Throughout nature, a decrease in growth, and hence body size within species is associated with increased lifespan. Moreover, lifespan extension resulting from mutations of single genes in the insulin/IGF signaling pathway has pioneered and revolutionized modern studies on the biology of aging. Because epidemiologic studies suggest that low peripheral IGF-1 is associated with a lower risk of cancer but increase risk of CVD, stroke, T2DM, and osteoporosis, we question if all the evidence from other models are relevant to humans. In addition to the known benefits of peripheral and central IGF-1, we have recently uncovered novel positive effects of central IGF-1 action on the periphery, and here we suggest that strategies designed to """"""""tip the balance"""""""" of IGF-1 action from peripheral to central may maximize the 'good'effects of IGF-1 while minimizing the 'bad'effects of IGF-1 on cancer risk. Indeed, our lab has recently uncovered remarkable positive effects of central IGF-1 action including improved peripheral insulin action and selective depletion of visceral fat, suggesting that some actions of IGF-1 may be favorable for aging. This is in contrast to the purported 'bad'effects of peripheral IGF-1 which is linked to increased cancer risk. The overall hypothesis of the research plan is that healthy aging and longevity is best achieved by increasing IGF-1 action in the hypothalamus to reap the 'good'effects while decreasing it in the periphery to avoid the 'bad'effects, such as cancers. Ultimately, these studies may yield important new insights regarding the complex role of IGF-1 on health and aging with relevance to humans. In order to test the overall hypothesis;
Aim 1 will focus on the contribution of the hypothalamus in mediating an acute central or peripheral IGF-1 infusion on insulin action by hyperinsulinemic-euglycemic clamp in young and old rats and assess hypothalamic signaling pathways stimulated by IGF-1.
Aim 2 focuses on the contribution of the hypothalamus in mediating chronic central or peripheral IGF-1 treatment on body fat distribution and insulin action. The goal of Aim 3 will be to study the lifelong effects of chronic central IGF-1 overexpression by lentivirus targeted to the hypothalamus and lifelong peripheral IGF-1 receptor blockade with an antibody, alone or in combination, on healthy aging and longevity in rats.

Public Health Relevance

Growth hormone/IGF-1 axis is central in aging and longevity, and controversial and it's translation to treatment. Here we suggest that strategies designed to tip the balance of IGF-1 action from peripheral to brain may maximize the good effects of IGF-1 while minimizing the bad effects of IGF-1 on cancer risk, leading to healthy life-span.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG018381-14
Application #
8523705
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Finkelstein, David B
Project Start
2000-09-01
Project End
2015-05-31
Budget Start
2013-09-01
Budget End
2014-05-31
Support Year
14
Fiscal Year
2013
Total Cost
$309,105
Indirect Cost
$122,897
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461
Huffman, Derek M; Farias Quipildor, Gabriela; Mao, Kai et al. (2016) Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline. Aging Cell 15:181-6
Callisaya, Michele L; Ayers, Emmeline; Barzilai, Nir et al. (2016) Motoric Cognitive Risk Syndrome and Falls Risk: A Multi-Center Study. J Alzheimers Dis 53:1043-52
Milman, Sofiya; Huffman, Derek M; Barzilai, Nir (2016) The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research. Cell Metab 23:980-9
Longo, Valter D; Antebi, Adam; Bartke, Andrzej et al. (2015) Interventions to Slow Aging in Humans: Are We Ready? Aging Cell 14:497-510
Milman, Sofiya; Barzilai, Nir (2015) Dissecting the Mechanisms Underlying Unusually Successful Human Health Span and Life Span. Cold Spring Harb Perspect Med 6:a025098
Verghese, Joe; Annweiler, Cedric; Ayers, Emmeline et al. (2014) Motoric cognitive risk syndrome: multicountry prevalence and dementia risk. Neurology 83:718-26
Milman, Sofiya; Atzmon, Gil; Huffman, Derek M et al. (2014) Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity. Aging Cell 13:769-71
Verghese, Joe; Ayers, Emmeline; Barzilai, Nir et al. (2014) Motoric cognitive risk syndrome: Multicenter incidence study. Neurology 83:2278-84
Einstein, Francine; Thompson, Reid F; Bhagat, Tushar D et al. (2010) Cytosine methylation dysregulation in neonates following intrauterine growth restriction. PLoS One 5:e8887
Huffman, Derek M; Barzilai, Nir (2010) Contribution of adipose tissue to health span and longevity. Interdiscip Top Gerontol 37:1-19

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