The insulin paradox: aging, proteotoxicity and neurodegeneration

• Published in: Nature reviews. Neuroscience Vol. 9; no. 10; pp. 759 - 767
• Main Authors: Cohen, Ehud, Dillin, Andrew
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.10.2008
• Subjects: Aging; Aging - metabolism; Animals; Biological and medical sciences; Degeneration; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Diabetes Mellitus - metabolism; Diabetes Mellitus - physiopathology; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Homeostasis; Humans; Inclusion Bodies - metabolism; Inclusion Bodies - pathology; Insulin; Insulin - metabolism; Insulin-Like Growth Factor I - metabolism; Longevity - physiology; Medical sciences; Nerve Tissue Proteins - metabolism; Nervous system; Neurodegeneration; Neurodegenerative Diseases - metabolism; Neurology; Physiological aspects; Polypeptides; Protein folding; Signal Transduction - physiology; Toxicity; United States; Endocrinopathy; Human; Pancreatic hormone; Skin disease; Toxicity; Diabetes mellitus; Review; Insulin like growth factor 1; Metabolism; Temporal pattern; Insulin; Protein; Stress; Infection; Familial disease; Treatment; Erythema infectiosum
• ISSN: 1471-003X; 1471-0048; 1469-3178
• DOI: 10.1038/nrn2474

Distinct human neurodegenerative diseases share remarkably similar temporal emergence patterns, even though different toxic proteins are involved in their onset. Typically, familial neurodegenerative diseases emerge during the fifth decade of life, whereas sporadic cases do not exhibit symptoms earlier than the seventh decade. Recently, mechanistic links between the aging process and toxic protein aggregation, a common hallmark of neurodegenerative diseases, have been revealed. The insulin/insulin-like growth factor 1 (IGF1) signalling pathway - a lifespan, metabolism and stress-resistance regulator - links neurodegeneration to the aging process. Thus, although a reduction of insulin signalling can result in diabetes, its reduction can also increase longevity and delay the onset of protein-aggregation-mediated toxicity. Here we review this apparent paradox and delineate the therapeutic potential of manipulating the insulin/IGF1 signalling pathway for the treatment of neurodegenerative diseases.