Markers of T-cell senescence and physical frailty: insights from Singapore Longitudinal Ageing Studies

Abstract

Elderly individuals have an eroded immune system but whether immune senescence is implicated with the development of frailty is unknown. The underlying immune mechanisms and the link between markers of senescence and physical frailty is not well established. We explored the association of specific T-cell subset markers of immune differentiation and senescence on CD4+ and CD8+ cells (CD28−, CD27− and CD57+) and the immune risk profile (inverted CD4/CD8 ratio <1) with physical frailty among 421 participants who were frail (N=32), prefrail (N=187) and robust (N=202) in the Singapore Longitudinal Ageing Study cohort. In ordinal logistic regression models relating tertile category rank scores of immune biomarker with frailty status (robust, prefrail and frail), CD8+CD28−CD27+ (odds ratio (OR)=1.35, P=0.013), CD4+CD28−CD27+ (OR=1.29, P=0.025), CD8+CD28− (OR=1.31, P=0.022), and CD4/CD8 ratio (OR=1.27, P=0.026) were positively associated with frailty, controlling for age, sex and multimorbidity. CD4/CD8 ratio less than one was not associated with frailty (OR=0.84, P=0.64). In stepwise multinomial logistic regression controlling for age, sex and comorbidity, only CD8+CD28−CD27+ was the independent predictor of prefrailty: highest tertile of the immune marker significantly predicted prefrailty (versus low tertile, OR=1.72, P=0.037) and frailty (OR=2.56, P=0.06). The study supports the hypothetical role of immune senescence in physical frailty, particularly in regard to the observed loss of CD28 expression from both CD8+ cells and CD4+ cells, but not for CD27 or CD4/CD8 ratio as a marker of senescence. The potential of CD8+CD28−CD27+ as a biological marker of frailty should be further investigated in prospective studies. Declining function in a subset of immune cells may render certain elderly individuals especially weak and prone to hospitalization. As we age, a process called immunosenescence undermines the body''s ability to fight infection and recover from injury. Researchers led by Tze Pin Ng at the National University of Singapore have now found evidence that this process contributes to the increased weakness and overall physiological decline observed among the ''frail'' elderly. The researchers analyzed immune cells collected from 421 elderly Singaporeans, and found that T cells from frail patients tended to lack CD28. This protein is associated with immune function, and its absence is a signature of immunosenescence. Importantly, T-cells from patients who subsequently developed frailty also showed reduced CD28. This suggests a link between immunosenescence and frailty, and may offer a useful predictor for unhealthy aging.