Circulating IGF-1 and the Regulation of Healthspan, Pathology and Lifespan

 

Funded by the National Institute on Aging

Previous studies have provided compelling evidence that the Growth Hormone (GH)–IGF-1 axis is a conserved pathway important for determination of both healthspan and lifespan in diverse organisms. Nevertheless, controversies related to the effects of these hormones remain and will continue until appropriate and translationally relevant animal models that can be developed and used to regulate GH and IGF-1 levels throughout the lifespan. We and our colleagues in several scientific consensus reports have recognized the necessity of new animal models for advancement of the field. The ongoing studies in our laboratory use novel animal models and interventions that are designed to produce one of the most comprehensive and rigorous analyses of the effects of age-related changes in IGF-1 on pathology and lifespan using a pre-clinical, translationally relevant approach.

Data from several rodent models indicate that lifelong deficiency of GH and/or IGF-1 or perturbations that suppress their signaling pathways result in increased lifespan, reduced age-related pathologies and beneficial effects on cardiac and cognitive function. Nevertheless, the concept that reduced levels or signaling of these hormones are beneficial for the aging organism remains controversial since there are numerous studies that have reported beneficial effects of GH and/or IGF-1 replacement on the aging cardiovascular system and an overwhelming database indicating beneficial effects of these hormones on the aging brain. The question of whether GH and IGF-1 deficiency is directly associated with increased longevity and whether GH and/or IGF-1 replacement have beneficial effects on individual organ systems (e.g. healthspan) remains a seminal question in the field of biogerontology. This controversy will continue until appropriate and translationally relevant animal models that can be used to regulate GH and IGF-1 levels throughout the lifespan are available. The on-going experiments are in response to NIH Program Announcement -10-014 (Development and Characterization of Animal Models for Aging Research) and our goal is to conduct translationally relevant mechanistic studies as well as basic lifespan, metabolic, behavioral and pathological analyses to address the hypothesis that circulating IGF-1 deficiency increases healthspan, in part, by suppressing the NRF2 cellular antioxidant response pathway resulting in reduced neoplastic disease. Paradoxically, IGF-1 deficiency increases oxidative stress within the vasculature and brain and impairs function. These effects are dependent on paracrine (local) expression of IGF-1 and is sensitive to the age that IGF-1 deficiency is induced. The following specific aims are in progress: 1) Analyze the effects of hepatic IGF-1 deficiency initiated peri-natally by crossing alb-cretg/+ and igff/f mice or post-natally at 30 days, 6 or 16 months by injecting the igff/f mouse with TBG-iCre-AAV8 or control vectors and assessing effects on lifespan and end-of-life pathology; 2) Determine the effects of IGF-1 deficiency initiated peri-natally or at 30 days, 6 or 16 months of age on a) accumulation of age-specific pathological changes using a cross-sectional design, b) paracrine IGF-1 gene and protein expression, c) circulating hormone levels as well as whole body insulin action, glucose production and rates of glucose utilization in individual tissues; and 3) Assess whether hepatic IGF-1 deficiency initiated peri-natally or at 30 days, 6 or 16 months of influences cellular redox homeostasis and inflammatory processes in vasculature, heart, liver, brain, muscle and kidney during aging through the NRF2 pathway. The studies presented are designed to produce one of the most comprehensive and rigorous analyses of the effects of IGF-1 deficiency on pathology and lifespan using a pre-clinical, translationally relevant approach.

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