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

Zhang, William B., Aleksic, Sandra, Gao, Tina, Weiss, Erica F., Demetriou, Eleni, Verghese, Joe, Holtzer, Roee, Barzilai, Nir, Milman, Sofiya·2020·Cells
DOI 10.3390/cells9061368PMC PMC7349399
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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.

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Figure 1 Insulin-like growth factor (IGF)-associated proteins and mortality. Unadjusted survival curves for individuals with high and low levels of IGF-1 (a. combined cohort; b. males; c. females), IGFBP-1 (d–f), IGFBP-3 (g–i), and IGF-1/IGFBP-3 molar ratio (j–l).
Figure 1 Insulin-like growth factor (IGF)-associated proteins and mortality. Unadjusted survival curves for individuals with high and low levels of IGF-1 (a. combined cohort; b. males; c. females), IGFBP-1 (d–f), IGFBP-3 (g–i), and IGF-1/IGFBP-3 molar ratio (j–l).CC BY · PubMed Central
Figure 2 IGF-associated proteins and mortality hazard. Sex and age-adjusted survival hazards for combined cohort (a) and age-adjusted survival hazard for males (b) and females (c) with high levels of IGF-associated proteins as compared to individuals with low levels.
Figure 2 IGF-associated proteins and mortality hazard. Sex and age-adjusted survival hazards for combined cohort (a) and age-adjusted survival hazard for males (b) and females (c) with high levels of IGF-associated proteins as compared to individuals with low levels.CC BY · PubMed Central
Figure 3 IGF-1 levels and morbidity. Unadjusted survival curves for multiple-domain cognitive impairment (MDCI) (a. combined cohort; b. males; c. females), diabetes (d–f), cardiovascular disease (g–i), cancer (j–l), and composite incident morbidity (m–o) in individuals with high and low levels of IGF-1.
Figure 3 IGF-1 levels and morbidity. Unadjusted survival curves for multiple-domain cognitive impairment (MDCI) (a. combined cohort; b. males; c. females), diabetes (d–f), cardiovascular disease (g–i), cancer (j–l), and composite incident morbidity (m–o) in individuals with high and low levels of IGF-1.CC BY · PubMed Central
Figure 4 IGF-1 and morbidity hazard. Sex and age-adjusted morbidity hazards for all individuals in cohort (a), and age-adjusted morbidity hazards for males (b) and females (c) with high levels of IGF-1 as compared to individuals with low levels.
Figure 4 IGF-1 and morbidity hazard. Sex and age-adjusted morbidity hazards for all individuals in cohort (a), and age-adjusted morbidity hazards for males (b) and females (c) with high levels of IGF-1 as compared to individuals with low levels.CC BY · PubMed Central
Figure 5 IGFBP-1 levels and morbidity. Unadjusted survival curves for MDCI (a. combined cohort; b. males; c. females), diabetes (d–f), cardiovascular disease (g–i), cancer (j–l), and composite incident morbidity (m–o) in individuals with high and low levels of IGFBP-1.
Figure 5 IGFBP-1 levels and morbidity. Unadjusted survival curves for MDCI (a. combined cohort; b. males; c. females), diabetes (d–f), cardiovascular disease (g–i), cancer (j–l), and composite incident morbidity (m–o) in individuals with high and low levels of IGFBP-1.CC BY · PubMed Central
Figure 6 IGFBP-1 and morbidity hazard. Sex and age-adjusted morbidity hazards for all individuals (a), and age-adjusted morbidity hazard for males (b) and females (c) with high levels of IGFBP-1 as compared to individuals with low levels.
Figure 6 IGFBP-1 and morbidity hazard. Sex and age-adjusted morbidity hazards for all individuals (a), and age-adjusted morbidity hazard for males (b) and females (c) with high levels of IGFBP-1 as compared to individuals with low levels.CC BY · PubMed Central

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Metadata

Authors
Zhang, W. B., Aleksic, S., Gao, T., Weiss, E. F., Demetriou, E., Verghese, J., Holtzer, R., Barzilai, N., & Milman, S.
Affiliations
  • Department of Medicine, Division of Endocrinology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA
  • Department of Neurology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
  • Ferkauf Graduate School of Psychology, Yeshiva University, New York, NY 10033, USA
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2020-06-01
Volume
9
Issue
6
Pages
1368
ISSN
2073-4409
DOI
10.3390/cells9061368
PMC
PMC7349399
Cited by
64
References
7
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institute on Aging (K23AG051148, R01AG061155, P30AG038072, R01AG057909, R01AG044829-01A1, R01AG050448, T32AG023475-18)
  • National Institute of Neurological Disorders and Stroke (2R37NS43209, 1UG3NS105565–01, R01NS109023)
  • National Center for Advancing Translational Sciences (Einstein/Montefiore CTSA UL1TR002556)

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