Yet More Evidence for Long-Term CMV Infection to Increase Disease and Mortality in Old Age

A few weeks ago I pointed out recent study data from a German population on cytomegalovirus (CMV) and its role in immune aging. Today I'll note a companion study of a different population of older people that focuses more on the relationship between CMV and mortality. It is the story you might expect if you've been reading on this topic for any great length of time, as testing positive for CMV infection is here found to be associated with a significantly greater rate of age-related disease and mortality. Cytomegalovirus (CMV) is a pervasive herpesvirus that, like its peers, cannot be effectively cleared from the body by the immune system. Unlike its peers CMV has no obvious and immediate effect on health for anyone with a normally functioning immune system. You probably have it already, you never noticed your initial infection, and the overwhelming majority of people test positive for CMV infection by the time they are old. A growing body of evidence implicates long-term CMV infection in the development of immunosenescence, the processes that result in declining effectiveness and growing dysfunction of the immune system in aging.

The immune system is one of the more intricate cellular systems in the body, and it is far from fully understood at the detail level. Most of the ways in which it can fall into persistent dysfunction, as is the case in autoimmune disease and aging, are similarly at best currently understood only in outline. Yet the immune system is very important in the progression of degenerative aging. It has numerous roles that go beyond defending against invading pathogens, such as the elimination of potentially cancerous or senescent cells, both of which can be a source of harm. Further, a dysfunctional, aged immune system generates ever greater levels of chronic inflammation, and this inflammation contributes to the development of all of the common, ultimately fatal age-related conditions.

The immune system in adults has a very slow rate of generation of new immune cells, and this and other factors give it many of the characteristics of a system that is limited by space. Present thinking on CMV is that its constant presence causes the immune system to devote ever more of this limited space to cells that are specialized for CMV and useless for everything else. Further, constant immune activity, such as when battling pathogens like CMV that cannot be cleared, tends to force more immune cells into an exhausted, senescent state - this is a well studied phenomenon for HIV and AIDS, for example. This is no doubt an incomplete sketch of a complicated and nuanced collection of destructive processes, but what can be done about it? A way to clear CMV won't fix the damage done to date, and infection doesn't appear to do any harm beyond this slow immune destruction, so targeting CMV is probably not the best of approaches - more of a nice to have for the long term. Delivering lots of new immune cells on a regular basis to circumvent natural limits, such as via cell therapies or rejuvenation of the thymus will be more effective for the elderly. The other side of the coin is targeted destruction of CMV-specialized and useless immune cells, which should spur replacement with unspecialized and useful cells. As the paper quoted below demonstrates, something effective must be done:

CMV seropositivity and T-cell senescence predict increased cardiovascular mortality in octogenarians: results from the Newcastle 85+ study

Human cytomegalovirus (CMV) is a ubiquitous herpes virus and shares a high prevalence in developed countries. A growing body of evidence suggests an important role of CMV during aging. Seropositivity for CMV is one of the parameters in the immune risk profile (IRP), associated with increased mortality in longitudinal studies in octo- and nonagenarians. While the IRP was present in only 20% of the 85-year-olds, CMV seropositivity is present in approximately 80-90% of octogenarians. CD8 T-cell responses in CMV-seropositive elderly are characterized by an accumulation of dysfunctional T cells with short telomeres and low proliferation potential, often considered as replicative senescent. Clinically, CMV has been linked to an increased incidence of coronary heart disease (CHD) in a number of studies. It has been proposed that CMV-driven cardiovascular mortality might be the main cause for the observed increase in mortality in CMV-seropositive people over the age of 65 years.

The goal of our study was to evaluate whether in octogenarians CMV seropositivity and T-cell senescence are independent predictors of all-cause and especially cardiovascular and CHD-mediated mortality. we prospectively analyzed peripheral blood samples from 751 octogenarians (38% males) from the Newcastle 85+ study for their power to predict survival during a 65-month follow-up (47.3% survival rate). CMV-seropositive participants showed a higher prevalence of CHD (37.7% vs. 26.7%) compared to CMV-seronegative participants together with lower CD4/CD8 ratio and higher frequencies of senescent-like CD4 memory cells and senescent-like CD8 memory cells. CMV seropositivity was also associated with increased six-year cardiovascular mortality (hazard ratio 1.75) or death from myocardial infarction and stroke (hazard ratio 1.89). Analysis revealed that low percentages of senescent-like CD4 T cells and near-senescent CD8 T cells reduced the risk of cardiovascular death. We conclude that CMV seropositivity is linked to a higher incidence of CHD in octogenarians and that senescence in both the CD4 and CD8 T-cell compartments is a predictor of overall cardiovascular mortality as well as death from myocardial infarction and stroke.

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