Biomarkers of the ageing immune system and their association with frailty – A systematic review

Ageing is associated with several physiological changes, including changes in the immune system. Age-related changes in the innate and adaptive immune system are thought to contribute to frailty. Understanding the immunological determinants of frailty could help to develop and deliver more effective care to older people. This systematic review aims to study the association between biomarkers of the ageing immune system and frailty. The search strategy was performed in PubMed and Embase, using the keywords "immunosenescence", "inflammation", "inflammaging" and "frailty". We included studies that investigated the association of biomarkers of the ageing immune system and frailty cross-sectionally in older adults, without an active disease that affects immune parameters. Three independent researchers selected the studies and performed data extraction. Study quality was assessed using the Newcastle-Ottawa scale adapted for cross-sectional studies. A total of 44 studies, with a median number of 184 participants, was included. Study quality was good in 16 (36 %), moderate in 25 (57 %) and poor in 3 (7 %) of studies. The most frequently studied inflammaging biomarkers were IL-6, CRP and TNF-α. Associations with frailty were observed for increased levels of (i) IL-6 in 12 of 24 studies, (ii) CRP in 7 of 19 studies, and (ii) TNF-α in 4 of 13 studies. In none of the other studies were associations observed of frailty with these biomarkers. Different types of T-lymphocyte subpopulations were studied but each subset was studied only once, and the study sample sizes were low. Our review of 44 studies on the relation between immune biomarkers and frailty identified IL-6 and CRP as the biomarkers that were most consistently associated with frailty. T-lymphocyte subpopulations were investigated but too infrequently to draw strong conclusions yet, although initial results are promising. Additional studies are required in order to further validate these immune biomarkers in larger cohorts. Furthermore, prospective studies in more uniform settings and larger cohorts are needed to further investigate the association with immune candidate biomarkers for which potential associations with ageing and frailty were previously observed, before these can be used in clinical practice to help assess frailty and improve the care treatments of older patients.