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A Study of Early Life Adversity versus Later Immune Aging Points to Cytomegalovirus as the Problem


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Posted 13 November 2017 - 11:59 AM


A fair number of research groups study psychological stress and aging, and investigations of early life adversity versus later risk of age-related disease fall into this category. The paper here finds that persistent cytomegalovirus infection is likely the mediating mechanism linking early life stress and later increased risk of age-related disease, acting through accelerated immune system dysfunction. This implies that the early stress may or may not be all that important, as - for whatever reason - the groups selected as examples of stress in early life are also more likely to be infected. That might be the short-term detrimental effects of stress on immune function, or it could be a matter of being in close contact with more distinct groups of people during childhood, as is the case for the adopted individuals in the study here.

Cytomegalovirus is a persistent herpesvirus that the immune system cannot effectively clear from the body. Near everyone becomes infected at some point in life, and extensive evidence links this infection with immune system dysfunction. Increasing numbers of immune cells become dedicated to uselessly fighting cytomegalovirus, and ever fewer are left for everything else the immune system must accomplish. Other than this long-term corrosion, cytomegalovirus doesn't cause obvious symptoms in the vast majority of people - few notice the initial infection. Removing cytomegalovirus isn't that helpful, as the damage is already done in the old, and the young will be reinfected. A more useful approach might be to selectively target and destroy cytomegalovirus-specific immune cells to free up space for their replacement.

Adverse and stressful events in childhood, such as parental loss, low childhood socioeconomic status, or institutionalization, have been associated with elevated levels of inflammation and an increased risk for multiple age-related diseases, such as cardiovascular disease. Many efforts have been made to understand the mechanisms underlying long-term effects of ELA. One of the mechanisms proposed is accelerated aging of the immune system, also known as immunosenescence. Immunosenescence refers to the process of progressive deterioration of immune functions that go hand in hand with normal aging. If ELA affects the rate of immunosenescence, this may explain an increased risk and earlier onset of age-related disorders.

It remains an open question as to what drives ELA-associated immunosenescence. Besides ELA, several other environmental factors have been found to modulate the rate of immunosenescence, such as persistent viral infections. Herpes simplex virus (HSV), Epstein-Barr virus (EBV), and cytomegalovirus (CMV) are among the most prevalent viral infections that establish latency after primary infection and reactivate when the immune system is compromised. Latent infections with CMV in particular are believed to play an important role in immunosenescence and are associated with age-related alterations of T cell immunity.

In this study, we investigated T cell-specific immunosenescence (T cell differentiation and CD57 expression) in participants with and without a history of ELA. Participants in the ELA group had experienced separation from their parents in early childhood and were subsequently adopted, which is a standard model of ELA. This study cohort is a healthy subset of the EpiPath cohort, excluding all participants with acute or chronic diseases. With a mediation analysis we examined whether CMV titers may account for immunosenescence observed in ELA.

In this study, we have shown that ELA is associated with higher levels of T cell senescence in healthy participants. Not only did we find a higher number of senescent cells (CD57+), these cells also expressed higher levels of CD57, a cell surface marker for senescence, and were more cytotoxic in ELA compared to controls. Control participants with high CMV titers showed a higher number of senescent cells, compared to controls with low titers. Importantly, we found that the effect of ELA on immunosenescence was associated with CMV infection specifically, rather than being the consequence of continued reactivation of latent viruses in general.

Our findings have important implications for this literature on senescence in ELA. Most evidence for accelerated immunosenescence in ELA comes from telomere length, but none of these studies have accounted for CMV infections. Our results suggest that the association between ELA and shorter telomeres - or immunosenescence in general - may have been largely mediated by CMV infection. First of all, because there is a clear link between CMV infection and immunosenescence. CMV infection is related to expanding populations of specific memory T cells, and a shrinking population of naïve T cells, similar to what is observed in aging. CMV seropositivity has been shown to reduce life expectancy by almost 4 years in an elderly population, especially due to an increase in cardiovascular deaths.

Second, there is reason to believe that children in adverse circumstances are at higher risk for CMV infection. For instance, the likelihood of CMV infection is higher in children raised in poverty and low socioeconomic status. There is no clear epidemiological data on the prevalence of infection in international adoptees, as were included in this study. However, most adopted children have been institutionalized prior to adoption, which arguably increases the risk for CMV infection, as is the case for day-care center attendance.

Link: https://doi.org/10.3...immu.2017.01263


View the full article at FightAging




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