The insulin paradox: aging, proteotoxicity and neurodegeneration

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Abstract
Aging is the single major risk factor for the development of human neurodegenerative diseases. Typically, familial mutation-linked neurodegeneration emerges during the fifth decade of life, whereas the onset of sporadic neurodegenerative disease is usually during the seventh decade or later. Human neurodegenerations share a tight mechanistic link to toxic protein aggregation. Insulin/insulin-like growth factor 1 (IGF1) signalling (IIS) is a prominent lifespan and stress-resistance regulator. Altering aging by reducing IIS protects model animals from the toxicity that is associated with the aggregation of disease-linked proteins. Two opposing mechanisms mediate the counter-toxic effect of a reduction in IIS: disaggregation and active aggregation. These protective activities are regulated by heat-shock factor 1 (HSF1) and by the IIS downstream transcription factor DAF-16, respectively. Contradictory data indicate that IGF1 infusion protects rodents from the aggregation that is associated with the Alzheimer's-disease-linked peptide amyloid-β. A model that predicts an optimal IIS level could accommodate this apparent paradox.