While the growth hormone/insulin-like growth factor-1 (GH/IGF-1) pathway plays essential roles in growth and development, diminished signaling via this pathway in model organisms extends lifespan and health-span. In humans, circulating IGF-1 and IGF-binding proteins 3 and 1 (IGFBP-3 and 1), surrogate measures of GH/IGF-1 system activity, have not been consistently associated with morbidity and mortality. In a prospective cohort of independently-living older adults (n = 840, mean age 76.1 ± 6.8 years, 54.5% female, median follow-up 6.9 years), we evaluated the age- and sex-adjusted hazards for all-cause mortality and incident age-related diseases, including cardiovascular disease, diabetes, cancer, and multiple-domain cognitive impairment (MDCI), as predicted by baseline total serum IGF-1, IGF-1/IGFBP-3 molar ratio, IGFBP-3, and IGFBP-1 levels. All-cause mortality was positively associated with IGF-1/IGFBP-3 molar ratio (HR 1.28, 95% CI 1.05–1.57) and negatively with IGFBP-3 (HR 0.82, 95% CI 0.680–0.998). High serum IGF-1 predicted greater risk for MDCI (HR 1.56, 95% CI 1.08–2.26) and composite incident morbidity (HR 1.242, 95% CI 1.004–1.538), whereas high IGFBP-1 predicted lower risk for diabetes (HR 0.50, 95% CI 0.29–0.88). In conclusion, higher IGF-1 levels and bioavailability predicted mortality and morbidity risk, supporting the hypothesis that diminished GH/IGF-1 signaling may contribute to human longevity and health-span.

While insulin‐like growth factor‐1 (IGF‐1) is a well‐established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF‐1 levels and clinical disease. We examined prospective associations of serum IGF‐1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns: First, IGF‐1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF‐1 are protected from disease, while older individuals with high IGF‐1 are at increased risk for incident disease or death. Second, the association between IGF‐1 and risk is generally U‐shaped, indicating that both high and low levels of IGF‐1 may be detrimental. With the exception of a more uniformly positive relationship between IGF‐1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age‐associated diseases. These data suggest that IGF‐1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.

Frailty is a state of decreased physiological reserve and increased vulnerability to adverse outcomes in aging, and is characterized by dysregulation across various biological pathways. Frailty may manifest biologically as alteration in protein expression, possibly regulated at genetic, transcriptional and epigenetic levels. In this study, we examined the proteomic profile associated with frailty defined by an established cumulative frailty index (FI). Using the SomaScan^® assay, 4265 proteins were measured in plasma, of which 55 were positively associated and 88 were negatively associated with the FI. The proteins most strongly associated with frailty were fatty acid‐binding proteins, including fatty acid‐binding protein (FABP) (p = 1.96 × 10⁻¹⁹) and FABPA (p = 8.10 × 10⁻¹⁶), leptin (p = 1.43 × 10⁻¹⁴), and ANTR2 (p = 7.95 × 10⁻²⁰). Pathway analysis with the top 143 frailty‐associated proteins revealed enrichment for proteins in pathways related to lipid metabolism, musculoskeletal development and function, cell‐to‐cell signaling and interaction, cellular assembly, and organization. Frailty prediction model constructed with elastic net regression utilizing 110 proteins demonstrated a correlation between predicted frailty and observed frailty (r = 0.57, p < 2.2 × 10⁻¹⁶). Predicted frailty was also more strongly correlated with chronological age (r = 0.54, p < 2.2 × 10⁻¹⁶) than observed frailty (r = 0.37, p = 1.2 × 10⁻¹⁵). This study identified novel proteins and pathways related to frailty that may offer improved frailty phenotyping and prediction.