Immunosenescence—immune deterioration associated with age—and social stress
Immunosenescence, immune system exhaustion associated with aging, can be accelerated by additional factors including stress.
The shift in the populations of white blood cells referred to as immunosenescence drives the chronic inflammation and vulnerability that are associated with so many of the diseases of aging.
Aging is the greatest risk factor for many conditions including cardiovascular disease, cancer, dementia, arthritis, etc., a core factor being the increase in the systemic burden of inflammation driven by the exhaustion of well functioning immune cells and their replacement by others that just increase non-purposeful inflammation, the process referred to as immunosenescence. It’s already well known that immune system demands such as those involved in recurrent responses to viral burdens drive immunosenescence. A research article just published in PNAS (Proceedings of the National Academy of Sciences) linking social stress to immune aging offers a good illustration of immunosenescence fundamentals.
The authors state:
Age is a robust determinant of immune cell population composition (11, 12), with aging immune systems characterized by a reduced pool of naïve B and T cells, increased pool of terminally differentiated T cells, increased supply of CD8+ cells relative to CD4+ T cells, and increased systemic inflammation (13). However, there is substantial variance in the rate of these changes and consequent alterations in immune cell composition among older adults (14). Understanding the contributors to this variance is critical given that immune aging is associated with chronic diseases [e.g., cancer (15) and cardiovascular disease (16)], weakened response to acute infections, increased risk of pneumonia, reduced efficacy of vaccines (17), and organ system aging (10).
“In addition to localized tissue-specific aging (9), age-related changes in immune function contribute to systemic aging, organ failure, and premature mortality, making immunosenescence a critical player in aging and disease (10).
“This study utilizes a national sample of 5,744 US adults over age 50 to assess the relationship of social stress (viz., everyday discrimination, stressful life events, lifetime discrimination, life trauma, and chronic stress) with flow cytometric estimates of immune aging, including naïve and terminally differentiated T cell percentages and the ratio of CD4+ to CD8+ cells.”
Reduced pool of naïve CD4+ and CD8+ T cells
CD4+ cells (aka helper cells) aid in directing immune responses, while CD8+ cells attack pathogens (aka cytotoxic T cells). These T cells in their ‘naïve’ state have not yet been committed to reacting to a specific virus, bacteria, etc. and are like a reservoir of ‘fresh recruits’ to draw from as needed for fighting off novel attacks. Without a broad range of naïve cells, we are limited in the scope of immune responses to new agents. With age, the number and percent of naïve Cytotoxic T-cells declines.Aging entails diminished production of naïve CD4+ and CD8+ cells. The authors examined percentages of naïve CD4+ T cells (CD4+/CD3+/CD19−/CD45RA+/CCR7+/CD28+) and naïve CD8+ T cells (CD8+/CD3+/CD19−/CD45RA+/CCR7+/CD28+) and found them reduced by specific kinds of stress.
Increased “zombie” T cells
CD4+ and CD8+ T cells that are negative for CD28, an important protein on the surface of these cells, therefore designated as CD28- and referred to by the authors as “terminally differentiated” cells, are unhealthy, or “aged” and less capable of killing abnormal cells such as cells invaded by a virus—while at the same time migrating throughout the body spewing pro-inflammatory cytokines that increase the burden of non-beneficial inflammation (“zombies”). The authors found both CD4+/CD28- and CD8+/CD28- (terminally differentiated) cells to be increased by specific kinds of stress.
Aging naturally entails lower production of naïve T cells and an accumulation of older terminally differentiated T cells, but other factors including CMV (cytomegalovirus) infection and the expansion of other viral ‘remnants’ can accelerate immunosenescence.
Reduced CD4 to CD8 ratio
A reduced CD4:CD8 ratio is another indicator of immunosenescence. Ratios between 1.5 and 2.5 are generally considered normal, while a low or inverted (less than 1:1) ratio is associated with altered immune function—immunosenescence, chronic inflammation and conditions involving immunodeficiency or autoimmunity. The prevalence of an inverted CD4:CD8 ratio increases with age.
CD4 counts and viral loads were formerly used to judge immune competence and the response to HIV treatment, but the immune system can be impaired even with a normal CD4 count. The CD4:CD8 ratio is a more accurate indicator.
How different social stresses increase immunosenescence
Interestingly, the authors observed that social stress accelerates immune aging differently according to the well researched categories five stress variables: stressful life events, chronic stress, everyday discrimination, lifetime discrimination, and life trauma.
“Using a national sample of older US adults, we found that exposure to social stress was associated with T cell distributions indicative of accelerated immune aging. Specifically, life trauma and chronic stress were associated with a lower percentage of CD4+ naïve T cells, whereas everyday discrimination, lifetime discrimination, and chronic stress were associated with a greater percentage of terminally differentiated CD4+ T cells. Stressful life events, lifetime discrimination and life trauma were associated with a lower percentage of CD8+ naïve T cells, whereas stressful life events, lifetime discrimination, and chronic stress were significantly associated with a higher percentage of terminally differentiated CD8+ T cells. Lifetime discrimination and chronic stress was associated with a lower CD4:CD8 ratio. These effects were all independent of chronological age, sex, and race/ethnicity.”
As is found throughout the literature on immunosenescence, a particularly strong effect of CMV seropositivity (high cytomegalovirus IgG antibodies) appears to be particularly adverse, and in several cases eclipses the effects of social stress.
“Lifetime discrimination and chronic stress associations with terminally differentiated CD8+ T cells and the CD4:CD8 ratio became nonsignificant after controlling for CMV seropositivity and the association between stressful life events and terminally differentiated CD8+ T cells became nonsignificant after controlling for lifestyle and socioeconomic status factors and CMV seropositivity. This is consistent with past research showing that stress is associated with impaired immunological control of latent viruses like CMV (26). More stressed individuals may have reduced control over and more frequent activation of CMV, leading to an increase in memory T cells and decrease in the CD4:CD8 ratio (18, 41–43).”
Telomere Length
As defined by the National Human Genome Research Institute of the NIH:
“A telomere is a region of repetitive DNA sequences at the end of a chromosome. Telomeres protect the ends of chromosomes from becoming frayed or tangled. Each time a cell divides, the telomeres become slightly shorter. Eventually, they become so short that the cell can no longer divide successfully, and the cell dies.”
Thought to be interpreted as a stand-alone measure for pathology or mortality, as noted in Telomere Length as a Marker of Biological Age: State-of-the-Art, Open Issues, and Future Perspectives published last year in Frontiers in Genetics:
“Telomere shortening is a well-known hallmark of both cellular senescence and organismal aging. An accelerated rate of telomere attrition is also a common feature of age-related diseases. Therefore, telomere length (TL) has been recognized for a long time as one of the best biomarkers of aging.”
In the research paper on stress and immunosenescence discussed here, the authors state:
“Lifetime exposure to stressful conditions is a known risk factor for poorer health, increasing the risk for early onset of age-related disease and premature death (1–3). Models examining the mechanisms driving these effects have centered on the sequelae of repeated activation and prolonged activation of the sympathoadrenal and hypothalamic pituitary adrenal systems, leading to wear and tear at the biological level (4). Many have postulated that this wear and tear manifests at the cellular level, causing accumulation of DNA damage, increasing inflammation, shortening telomere length, and driving cellular aging (5, 6). Critically short telomere length within immune cells and cellular stress (e.g., DNA damage) can drive cells into a nonreplicating state termed cellular senescence (7, 8).”
And in Lifespan adversity and later adulthood telomere length in the nationally representative US Health and Retirement Study, those authors state:
“Stress over the lifespan is thought to promote accelerated aging and early disease. Telomere length is a marker of cell aging that appears to be one mediator of this relationship…adverse experiences throughout the life course predicted increased odds of falling into the lowest quartile in telomere length in late adulthood, even after adjustment for potential covariates. These findings appear to be driven most strongly by experiences during childhood in fully adjusted models. Participants were at 11% increased odds of being categorized as short in telomere length for each additional childhood adverse experience…
Confidence that telomeres are important to disease pathogenesis is increasing with recent Mendelian randomization studies demonstrating that genetic variants associated with shorter telomeres are associated with cardiovascular, pulmonary, and Alzheimer’s diseases (23, 24) and a recent meta-analysis that includes prospective associations between telomere length and cardiovascular disease (7).”
Clinical Notes
The authors conclude:
“In addition to localized tissue-specific aging (9), age-related changes in immune function contribute to systemic aging, organ failure, and premature mortality, making immunosenescence a critical player in aging and disease (10)…These results raise the possibility that interventions such as CMV vaccination and senolytic therapies might potentially help reduce social disparities in T cell immunologic aging (13).”
The UCLA Immune Assessment Core is a CLIA certified laboratory that provides comprehensive immunological testing services for basic, clinical, and translational studies. They offer a panel that includes absolute numbers and percentages of the terminally differentiated (CD28-) CD4 and CD8 and naïve CD 4 and CD8 T cells discussed here. It is not a commercial laboratory, but clinicians can arrange the test for their patients through T.A. Sciences [contact: Eric McDonald, 973-476-3165, eric@tasciences.com].
CMV antibodies and the CD4:CD8 ratio are readily available through Labcorp or Quest.
Research supports the effectiveness of TA-65, a telomerase enzyme activator, in decreasing Immunosenescent CD8+CD28- T cells while increasing telomere length.
Stress over-activation of the hypothalamus-pituitary-adrenal axis entails a sympathetic nervous system barrage that can drive inflammation chemistry (including NFkB), cause apoptosis of healthy innate and Th1 immune cells, and suppress vagal outflow from the brain. Diminished vagal effect introduces a host of ills that include polarization of immune cells that increase autoimmune and other types of non-purposeful inflammation. Supporting vagal function through resources such as tVNS (transcutaneous vagus nerve stimulation, aka aVNS—auricular vagus nerve stimulation), the Safe and Sound Protocol, etc. can be deeply beneficial.
This paper offered a platform to highlight the fundamental features of immunosenescence. Those interested in a substantial survey of the scientific literature on immunosenescence may download a pdf file composed of links to research papers with selected quotes here.
