Abstract
Disclosure: S. Yuksel: None. K. Ye: None. J.R. Weinberg: None. T. Gao: None. S. Aleksic: None. T. Wang: None. N. Barzilai: None. S. Milman: None. Background: The increasing prevalence of morbidities with aging is a major burden for older individuals. Aging is in part regulated by the insulin-like growth factor-1 (IGF-1) axis. IGF-1 level has emerged as a biomarker, as higher levels predict mortality and morbidity from aging-related diseases. However, IGF-1 levels may vary in response to disease, posing a limitation to single value utility. We investigated the relationship between IGF-1 and IGF binding proteins 1 & 3 (IGFBP 1 & 3) with major clinical events. We hypothesized that intraindividual variations in IGF-1 and IGFBPs levels are significantly associated with major clinical events. Methods: The study included 645 individuals (54% female) with a mean age of 74 from the LonGenity cohort. IGF-1, IGFBP-3 and IGFBP-1 blood levels and self-reported interim medical histories were collected biennially. Major clinical events were defined as onset of cancer, major surgery or hospitalization for major illness. In individuals with at least 3 measurements of IGF-1 and IGFBPs (n-428), linear regression was used to compare the log- intra-person standard deviation between the two groups (with or without major events) with sex and average age at the measurements as covariates. Additionally, the occurrence of any major clinical event within an interval of two IGF-1 measures was modelled by logistic mixed effect model, with the time duration of the interval, age and sex as covariates. The explanatory variable of interest was the absolute value of change of IGF-1 levels. Results: Linear regression model showed that intra-individual variability was positively associated with occurrence of major clinical events (p=0.026). In a sex-stratified analysis, men with events had greater IGF-1 variability compared to men without events (p=0.0016); however, this association was not found among women (p=0.95). Intra-individual variability of IGFBP-3 was significantly associated with occurrence of clinical events in both sexes (p=0.025 in men and p=0.016 in women). Absolute change in IGF-1 level was associated with higher odds of major clinical events (p=0.025). When stratified by sex, the association remained significant among males only (p=0.01). The same analysis of IGFBP-1 and IGFBP-3 found similar association between the higher risk of major events and the greater changes in IGFBPs levels (p=0.045 and p=0.007, respectively), but the associations were similar between males and females. Conclusions: Levels of IGF-1 and IGFBPs fluctuate over time. Greater variability in levels was associated with occurrence of major clinical events, especially among men. These findings warrant cautious interpretation of results from epidemiologic studies that rely on a single IGF hormone measurement, especially since the results of these studies may be impacted by reverse causation. Presentation: Monday, July 14, 2025