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The insulin paradox: aging, proteotoxicity and neurodegeneration

Key Points

  • 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.

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.

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Figure 1: The Caenorhabditis elegans IIS pathway.
Figure 2: The IIS pathway links aging and proteotoxicity.
Figure 3: Optimal-IIS-rate model.
Figure 4: Age-associated decline of counter-proteotoxic activities leads to late-onset neurodegeneration.

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Andrew Dillin is the founder of Prosteosis Therapeutics, Inc.

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DATABASES

Entrez-Gene 

α-synuclein

AGE-1

AKT2

APP

DAF-2

DAF-16

DAF-18

IGF1

Igf1r

IRS2

IST-1

PHA-4

sir-2

SKN-1

OMIM

AD

HD

PD

Glossary

Youthfulness

The physical capabilities and conditions, such as agility, speed of crawling, rate of food intake and tissue integrity, that are typical of young but not old animals.

Proteostasis

The favourable protein-homeostasis condition, in which the protein's composition, distribution, integrity, folding and protein–protein interactions are properly maintained, enabling optimal function at the cellular level.

Protein folding

The post-translational process that a polypeptide has to complete in order to attain its optimal three-dimensional structure. Protein folding is often assisted by chaperones. Proteins that fail to achieve their correct folding are termed 'misfolded proteins'.

Proteome

All of the functional proteins in a cell at a certain time point. The proteome can change as a function of age, stress conditions, et cetera.

Amyloid-β

(Aβ). A highly aggregative peptide that is associated with and causative of AD.

PolyQ

A stretch of glutamine repeats in a protein sequence. Abnormally long polyQ stretches are associated with various diseases, including HD.

Protofibril

A small, soluble protein aggregate that is thought to be the cause of various neurodegenerative maladies.

Long-term potentiation

(LTP). A long-lasting form of synaptic plasticity that results in an increase in the strength of synaptic transmission and is thought to be critical for memory function.

Transcriptome

The gene network that is regulated by an activated transcription factor under certain conditions. Different transcriptomes can be regulated by the same transcription factor under distinct conditions.

Protein clearance

A set of cellular activities aimed at identifying misfolded proteins, targeting them to specialized degradation complexes and mediating their digestion by specialized degradation machineries, such as proteasomes or lysosomes.

RNA interference

(RNAi). A technique used to knock down the expression of a specific gene by introducing a double stranded RNA molecule that complements the gene of interest and triggers the degradation of the gene's mRNA molecules.

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Cohen, E., Dillin, A. The insulin paradox: aging, proteotoxicity and neurodegeneration. Nat Rev Neurosci 9, 759–767 (2008). https://doi.org/10.1038/nrn2474

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