Frailty, Phagocytosis and Respiratory Microbiome

Advanced age is a predominant risk factor for pulmonary infections, which are the leading cause of death in older adults. Over 70% of pneumonia cases requiring hospital treatment occur in the over 65s, with 20% mortality in this age group. The innate immune system is heavily implicated in the pathophysiology of age-related lung diseases, with the concept of 'inflammaging 'describing the aging of the immune system. Inflammaging is characterised by increased circulating and tissue pro-inflammatory cytokines, including C-reactive protein (CRP), IL-6, and TNFa , linked to an increased susceptibility to chronic morbidity, disability and frailty. Aging is also linked to declined overall health, with increased age associated with higher incidence of co-morbidities including frailty. Frailty is a manifestation of unhealthy ageing and is an independent predictor of poor outcomes and heightened susceptibility to infection. Frail older adults exhibit increased systemic inflammation, altered adaptive immune cell populations, and impaired neutrophil function. Most of our knowledge of immune ageing has been gathered through rodent models, which, while informative, do not fully replicate the human condition. This is specifically notable in myeloid cells, where monocyte and macrophage populations differ between species. In mice, advanced age is linked to impaired AM phagocytosis, antiviral responses, and TLR signalling, as well as impaired bacterial clearance, pro-inflammatory cytokine release and features of mitochondrial dysfunction. Aged murine AM display decreased ATP production, enhanced reactive oxygen species (ROS) generation, and diminished antioxidant responses to respiratory bacteria. These murine studies suggest that impairment in macrophage function in the lungs may drive lung damage, contributing to the decline in lung function observed in normal human ageing. In humans, impaired macrophage function, characterised by reduced phagocytosis and bacterial killing, and altered inflammatory mediator release is linked to age related diseases including chronic respiratory disease (COPD, IPF) and cancer, but how macrophage function related to non-disease related aging is unclear. Common pneumonia causing bacteria include Streptococcus pneumoniae, Haemophilus influenzae…and are often organisms that can be acquired or also carried in health. This has led to considering how the immune system interacts with carried strains of bacteria and the respiratory microbiome to become permissive to infections by these pathobionts. The nasopharynx microbiome reveals reduced bacterial density, and reduced diversity with age. Though frailty is understood as a distinct immune state and not an inevitable consequence of aging, we do not understand the interactions between sentinel immune cells and the microbiome in ageing or frailty. Understanding these interactions may give us tools to reduce the morbidity and mortality associated with increased infection risk with increasing age. In this study we sought to assess age and frailty related changes in human monocyte-derived macrophage function and the respiratory microbiome.