Associations of IGF1 and IGFBPs 1 and 3 with all-cause and cardiovascular mortality in older men: the Health In Men Study

Objective: Circulating IGF1 declines with age while ill-health increases. Controversy remains whether differences in the levels of IGF1 and its binding proteins 1 and 3 (IGFBP1 and IGFBP3) determine health outcomes during ageing. We examined associations of IGF1, IGFBP1 and IGFBP3 with all-cause and cardiovascular mortality in older men. Design: We conducted a prospective cohort study of community-dwelling men aged >= 70 years. Methods: Plasma collected at baseline (2001-2004) was assayed for total IGF1, IGFBP1 and IGFBP3. Incidence and causes of death from time of recruitment to 31 December 2008 were ascertained using the Western Australian Data Linkage System. Cox regression analyses were performed, adjusting for conventional cardiovascular risk factors. Results: Among 3983 men followed for 5.2 years (median), 694 deaths occurred, 243 from cardiovascular disease (CVD). There was no difference in survival according to quintiles of IGF1. Increased IGFBP1 predicted increased all-cause mortality (highest versus lowest quintile: adjusted hazard ratio (HR) = 1.98, 95% confidence interval (CI) = 1.52-2.57, P < 0.001 for trend) and increased cardiovascular mortality (HR = 3.42 (2.03-5.77), P! 0.001 for trend). Decreased IGFBP3 predicted increased all-cause mortality (lowest versus highest quintile: HR = 1.57, 95% CI = 1.23-2.01, P = 0.007 for trend). Associations of IGFBP1 and IGFBP3 with all-cause mortality were not attenuated by adjustment for IGF1 levels. Conclusions: In older men, higher IGFBP1 and lower IGFBP3 levels predict overall and CVD-related mortality, while IGF1 levels are not associated with mortality. Further studies are needed to clarify the underlying mechanisms by which IGFBP1 and IGFBP3 levels are associated with mortality risk, and whether this occurs independently of IGF1.