The insulin paradox: aging, proteotoxicity and neurodegeneration

Nat Rev Neurosci. 2008 Oct;9(10):759-67. doi: 10.1038/nrn2474. Epub 2008 Sep 4.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Aging / metabolism*
  • Animals
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / physiopathology
  • Humans
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Insulin / metabolism*
  • Insulin-Like Growth Factor I / metabolism*
  • Longevity / physiology
  • Nerve Tissue Proteins / metabolism*
  • Neurodegenerative Diseases / metabolism*
  • Signal Transduction / physiology

Substances

  • Insulin
  • Nerve Tissue Proteins
  • Insulin-Like Growth Factor I