The age‐related increase in low‐grade systemic inflammation (Inflammaging) is not driven by cytomegalovirus infection

Abstract

SummaryAging is accompanied by the development of low-grade systemic inflammation, termed 'inflammaging', characterized by raised serum C-reactive protein (CRP) and pro-inflammatory cytokines. Importantly, inflammaging is implicated in the pathogenesis of several of the major age-related diseases including cardiovascular disease, type 2 diabetes, and dementia and is associated with increased mortality. The incidence of infection with the persistent herpes virus cytomegalovirus (CMV) also increases with age. Cross-sectional studies have proposed CMV infection as a significant driver of inflammaging, but a definitive case for CMV as a causative agent in inflammaging has not yet been made. We studied longitudinally 249 subjects (153 men, 96 women) who participated in the Hertfordshire Ageing Study at baseline (1993 ⁄ 5, mean age 67AE5 years) and at 10 year follow-up. At both times, anthropometric measurements were made and subjects provided blood samples for analysis of inflammatory status and CMV seropositivity. In the cohort as a whole, serum CRP (P < 0AE02) and proinflammatory cytokines TNFa (P < 0AE001) and IL-6 (P < 0AE001) were increased between baseline and follow-up sampling whereas levels of the anti-inflammatory cytokine IL-10 were decreased (P < 0AE001). These changes to cytokine status over time occurred equally in the 60% of subjects who were seropositive for CMV at baseline and follow-up, the 8% who were CMV negative at baseline but who became CMV positive by the 10 year follow-up, and also in the 32% who were CMV seronegative throughout. We conclude that CMV infection is not a primary causative factor in the age-related increase in systemic inflammation.Key words: aging; cytokines; inflammation.Physiological aging is associated with a chronic sub-clinical systemic inflammatory state, termed inflammaging (Franceschi et al., 2000), characterized by elevated levels of serum pro-inflammatory cytokines such as interleukin 6 (IL-6) and TNFa and acute phase proteins such as C-reactive protein (CRP; Franceschi et al., 2000). Further, the levels of cytokines that counteract the inflammatory state, such as IL-10, are reduced with age (Lio et al., 2002) compounding the inability to maintain immune homoeostasis. Importantly, inflammaging is a predictor of frailty (Baylis et al., 2012) and chronic low-grade inflammation is now accepted as a key pathogenic factor in the development of several age-related pathologies including cardiovascular disease (Libby et al., 2010) and type 2 diabetes (Paolisso et al., 1998). Further, studies in centenarians (Franceschi et al., 1995) show that these extremely long-lived individuals maintain the cytokine profile of younger adults and do not develop inflammaging. Understanding the causes of inflammaging is therefore important for developing interventions to prevent its occurrence and extend the healthy lifespan of our aging population.Various factors have been proposed to drive inflammaging including increased adiposity with age (Forsythe et al., 2008), and decreased production ...

Adipose stromal cell and sarpogrelate orchestrate the recovery of inflammation‐induced angiogenesis in aged hindlimb ischemic mice

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Physical Function Impairment of Older, HIV-Infected Adults Is Associated with Cytomegalovirus Immunoglobulin Response

“…15,36,[41][42][43][44] Our study provides the first demonstration of a strong relationship between CMV IgG and impaired physical function in HIV infection. Whether CMV alone plays a causative role in the deterioration of physical function or is a marker of another variable that is associated with decreased physical function could not be determined in this study.…”

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

“…It should also be noted that some studies have doubted a role for CMV in immunosenescence and aging‐associated inflammation (Cicin‐Sain et al ., 2011; Bartlett et al ., 2012). However, one of them used a rhesus macaque model of aging (Cicin‐Sain et al ., 2011), where old was defined as up to 26 years, and probably not comparable with the age of our octogenarians.…”

“…However, one of them used a rhesus macaque model of aging (Cicin‐Sain et al ., 2011), where old was defined as up to 26 years, and probably not comparable with the age of our octogenarians. The study by Bartlett took CMV seropositivity into consideration, but not T‐cell immunity specifically (Bartlett et al ., 2012). Derhovassian and coworkers have shown that the response to CMV can be very heterogeneous and that immunological control of the virus can contribute to decreased mortality rate (Derhovanessian et al ., 2010).…”