Inflammaging is characterized by the upregulation of the inflammatory response that occurs with advancing age; its roots are strongly embedded in evolutionary theory.Inflammaging is believed to be a consequence of a remodelling of the innate and acquired immune system, resulting in chronic inflammatory cytokine production.Complex interrelated genetic, environmental and age-related factors determine an individual’s vulnerability or resilience to inflammaging. These factors include polymorphisms to the promoter regions of cytokines, cytokine receptors and antagonists, age-related decreases in autophagy and increased adiposity. Anti-inflammaging describes the upregulation of the hypothalamic-pituitary axis in response to inflammaging, leading to higher levels of cortisol, which in turn may be detrimental, contributing to less successful ageing and frailty. This may be countered by the adrenal steroid dehydroepiandrosterone, which itself declines with age, leaving certain individuals more vulnerable. Inflammaging and anti-inflammaging have both been linked with a number of age-related outcomes, including chronic morbidity, functional decline and mortality. This important area of research offers unique insights into the ageing process and the potential for screening and targeted interventions.

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Frailty is a multidimensional geriatric syndrome characterised by a state of increased vulnerability to disease. Its causes are unclear, limiting opportunities for intervention. Age-related changes to the immune-endocrine axis are implicated. This study investigated the associations between the immune-endocrine axis and frailty as well as mortality 10 years later among men and women aged 65 to 70 years. We studied 254 participants of the Hertfordshire Ageing Study at baseline and 10-year follow-up. At baseline, they completed a health questionnaire and had collection of blood samples for immune-endocrine analysis. At follow-up, Fried frailty was characterised and mortality ascertained. Higher baseline levels of differential white cell counts (WCC), lower levels of dehydroepiandosterone sulphate (DHEAS) and higher cortisol:DHEAS ratio were all significantly associated with increased odds of frailty at 10-year follow-up. Baseline WCC and cortisol:DHEAS clearly discriminated between individuals who went on to be frail at follow-up. We present the first evidence that immune-endocrine biomarkers are associated with the likelihood of frailty as well as mortality over a 10-year period. This augments our understanding of the aetiology of frailty, and suggests that a screening programme at ages 60-70 years could help to identify individuals who are at high risk of becoming frail and who would benefit from early, targeted intervention, for example with DHEA supplementation or anti-inflammatory strategies. Progress towards the prevention of frailty would bring major health and socio-economic benefits at the individual and the population level.

Cross-sectional studies show that higher blood concentrations of inflammatory markers tend to be more common in frail older people, but longitudinal evidence that these inflammatory markers are risk factors for frailty is sparse and inconsistent. We investigated the prospective relation between baseline concentrations of the inflammatory markers C-reactive protein (CRP) and fibrinogen and risk of incident frailty in 2,146 men and women aged 60 to over 90 years from the English Longitudinal Study of Ageing. The relationship between CRP and fibrinogen and risk of incident frailty differed significantly by sex (p for interaction terms <0.05). In age-adjusted logistic regression analyses, for a standard deviation (SD) increase in CRP or fibrinogen, odds ratios (95% confidence intervals) for incident frailty in women were 1.69 (1.32, 2.17) and 1.39 (1.12, 1.72), respectively. Further adjustment for other potential confounding factors attenuated both these estimates. For an SD increase in CRP and fibrinogen, the fully-adjusted odds ratio (95% confidence interval) for incident frailty in women was 1.27 (0.96, 1.69) and 1.31 (1.04, 1.67), respectively. Having a high concentration of both inflammatory markers was more strongly predictive of incident frailty than having a high concentration of either marker alone. In men, there were no significant associations between any of the inflammatory markers and risk of incident frailty. High concentrations of the inflammatory markers CRP and fibrinogen are more strongly predictive of incident frailty in women than in men. Further research is needed to understand the mechanisms underlying this sex difference.

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 ...

Different combinations and relative quantities of three connexins-connexin43, connexin40 and connexin45-are expressed in different subsets of cardiomyocyte. In the healthy heart, gap junctions assembled from these different connexin combinations form the cell-to-cell pathways for the precisely orchestrated patterns of current flow that govern the normal heart rhythm. Remodelling of gap junction organization and connexin expression is a conspicuous feature of human heart disease in which there is an arrhythmic tendency. This remodelling may take the form of structural remodelling, involving disturbances in the distribution of gap junctions (i.e., disruption of the normal ordered pathways for cell-to-cell conduction), and remodelling of connexin expression, involving alteration in the amount or type of connexin(s) present. Most notable among quantitative alterations in connexin expression is a reduction in ventricular connexin43 levels in human congestive heart failure. By correlating data from studies in experimental animal models, gap junction and connexin remodelling emerges as a factor to be considered in understanding the pro-arrhythmic substrate characteristic of many forms of heart disease. However, our knowledge of the functional correlates of the specific patterns of multiple connexin expression found in different regions of the heart in health and disease remains rudimentary, and the development of new experimental cell models heralds advances in this area over the next few years.

Markers of inflammatory status were significantly associated with degree of hearing loss in older people. The findings are consistent with the possibility that inflammatory changes occurring with ageing may be involved in age-related hearing loss. Longitudinal data would enable this hypothesis to be explored further.

Poor appetite was common among the older hospitalised women studied, and was associated with higher risk of poor healthcare outcomes.