Stanniocalcin-PAPP-A-IGFBP-IGF axis and all-cause mortality risk in aged and middle-aged adults: A systematic review

Circulating insulin-like growth factor 1 (IGF-1) is associated with longevity, yet its activity is tightly regulated by IGF-binding proteins (IGFBPs) and the cleavage of IGF-IGFBP complexes, mediated by pappalysins (PAPP-A and PAPP-A2) and inhibited by stanniocalcins (STC1 and STC2). However, the association of these IGF-1-regulating proteins with mortality remains unclear. This study aimed to evaluate the association between serum STC-PAPP-A-IGFBP-IGF axis proteins and all-cause mortality in middle-aged and older adults.

A systematic review was conducted in MEDLINE, EMBASE, Web of Science, and Scopus, following the JBI and PRISMA parameters for study inclusion through December 2025. Findings were analyzed using vote counting based on direction of effect and synthesized according to SWiM guidelines for systematic reviews without meta-analysis, given exposure heterogeneity. Risk of bias was assessed using the Newcastle-Ottawa Scale. The protocol was registered in PROSPERO (CRD42024556008).

Thirty-eight observational studies were included across general and disease-specific cohorts, including cardiovascular, metabolic, cancer, and chronic kidney disease populations. Elevated IGFBP-1, IGFBP-2, and IGFBP-4 were associated with increased all-cause mortality, whereas higher IGFBP-3 was associated with lower risk. Overall, IGF-1 associations were inconsistent. Moreover, circulating PAPP-A was associated with increased all-cause mortality, with limited evidence suggesting a similar trend for STC2.

IGF-1 bioavailability-regulating proteins are associated with all-cause mortality in middle-aged and older adults. These findings suggest a role of IGF-1 signaling dysregulation through altered binary/ternary complexes in aging, supporting circulating STC-PAPP-A-IGFBP-IGF axis proteins as mechanistically grounded biomarkers for mortality risk stratification.