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The antagonistic pleiotropy of insulin-like growth factor 1

Zhang, William B., Ye, Kenny, Barzilai, Nir, Milman, Sofiya·2021·Aging Cell
DOI 10.1111/acel.13443PMC PMC8441393
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Abstract

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.

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FIGURE 1 Serum IGF‐1 levels decline with age. Each large dot represents the mean age and serum IGF‐1 level of an age ventile (1/20th of the overall cohort studied, stratified by baseline age). Smaller colored dots indicate 500 randomly selected individuals from each group. The error bars here indicate standard deviations of serum IGF‐1 level within each age group. The r 2 and p‐value reported here are for a linear fit to the group averages (large dots)
FIGURE 1 Serum IGF‐1 levels decline with age. Each large dot represents the mean age and serum IGF‐1 level of an age ventile (1/20th of the overall cohort studied, stratified by baseline age). Smaller colored dots indicate 500 randomly selected individuals from each group. The error bars here indicate standard deviations of serum IGF‐1 level within each age group. The r 2 and p‐value reported here are for a linear fit to the group averages (large dots)CC BY · PubMed Central
FIGURE 2 Clinical hazard is increased for both high and low IGF‐1 levels, but not for cancer. Each dot represents the hazard for incident disease or mortality of a subcohort of individuals grouped by IGF‐1 levels, relative to the central group, whose hazard is set at 1 by convention. The area of each dot is proportional to the number of individuals it represents, and error bars indicate 95% confidence intervals for hazard ratios. Reported p‐values are for an F‐test for a quadratic fit to the hazard data, excluding the linear fit component (additional details are available in the methods section). The clinical events evaluated were (a) mortality, (b) dementia, (c) diabetes, (d) vascular disease, (e) osteoporosis, and (f) cancer
FIGURE 2 Clinical hazard is increased for both high and low IGF‐1 levels, but not for cancer. Each dot represents the hazard for incident disease or mortality of a subcohort of individuals grouped by IGF‐1 levels, relative to the central group, whose hazard is set at 1 by convention. The area of each dot is proportional to the number of individuals it represents, and error bars indicate 95% confidence intervals for hazard ratios. Reported p‐values are for an F‐test for a quadratic fit to the hazard data, excluding the linear fit component (additional details are available in the methods section). The clinical events evaluated were (a) mortality, (b) dementia, (c) diabetes, (d) vascular disease, (e) osteoporosis, and (f) cancerCC BY · PubMed Central
FIGURE 3 Clinical hazard associated with IGF‐1 increases with age, but not for cancer. In the left column, each dot represents the hazard ratio for incident disease or mortality associated with one standard deviation higher serum IGF‐1 within an age group, controlled for sex and residual age differences. In the middle and right columns, each dot represents the hazard ratio for incident disease or mortality associated with membership in the lowest or highest IGF‐1 quintiles, respectively, relative to the middle IGF‐1 quintile. For all subfigures, the area of each dot is proportional to the number of individuals it represents. Error bars indicate 95% confidence intervals for the hazard ratio. The reported p‐values are for an F‐test for linear regression among the groups, and the reported r 2 values are for a Pearson association between the linear fit line (dotted red line) and the hazard ratios. The clinical events evaluated were (a–c) mortality, (d–f) dementia, (g–i) diabetes, (j–l) vascular disease, (m–o) osteoporosis, and (p–r) cancer
FIGURE 3 Clinical hazard associated with IGF‐1 increases with age, but not for cancer. In the left column, each dot represents the hazard ratio for incident disease or mortality associated with one standard deviation higher serum IGF‐1 within an age group, controlled for sex and residual age differences. In the middle and right columns, each dot represents the hazard ratio for incident disease or mortality associated with membership in the lowest or highest IGF‐1 quintiles, respectively, relative to the middle IGF‐1 quintile. For all subfigures, the area of each dot is proportional to the number of individuals it represents. Error bars indicate 95% confidence intervals for the hazard ratio. The reported p‐values are for an F‐test for linear regression among the groups, and the reported r 2 values are for a Pearson association between the linear fit line (dotted red line) and the hazard ratios. The clinical events evaluated were (a–c) mortality, (d–f) dementia, (g–i) diabetes, (j–l) vascular disease, (m–o) osteoporosis, and (p–r) cancerCC BY · PubMed Central
FIGURE 4 The U‐shape and age‐interaction effects are independent. After stratifying the population into sex‐specific age quartiles and IGF‐1 quintiles, each group's hazard relative to the age‐matched IGF‐1 quintile 3 is shown for (a) mortality, (b) dementia, (c) diabetes, (d) vascular disease, (e) osteoporosis, and (f) cancer. The area of each dot is proportional to the number of individuals it represents, and error bars indicate 95% confidence intervals for hazard ratios
FIGURE 4 The U‐shape and age‐interaction effects are independent. After stratifying the population into sex‐specific age quartiles and IGF‐1 quintiles, each group's hazard relative to the age‐matched IGF‐1 quintile 3 is shown for (a) mortality, (b) dementia, (c) diabetes, (d) vascular disease, (e) osteoporosis, and (f) cancer. The area of each dot is proportional to the number of individuals it represents, and error bars indicate 95% confidence intervals for hazard ratiosCC BY · PubMed Central
FIGURE 5 The U‐shape and age‐interaction effects are consistent across varied conditions in a combined Cox model. The (IGF‐1)2 term represents the U‐shape effect, while the Age*IGF‐1 term represents the age‐interaction effect. A linear IGF‐1 term, age, and sex are also included as covariates
FIGURE 5 The U‐shape and age‐interaction effects are consistent across varied conditions in a combined Cox model. The (IGF‐1)2 term represents the U‐shape effect, while the Age*IGF‐1 term represents the age‐interaction effect. A linear IGF‐1 term, age, and sex are also included as covariatesCC BY · PubMed Central

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Citations

Cites

Show all 8 references

Research works printed but not linked: 36

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Metadata

Authors
Zhang, W. B., Ye, K., Barzilai, N., & Milman, S.
Affiliations
  • Department of Medicine Albert Einstein College of Medicine Bronx New York USA
  • Department of Epidemiology and Population Health Albert Einstein College of Medicine Bronx New York USA
ORCID
Zhang, William B.
Venue
Aging Cell
Publisher
Wiley
Published
2021-08-07
Volume
20
Issue
9
ISSN
  • 1474-9718
  • 1474-9726
DOI
10.1111/acel.13443
PMC
PMC8441393
Cited by
62
References
8
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institute on Aging (K23AG051148, R01AG061155, T32AG023475‐18)
  • American Federation for Aging Research

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