Insulin-like Growth Factor-1 and IGF Binding Proteins Predict All-Cause Mortality and Morbidity in Older Adults

Abstract

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.

Can Blood-Circulating Factors Unveil and Delay Your Biological Aging?

“…A decrease in growth hormone and oxytocin levels with age, on the one hand, is associated with a general slowdown in growth and development of all body systems, including regeneration processes. On the other hand, due to an increase of the IGF-1/IGFBP-3 ratio, this stimulates the predominance of high mTOR-dependent metabolic activity and insulin resistance [ 150 ].…”

“…The blood level of IGF-1 reaches its maximum during adolescence and then gradually declines [ 149 ]. At the same time, the increased IGF-1/IGFBP-3 molar ratio in serum of the elderly is positively associated with the all-cause morbidity and mortality, including cancer, diabetes, cardiovascular and cognitive disorders, while the IGFBP-3 level itself is negatively associated with the all-cause mortality [ 150 ].…”

The antagonistic pleiotropy of insulin‐like growth factor 1

“…By contrast, epidemiological studies of the naturally occurring variation in circulating IGF-1 have shown null or mixed results (Milman et al, 2016). Some studies, including those from our longevity cohorts, have shown a positive association between high IGF-1 and adverse outcomes (Milman et al, 2014;Spoel et al, 2015;Zhang et al, 2020). Others, often from somewhat younger populations, have shown the opposite: higher IGF-1 being associated with protection from disease and death (Bourron et al, 2015;Friedrich et al, 2009).…”

Insulin-Like Growth Factor 1 (IGF-1) Signaling in Glucose Metabolism in Colorectal Cancer

“…In addition to insulin or GH, the production and secretion of IGF-1 are also influenced by other hormones, e.g., sex hormones [ 87 ], as well as factors such as age [ 19 , 88 ], sex, diet and nutrition [ 89 ], circadian rythm [ 90 ], and microbiota-derived metabolites [ 91 ]. Genetic defects with potential to affect both GH secretion and IGF-1 bioavailability and action are also a subject of a recent review [ 92 ].…”