Evidence increasingly points to chronic inflammation as an important contributing cause of age-related frailty. The immune system becomes increasingly dysfunctional with age, more so in some people than in others, for a range of causes. A part of that dysfunction is overactivation in response to issues such as a growing burden of senescent cells, molecular damage, and metabolic waste, as well as excess visceral fat and changes in the gut microbiome that lead to greater populations of inflammatory microbes. Inflammatory signaling throughout the body disrupts tissue maintenance, particularly that required for muscles. Physical weakness follows as this environment of dysfunction is sustained for years, causing loss of muscle mass and strength.
Immune processes can become out of balance in the elderly, leading to persistent low-grade inflammation. It is thought that those with long-lasting low-grade inflammation have reduced responses to pathogens and carcinogenesis, and are more prone to autoimmunity. This would render them more vulnerable to developing age-related diseases and becoming frail. In addition to ageing, a potential driver of chronic low-grade inflammation could be the amount of body fat, since adipocytes can activate the immune system directly.
It is still largely unknown when and how low-grade inflammation develops in the course of ageing, and how this is related to frailty. The few longitudinal studies on this subject showed that in frail people, often low-grade inflammation was present over a long period of time. In most studies, including our own, the presence of chronic low-grade inflammation was assessed by measuring the plasma concentrations of only one or two inflammatory markers, notably CRP and IL-6. However, inflammation is a complex process in which many proteins are involved. Some studies already suggested that looking at a larger panel of inflammatory biomarkers, including a broader range of (chemotactic) cytokines, would improve the understanding of the relationship between low-grade inflammation and age-related diseases.
In order to gain more insight into how long-lasting low-grade inflammation relates to frailty, and taking into account sex differences, we performed an exploratory study using data and blood samples from a selection of participants (n = 144) in the longitudinal Doetinchem Cohort Study. Blood samples and data were collected at 5-year intervals covering a period of approximately 20 years.
IFN-γ-related markers and platelet activation markers were found to change in synchrony. Chronically elevated levels of IL-6 pathway markers, such as CRP and IL-6R, were associated with more frailty, poorer lung function, and reduced physical strength. Being overweight was a possible driver of these associations. More and stronger associations were detected in women, such as a relation between increasing CD14 levels and frailty, indicating a possible role for monocyte overactivation. In conclusion, as BMI and waist circumference are related to elevations of immune markers in the IL-6 pathway, chronic inflammation might be an important mediator of the relationship between BMI and frailty.