IGF-I and the aging mammalian brain

Insulin-like growth factors (IGFs) are important modulators of organismal life-span all along phylogeny. These growth factors are widely viewed as detrimental for long life by reducing tissue resistance to oxidative stress. However, IGF-I has been consistently shown to be a potent neuroprotective factor in mammals, and as such, a deterrent of brain aging. Conversely, recent data suggest that IGF-I may contribute to amyloid neurodegeneration underlying Alzheimer's disease. These opposing observations underline an incomplete understanding of the significance of this ancestral hormone pathway in relation to brain aging. It is possible that these opposite results are the consequence of using different experimental approaches. Thus, brain amyloid injury is reduced in mutant mice partially defective in IGF-I receptor function, whereas IGF-I is neuroprotective when administered to animal models of neurodegenerative disease or normal brain aging. This approach-dependent effect of IGF-I highlights a fundamental gap in our knowledge of the relationship between peripheral and brain IGF-I function and the actual biological impact of experimental modulation of brain IGF-I function. We suggest to directly address brain IGF-I function in the varying experimental approaches used to confirm that changes have taken place in the desired way.

[1]  Pablo Blinder,et al.  Reduced IGF-1 Signaling Delays Age-Associated Proteotoxicity in Mice , 2009, Cell.

[2]  F. Metzger,et al.  Therapeutic actions of insulin-like growth factor I on APP/PS2 mice with severe brain amyloidosis , 2006, Neurobiology of Aging.

[3]  J. Bourhis,et al.  Mechanisms of Disease: signaling of the insulin-like growth factor 1 receptor pathway—therapeutic perspectives in cancer , 2007, Nature Clinical Practice Oncology.

[4]  N. Hooper,et al.  Increased circulating insulin-like growth factor-1 in late-onset Alzheimer's disease. , 2007, Journal of Alzheimer's disease : JAD.

[5]  M. Schwartz,et al.  Butovsky, O. et al. Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. Proc. Natl Acad. Sci. USA 103, 11784-11789 , 2006 .

[6]  W. Sonntag,et al.  Insulin-like growth factor-1 ameliorates age-related behavioral deficits , 1998, Neuroscience.

[7]  E. D. Haan,et al.  Insulin-like growth factor-I and cognitive function in healthy older men. , 1999, The Journal of clinical endocrinology and metabolism.

[8]  A. Aleman,et al.  Circulating insulin-like growth factor I and cognitive function: Neuromodulation throughout the lifespan , 2009, Progress in Neurobiology.

[9]  T. Gómez-Isla,et al.  Serum insulin-like growth factor I regulates brain amyloid-β levels , 2002, Nature Medicine.

[10]  I. Torres-Aleman,et al.  Toward a comprehensive neurobiology of IGF‐I , 2010, Developmental neurobiology.

[11]  M. Adams,et al.  Stability of local brain levels of insulin-like growth factor-I in two well-characterized models of decreased plasma IGF-I , 2009, Growth factors.

[12]  S. Bennett,et al.  Age and insulin-like growth factor-1 modulate N-methyl-D-aspartate receptor subtype expression in rats , 2000, Brain Research Bulletin.

[13]  C. Bondy,et al.  Insulin-like growth factor-1 promotes neuronal glucose utilization during brain development and repair processes. , 2002, International review of neurobiology.

[14]  N. Kato,et al.  Use of serum insulin-like growth factor-I levels to predict psychiatric non-response to donepezil in patients with Alzheimer's disease. , 2008, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[15]  M. Mimura,et al.  Preliminary use of insulin-like growth factor-I as a biomarker for sorting high-dose donepezil responders among Japanese patients with Alzheimer's disease , 2010, Regulatory Peptides.

[16]  I. Torres-Aleman,et al.  Role of insulin-like growth factor I signaling in neurodegenerative diseases , 2004, Journal of Molecular Medicine.

[17]  T. Katagiri,et al.  Relationship Between Serum Insulin‐Like Growth Factor‐1 Levels and Alzheimer's Disease and Vascular Dementia , 2005, Journal of the American Geriatrics Society.

[18]  Elizabeth J. Robertson,et al.  Role of insulin-like growth factors in embryonic and postnatal growth , 1993, Cell.

[19]  Martin Holzenberger,et al.  IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice , 2003, Nature.

[20]  P. Ye,et al.  The role of the insulin-like growth factors in the central nervous system , 1996, Molecular Neurobiology.

[21]  D. Leahy,et al.  Functionally significant insulin-like growth factor I receptor mutations in centenarians , 2008, Proceedings of the National Academy of Sciences.

[22]  C. Kenyon.  A Conserved Regulatory System for Aging , 2001, Cell.

[23]  S. Duan,et al.  Acute and gradual increases in BDNF concentration elicit distinct signaling and functions in neurons , 2010, Nature Neuroscience.

[24]  J. Muntané,et al.  Low doses of insulin-like growth factor-I induce mitochondrial protection in aging rats. , 2008, Endocrinology.

[25]  I. Torres-Aleman,et al.  Oral Administration of a GSK3 Inhibitor Increases Brain Insulin-like Growth Factor I Levels* , 2010, The Journal of Biological Chemistry.

[26]  I. Torres-Aleman,et al.  Central actions of liver-derived insulin-like growth factor I underlying its pro-cognitive effects , 2007, Molecular Psychiatry.

[27]  Tracy M. Brown,et al.  Peripheral elevation of IGF-1 fails to alter Abeta clearance in multiple in vivo models. , 2008, Biochemical pharmacology.

[28]  P. Hutchins,et al.  Decreases in cerebral microvasculature with age are associated with the decline in growth hormone and insulin-like growth factor 1. , 1997, Endocrinology.

[29]  I. Torres-Aleman,et al.  Targeting insulin-like growth factor-1 to treat Alzheimer's disease , 2007, Expert opinion on therapeutic targets.

[30]  J. Sevigny,et al.  Growth hormone secretagogue MK-677 , 2008, Neurology.

[31]  R. Klein,et al.  Brain IGF-1 Receptors Control Mammalian Growth and Lifespan through a Neuroendocrine Mechanism , 2008, PLoS biology.

[32]  I. Torres-Aleman,et al.  The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer's disease. , 2004, European journal of pharmacology.

[33]  Michal Schwartz,et al.  Glatiramer acetate fights against Alzheimer's disease by inducing dendritic-like microglia expressing insulin-like growth factor 1. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[34]  T. Kadowaki,et al.  Neuronal IGF‐1 resistance reduces Aβ accumulation and protects against premature death in a model of Alzheimer's disease , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[35]  I. Torres-Aleman,et al.  Role of serum insulin-like growth factor I in mammalian brain aging. , 2004, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[36]  E. Hafen,et al.  Extension of Life-Span by Loss of CHICO, a Drosophila Insulin Receptor Substrate Protein , 2001, Science.

[37]  S. Lovestone,et al.  Deletion of Irs2 reduces amyloid deposition and rescues behavioural deficits in APP transgenic mice , 2009, Biochemical and biophysical research communications.

[38]  F. de Pablo,et al.  Locally Born Olfactory Bulb Stem Cells Proliferate in Response to Insulin-Related Factors and Require Endogenous Insulin-Like Growth Factor-I for Differentiation into Neurons and Glia , 2003, The Journal of Neuroscience.

[39]  R. Tibshirani,et al.  Classification and prediction of clinical Alzheimer's diagnosis based on plasma signaling proteins , 2007, Nature Medicine.