy and remove these senescent cells. 6. This situation generates vicious spiral feedback of oxidation and inflammation with aging (oxi-inflamm-aging), in which immune cells play a central role.
Figure 3
Figure 3
Dual effect of different lifestyle situations on oxi-inflamm-aging. The communication between the regulatory systems (nervous, endocrine, and immune systems), known as neuroimmunoendocrine communication, ensures the homeostasis of the organism and, therefore, health. This crosstalk takes place by the existence of receptors in each homeostatic system for neurotransmitters (NT), hormones (H), and cytokines (CKS). Oxi-inflamm-aging alters the function of the regulatory systems as well as the neuroimmunoendocrine communication, which causes age-related increased morbidity and mortality. External factors, such as the social environment, nutrition, and exercise, can modify the oxidative and inflammatory stress of the organism and the function of immune, nervous, and endocrine cells, altering this communication, and consequently, modulating the aging rate of an individual. Thus, a negative social environment, which can be the isolation of an individual (rodents) or loneliness (humans), or the cohabitation with sick or older subjects, affects the neuroimmunoendocrine communication negatively, increasing the rate of aging while a positive social environment, understood as living with healthy or younger individuals, enhances this communication, decreasing the aging rate. With respect to nutrition, high-fat diets and obesity, as well as an excess of antioxidant supplementation, accelerate the rate of aging, whereas caloric restriction or supplementation with adequate amounts of vitamins, antioxidants, or probiotics decelerate it. Finally, whereas a sedentary life or overtraining can negatively impact the aging rate, low and moderate exercise was shown to slow down aging. All these conditions modulate the function of immune cells by increasing or decreasing oxidant, pro-inflammatory, antioxidant, and anti-inflammatory compounds; therefore, they can alter the rate of oxi-inflamm-aging. Antinf CKS: anti-inflamatory cytokines; Ax: antioxidants; CKS: cytokines; H: hormones; NT: neurotransmitters; Proinf CKS: pro-inflammatory cytokines.

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Source: PubMed

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