ESPE Abstracts (2015) 84 PL6

The complex Relationship between the GH/IGF Axis and Aging and Longevity - the Interface with Diet and Mitochondrial Peptides

Pinchas Cohena,b

aUSC, Los Angeles, USA; bUCLA, Los Angeles, USA

Background: Growth hormone (GH) has been used for over 50 years to benefit both children with GH deficiency (GHD) and other forms of short stature as well as to correct the metabolic abnormalities found in adults with GHD (AGHD). Moreover, low IGF levels have been associated with the risk of diabetes, heart disease and osteoporosis. On the other hand, epidemiological studies suggest that high IGF-1 levels may be associated with cancer risk in the general population. Furthermore, various animal models of reduced GH and IGF-1 have been demonstrated to have increased lifespan.

Objectives and hypotheses: We wanted to establish the nature of IGF-1 and other GH-dependent factors as regulators of lifespan and healthspan in humans

Methods: A series of human cohorts, as well as studies of animal models were employed

Results: We have demonstrated that in human centenarians, rare polymorphisms of the GH and IGF receptors that confer mild resistance, are associated with exceptional longevity. However, our studies in Laron patients show that while they have improved healthspan and reduced incidence of cancer and diabetes, their mortality rates are similar to their normal relatives. We also observed a strong relationship between protein intake in humans and mice and subsequent effects on IGF levels and life expectancy. In several studies of large populations, a “U”-shaped curve of mortality versus IGF-1 levels suggested that both high and low IGF levels are potentially hazardous. Recently, we also demonstrated that GH and IGF-1 suppress the levels of the mitochondrial peptide, humanin, which is related to healthspan and lifespan.

Conclusion: The practice of IGF-based dosing is a practical approach to maintain IGF levels in the normal range during GH therapy to reduce theoretical risks. We also propose that monitoring humanin levels during GH therapy may be potentially valuable.

References: Suh et al. PNAS 2008; Guevara-Aguirre et al. Science Translational Medicine 2011; Levine et al. Cell Metab. 2014; Cohen et al. Clin Endocrinol 2014; Milman et al. Aging Cell 2014; Lee et al Aging Cell 2014.

Declaration of interest: The author is a consultant to Teva, Ascendis, Opko, and Versartis. I am a Stock-holder and consultant to CohBar Inc.

Funding: NIH, NIA.

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