Longevity and stress resistance
The therapeutic potential of heat shock factor-1 (HSF-1) is immense. In the nematode C. elegans, it is responsible for stress resistance and mediates protection from neurodegeneration-linked toxic protein aggregation. The activity of this factor is negatively regulated by the insulin/IGF-signalling (IIS) pathway, therefore the inhibition of this signalling pathway activates HSF-1 conferring protection from toxic protein aggregation and promoting longevity. The HSF-1 LONGEVITY/PROT project has investigated the timing associated with HSF-1 and aggregation of peptide Aβ 1-42 associated with Alzheimer's disease. The researchers also looked at co-factors in operation when the longevity window is open. In the nematode C. elegans, HSF-1 acts during development to enable DAF-16 to promote stress resistance and protection from proteotoxicity during adulthood. This is achieved by inducing expression of genes that encode for proteins which serve as DAF-16 co-factors. Two of these, gtr-1 and nhl-1, are associated with DAF-16. Results showed that although providing partial protection from the aggregation of the Alzheimer's-associated peptide Aβ1-42, gtr-1 knockdown has no effect on longevity. nhl-1 has similar properties and its expression is regulated by the IIS; it is expressed in chemosensory neurons and its knock-down reduces stress resistance and provides protection from toxic protein aggregation. Project results have provided a sound platform on which to base further development of therapeutic strategies based on IIS reduction for late-onset disorders such as Alzheimer's disease. Treatment would involve selective manipulation of the ageing process. The work on gtr-1 has already featured in The Journal of Neuroscience, and publication of the research on nhl-1 is expected in the near future.
