September 3, 2014
Lower Insulin-like Growth Factor-1 and Live Longer?
Study suggests low levels of IGF-1 increase longevity
A groundbreaking study recently suggested that low levels of insulin-like growth factor-1 (IGF-1) may predict life expectancy in exceptionally long-lived individuals.
Milman S, Atzmon G, Huffman DM, et al. Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell. 2014;13(4):769-771. Epub 2014 Mar 12.
Low levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are associated with longer lifespan in several animal models. This study attempts to confirm a similar effect in humans by measuring IGF-1 levels in very long-lived people.
A group of 184 people in their 90s were divided by IGF-1 levels into 2 groups: a low IGF-1 group and a high IGF-1 group. There were 93 people in the low IGF-1 group (mean 55 ng/mL) and 91 people in the high IGF-1 group (mean 121 ng/mL). Mean age was 96.8 years in the low group and 96.7 years in the high group.
Kaplan-Meier analysis of overall mortality was constructed and compared between low and high IGF-1 groups.
Very old women with IGF-1 levels below the median had significantly longer survival compared with females with levels above the median. This survival advantage was not observed in males. In both males and females with a history of cancer, lower IGF-1 levels predicted longer survival (P<0.01). IGF-1 level remained a significant predictor of survival duration in linear regression models after multivariable adjustment in females (P=0.01) and individuals with a history of cancer (P<0.01). This may be the first time that low IGF-1 levels have been shown to predict life expectancy in exceptionally long-lived individuals.
Scientific understanding of IGF-1 is rapidly advancing. IGF-1 plays a central role in cellular growth, differentiation, survival, and cell cycle progression.1 Increasing or decreasing IGF-1 levels may prove to be fundamental in changing long-term outcomes in our patient population, in particular cancer survivors. IGF-1, while necessary to good health, may be harmful in excess.
The best evidence of this two-fold action is seen in people who have Laron Syndrome (LS), which is characterized by a deficiency of IGF-1 and resistance to GH. Since 1966, when Zvi Laron, MD, first described this condition, about 300 people with LS have been identified, about one third of whom live in a single village in Ecuador while most of the rest are scattered across the Middle East.2 Babies born with LS grow slowly and if untreated (synthetic IGF-1 is now available as a therapy) reach final heights of only 39 in to 54 in. Their limbs, hands, feet, organs, and facial features are all abnormally small.3 Clearly IGF-1 is necessary for growth and development. On the other hand, people with LS do not get diabetes, rarely if ever get cancer, and typically live to an advanced age.4 It is not all bad news, particularly as this relates to cancer.
High IGF-1 levels are associated with increased risk for most, if not all, cancers,5 including prostate,6,7 colorectal,8 multiple myeloma,9 breast,10,11 lung,12 thyroid,13 bone,14 brain,14 and ovarian cancers.14 Being tall as a child increases risk of all types of solid tumors and blood malignancies later in life.14,15 The data from this current study suggest low IGF-1 may also improve survivorship in cancer patients.
The biggest predictor of IGF-1 is dietary protein intake. The higher the percentage of daily calories derived from protein (animal protein rather than vegetable protein), the higher a person’s IGF-1 level. This may explain why high dietary protein is linked with numerous diseases, particularly cancer and diabetes.
This is the explanation that Levine et al give in their recent study that reported high dietary protein during middle age increases morbidity and mortality years later. Low protein intake during middle age is associated with lower mortality. High protein diets are associated with a 75% increase in overall mortality and a four-fold increase in cancer death risk. Where this gets complicated is that Levine reported that the association between low IGF-1 levels and mortality changes with age. Their data suggested high dietary protein was associated with reduced cancer diagnosis and lower mortality in patients after age 65.16
For obvious reasons, lowering IGF-1 may prove useful in cancer treatment17 at least in people younger than 65.
Several strategies are now used to lower IGF-1: caloric restriction, exercise, and fasting.18-21 Reducing protein may lower IGF-1 in humans more effectively than caloric restriction.22 In older women, high dietary folate is associated with low IGF-1.23 Perhaps this is an argument for eating green leafy vegetables: How naturopathic can you get? Use of proton pump inhibitors is also associated with low IGF-1 levels.24 Eating green leafy vegetables and taking omeprazole? Not so naturopathic!
Maintaining higher IGF-1 levels may be important for some particular patients. IGF-1 protects the brain from aging, reduces risk of stroke and Alzheimer’s disease,25 may help stroke patients recover faster,26,27and prevents osteoporosis.28
- Yakar S, Courtland HW, Clemmons D. IGF-1 and bone: New discoveries from mouse models. J Bone Miner Res. 2010;25(12):2543-2552.
- Bai N. Defective growth gene in rare dwarfism disorder stunts cancer and diabetes. Sci Am. February 17, 2011. Available at: http://www.scientificamerican.com/article/defective-growth-gene-in-dwarfism/. Accessed August 21, 2014.
- Laron Z. Insulin-like growth factor 1 (IGF-1): a growth hormone. Mol Pathol. 2001;54(5):311-316.
- Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011;3(70):70ra13.
- Cromie WJ. Growth factor raises cancer risk. Harvard University Gazette. April 22, 1999. Available at: http://www.news.harvard.edu/gazette/1999/04.22/igf1.story.html. Accessed August 21, 2014.
- Nimptsch K, Platz EA, Pollak MN, et al. Plasma insulin-like growth factor 1 is positively associated with low-grade prostate cancer in the Health Professionals Follow-up Study 1993-2004. Int J Cancer. 2011;128(3):660-667.
- Chan JM, Stampfer MJ, Ma J, et al. Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 as predictors of advanced-stage prostate cancer. J Natl Cancer Inst. 2002;94(14):1099-1106.
- Wei EK, Ma J, Pollak MN, Rifai N, Fuchs CS, Hankinson SE, Giovannucci E. A prospective study of C-peptide, insulin-like growth factor-I, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev. 2005;14(4):850-855.
- Birmann BM, Tamimi RM, Giovannucci E, et al. Insulin-like growth factor-1- and interleukin-6-related gene variation and risk of multiple myeloma. Cancer Epidemiol Biomarkers Prev. 2009;18(1):282-288.
- Kang HS, Ahn SH, Mishra SK, et al. Association of polymorphisms and haplotypes in the insulin-like growth factor 1 receptor (IGF1R) gene with the risk of breast cancer in Korean women. PLoS One. 2014;9(1):e84532.
- Kaaks R, Johnson T, Tikk K, et al. Insulin-like growth factor I and risk of breast cancer by age and hormone receptor status—A prospective study within the EPIC cohort. Int J Cancer. 2014;134(11):2683-2690.
- Cao H, Wang G, Meng L, et al. Association between circulating levels of IGF-1 and IGFBP-3 and lung cancer risk: a meta-analysis. PLoS One. 2012;7(11):e49884.
- Schmidt JA, Allen NE, Almquist M, et al. Insulin-like growth factor-I and risk of differentiated thyroid carcinoma in the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev. 2014;23(6):976-985. Epub 2014 Mar 19.
- Weroha SJ, Haluska P. The insulin-like growth factor system in cancer. Endocrinol Metab Clin North Am. 2012;41(2):335-350.
- Kabat GC, Anderson ML, Heo M, et al. Adult stature and risk of cancer at different anatomic sites in a cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2013;22(8):1353-1363.
- Levine ME, Suarez JA, Brandhorst S, et al. Low protein intake is associated with a major reduction in IGF-1, cancer, and overall mortality in the 65 and younger but not older population. Cell Metab. 2014;19(3):407-417.
- Arnaldez FI, Helman LJ. Targeting the insulin growth factor receptor 1. Hematol Oncol Clin North Am. 2012;26(3):527-542.
- Redman LM, Veldhuis JD, Rood J, Smith SR, Williamson D, Ravussin E; Pennington CALERIE Team. The effect of caloric restriction interventions on growth hormone secretion in nonobese men and women. Aging Cell. 2010;9(1):32-39.
- Kari FW, Dunn SE, French JE, Barrett JC. Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction. J Nutr Health Aging. 1999;3(2):92-101.
- Tam CS, Frost EA, Xie W, Rood J, Ravussin E, Redman LM; Pennington CALERIE Team. No effect of caloric restriction on salivary cortisol levels in overweight men and women. Metabolism. 2014;63(2):194-198.
- Wright JL, Plymate S, D’Oria-Cameron A, et al. A study of caloric restriction versus standard diet in overweight men with newly diagnosed prostate cancer: a randomized controlled trial. Prostate. 2013;73(12):1345-1351.
- Fontana L, Weiss EP, Villareal DT, Klein S, Holloszy JO. Long-term effects of calorie or protein restriction on serum IGF-1 and IGFBP-3 concentration in humans. Aging Cell. 2008;7(5):681-687.
- Carraro S, Veronese N, Bolzetta F, et al. Association between dietary folate intake and serum insulin-like growth factor-1 levels in healthy old women. Growth Horm IGF Res. 2013;23(6):267-271.
- Maggio M, Lauretani F, De Vita F, et al. Relationship between use of proton pump inhibitors and IGF system in older subjects. J Nutr Health Aging. 2014;18(4):420-423.
- Iso H, Maruyama K, Ikehara S, Yamagishi K, Tamakoshi A. Cellular growth factors in relation to mortality from cardiovascular disease in middle-aged Japanese: the JACC study. Atherosclerosis. 2012;224(1):154-160.
- Dong X, Chang G, Ji XF, Tao DB, Wang YX. The relationship between serum insulin-like growth factor I levels and ischemic stroke risk. PLoS One. 2014;9(4):e94845.
- Westwood AJ, Beiser A, Decarli C, et al. Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy. Neurology. 2014;82(18):1613-1619. Epub 2014 Apr 4.
- Chin KY, Ima-Nirwana S, Mohamed IN, et al. Insulin-like growth factor-1 is a mediator of age-related decline of bone health status in men. Aging Male. 2014;17(2):102-106. Epub 2014 Mar 5.