The Effects of an Increased Viral Burden in Aging and Chronic Inflammation
Abstract
The U.S. population is growing older and by 2030 21% of the population will be over the age of 65. Many of the diseases associated with aging directly correlate with chronic systemic inflammation. Previous studies show that aging results in less naïve lymphocytes and an increased production of highly differentiated effector lymphocytes, likely due to repeated stimulation of the immune system. These highly differentiated effector lymphocytes (called immunosenescence) spontaneously secrete pro-inflammatory mediators. What is driving immunosenescence is unknown. We hypothesize that this immunosenescent behavior is more prevalent in older individuals due to a higher percentage of persistent or latent viral infections accumulated over a lifetime. We also hypothesize that the repeated T cell stimulation from a high viral burden results in an increase of immunosenescent markers and inflammatory mediators among older patients. In this study we collected blood plasma from older subjects aged 65 and older and young subjects between the ages of 20 and 40 to compare the presence of plasma inflammatory markers (using a bead array assays system) and evidence of T immunosenescence and activation (using flow cytometry). We further sought to determine whether any differences seen correlate with evidence of cytomegalovirus (CMV) infection, a classic chronic viral infection capable of establishing lifelong latency. We hypothesize that the immunosenexcent T cell phenotype and plasma inflammatory mediators will show a correlation to evidence of CMV viral burden, and the frequency of T cell activation will be higher in older adults compared to younger adults.
Background
Due to medical and technological advances the life expectancy of the human population has increased significantly. Many of the deadly infectious diseases that affected the public are now treatable. As a result, a prevalence of chronic diseases associated with aging have occurred in older populations, some examples being musculoskeletal, cardiovascular, neurodegenerative, and metabolic diseases. It is now understood that aging is the most important risk factor for the previously mentioned chronic diseases, as well as other illnesses. So what causes this? It is plausible that immunologic mechanisms associated with aging also play a role in some age-related chronic diseases.
Rauf, D. (n.d.). Antibiotics may make flu vaccine less effective by disrupting gut microbes. EverydayHealth.com. Retrieved March 28, 2022, from https://www.everydayhealth.com/flu/antibiotics-may-make-flu-vaccine-less-effective-disrupting-gut-microbes
Commonly found in normal aging as well as in age-associated chronic diseases is low-level inflammation. This results from elevated levels of pro-inflammatory cytokines and acute phase reactants. Although low-level inflammation in aging is not well understood, it is likely to occur based on an aging immune system and environmental microorganisms over the lifespan. An aspect of immune aging is immunosenescence which is characterized by a scarcity of naive lymphocytes due to production and a predominance of highly differentiated effector lymphocytes. These effector lymphocytes are likely generated by repeated antigenic stimulation of the immune system. Some effector cells, such as CD8 T cells are capable of secreting pro-inflammatory mediators that lead to chronic inflammation. In addition, viruses are thought to be the most likely cause of persistent antigenic stimulation due to their viral latency. Continuous infections have the potential to repeatedly stimulate innate and adaptive immunity, resulting in increased inflammation. This model is well established in the cytomegalovirus (CMV). People who are infected with CMV have a robust number of CD8 T cells, which produce inflammatory cytokines, which leads to system inflammation.
Key Terms to Understand:
Adaptive Immunity: Immunity that has memory and occurs AFTER exposure to an antigen
Innate Immunity: The immune defense system you are born with.
Cell-mediated immune response: Adaptive immune response carried out by T-cells
Effector Cell: A lymphocyte that has differentiated. Example: cytotoxic T lymphocyte
Memory Cell: Antigen specific B or T cell that will become an effector cell after re-exposure to the same pathogen.
Immunosenescence: Immune disfunction that occurs with age. It characterizes low levels of naive lymphocyte production and an increased amount of highly differentiated effector lymphocytes.
Cytomegalovirus: CMV is a common virus that most likely causes persistent antigenic stimulation. Once infected, it is a virus you obtain throughout your lifetime, but for most individuals it rarely causes problems.
Hypothesis
We hypothesize that immunosenescence is more prevalent in older individuals due to a higher lifetime prevalence of viral infections, especially those capable of establishing latency, which results in repetitive T cell stimulation due to recurrent reactivation. We also hypothesize that the immunosenescent T cell phenotype and plasma inflammatory mediators will exhibit a correlation to evidence of CMV viral burden, and the frequency of T cell activation will be higher in older adults.
Materials and Methods
To address this hypothesis, we analyzed 122 samples from subjects aged 21-40 years-old and 127 samples from subjects who are 65 years or older. Women and men are included in both cohorts, but the study is weighted more towards women due to their longer life expectancy. Inflammatory mediator proteins (chemokines and cytokines) were measured using cytokine bead array kits from Becton Dickinson. The cytokines assayed were IL-1ß, IL-1ra, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17, IFN-gamma, TGF-ß, TNF-alpha, soluble TNFR 1 and 2, RANTES, MIGF, IP-10, and IL-8. Lymphocyte phenotyping was performed on CD4 and CD8 T Cells by flow cytometry using markers of cellular differentiation (naive, central memory, effector memory), immunosenescence (CD57, TEMRA), and cellular activation (HLA-DR and CD38). Finally, the above markers of immunosenescence and inflammation were correlated with cytomegalovirus (CMV) antibody titers.