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Meta-Analysis Discovers Goldilocks Zone for IGF-1

In biology, there can be too little of a bad thing.

Balanced stonesBalanced stones
 

A new meta-analysis from Aging Cell has shown that both high and low levels of IGF-1 are related to mortality risk [1].

Insulin-like growth factor 1 (IGF-1)

IGF-1 is one of the body’s major metabolic hormones. It can have effects similar to insulin, and it mediates the effects of growth hormone. IGF-1 has growth-promoting effects in almost every tissue, inhibiting apoptosis and increasing the synthesis of proteins and DNA [2]. High expression of IGF-1 has been shown to reduce lifespan and healthspan in worms, mice, and flies [3-5]. In fact, the expression of very low levels of IGF-1 has increased mouse lifespan by as much as 40% [6].

Serum levels of IGF-1 are commonly measured in the clinic. This has provided researchers with a wealth of data on the hormone, but studies of IGF-1 levels in humans have shown mixed results. High IGF-1 is associated with an increased risk of several cancers [7]. However, low levels of IGF-1 are associated with diseases such as cardiovascular disease, diabetes, and frailty [8]. Many studies have linked both high and low levels of IGF-1 to mortality, while others have found no relationship [9].

Because of these conflicting results, it is unclear whether there is any value in measuring IGF-1 to predict remaining lifespan. However, an international collaboration of researchers recently conducted a meta-analysis of these findings to determine if an ideal range exists for IGF-1 to predict all-cause mortality [1].

IGF-1 shows a U-shaped relationship with mortality

19 studies that included a total of 30,876 participants were included in the meta-analysis. The studies were conducted from 2007 to 2018 and included populations from the United States, Japan, China, and various European nations.

First, the authors looked at high versus low IGF-1 and mortality, similar to the methodology of previous studies. In this analysis, no difference in risk of death was found between the high and low levels of IGF-1 groups.

Rather than only grouping participants into “high” and “low” levels of IGF-1, 9 of the studies included detailed enough information to conduct a dose-response meta-analysis. This analysis showed a U-shaped response, with both the lowest levels and highest levels of IGF-1 being associated with higher mortality.

The researchers then analyzed their dataset using an intermediate group that approximately aligned with the lowest mortality from the dose-response analysis (120-160 ng/mL). With low, intermediate, and high IGF-1 groupings, mortality risk still did not differ between high and low IGF-1 levels. However, the intermediate group had statistically significant lower mortality risks than both the high and the low groups. These findings did not change when the intermediate range was expanded to 100-180 ng/mL IGF-1 or when excluding studies that did not include participants older than 70.

Lastly, researchers used the Third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) to see which dietary differences were correlated with IGF-1. Higher consumption of proteins, carbohydrates, and 13 different vitamins and minerals were associated with higher IGF-1 levels, as were eggs, milk, cheese, yogurt, and butter. These findings were similar to previous studies and confirm that IGF-1 levels can be modified by dietary changes.

In conclusion, by analyzing and comparing different ranges of IGF-1 in 30,876 subjects, we find that both high and low levels of IGF-1 increase mortality risk, and for the first time, we identify a specific mid-range being associated with the lowest mortality (120–160 ng/ml). Using the NHANES III survey, we show an association between high intake of animal proteins, carbohydrates, and milk-based products and IGF-1 levels. These results can point to diagnostic, nutritional, and pharmacological strategies to optimize IGF-1 levels and help reduce mortality.

Conclusion

IGF-1 has been of great interest to longevity researchers due to its key role in metabolism, influence on healthspan and lifespan in model organisms, and association with mortality in humans. Its association with mortality has been scrutinized in recent years with the publication of several seemingly conflicting results. This study appears to explain these contradictory findings by identifying the relationship between IGF-1 and mortality as U-shaped rather than linear.

As always, the conclusions that can be drawn from these sorts of studies are limited. It cannot be said whether low and high IGF-1 contributed to mortality in these participants or if it was simply correlated. Additionally, it is well established in the scientific literature that studies with nonsignificant results disproportionately go unpublished. While the authors did not detect any publication bias in their statistical analysis, meta-analyses can only be as good as the studies that go into them.

Ultimately, these results do well to highlight the complexity of aging biology. It is not always enough to simply lower the concentration of a protein that is problematic at high levels or raise one that is problematic at low levels. If the concentration is raised or lowered too far, it can become problematic once again. If the level of IGF-1 is a contributor to aging (as opposed to simply the result of aging), this study highlights for the first time an ideal “healthy” range and includes several dietary measures that may be used to modulate its concentration in the body.

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Literature

[1] Rahmani, J. et al. Association between IGF-1 levels ranges and all-cause mortality: A meta-analysis. Aging Cell (2022). https://doi.org/10.1111/acel.13540

[2] Clemmons, D.R. Metabolic actions of insulin-like growth factor-I in normal physiology and diabetes. Endocrinology and Metabolism Clinics of North America (2012). https://doi.org/10.1016%2Fj.ecl.2012.04.017

[3] Fontana, L., Partridge, L., & Longo, V.D. Extending healthy lifespan—From yeast to humans. Science (2010). https://doi.org/10.1126/scien ce.1172539

[4] Kenyon, C. A pathway that links reproductive status to lifespan in Caenorhabditis elegans. Annals of the New York Academy of Sciences (2010). https://doi.org/10.1111/j.1749-6632.2010.05640.x

[5] Podshivalova, K., Kerr, R. A., & Kenyon, C. How a mutation that slows aging can also disproportionately extend end-of-life decrepitude. Cell Reports (2017). https://doi.org/10.1016/j.celrep.2017.03.062

[6] Bartke, A., Sun, L.Y., & Longo, V. Somatotropic signaling: Trade-offs between growth, reproductive development, and longevity. Physiological Reviews (2013). https://doi.org/10.1152/physr ev.00006.2012

[7] Renehan, A.G. et al. Insulin-like growth factor (IGF)-I, IGF binding protein-3, and cancer risk: Systematic review and meta-regression analysis. The Lancet (2004). https://doi.org/10.1016/s0140-6736(04)16044-3

[8] Higashi, Y. et al. IGF-1, oxidative stress and atheroprotection. Trends in Endocrinology & Metabolism (2010). https://doi.org/10.1016/j.tem.2009.12.005

[9] Burgers, A.M.G. et al. Meta-analysis and dose-response metaregression: Circulating insulin-like growth factor I (IGF-I) and mortality. The Journal of Clinical Endocrinology & Metabolism (2011). https://doi.org/10.1210/jc.2011-1377

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About the author

Greg Gillispie

Greg is a recent graduate from the Wake Forest Institute for Regenerative Medicine. He strongly believes that age-related diseases have common underlying mechanisms at play and that an ounce of prevention is worth a pound of cure. In addition to writing for LEAF, Greg continues to conduct laboratory research in stem cell regeneration and cellular senescence. He is also an avid runner, curious reader, proud dog owner, and a board game enthusiast.
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