22 Since both DAF-16 and HSF-1 are known to be regulators of several genes encoding heat-shock proteins,27,28 it is plausible that these transcription factors promote longevity via the maintenance of proper protein homeostasis in late stages of life.4 Several studies in mouse models have indicated that the role of the IIS as a lifespan and aging regulator is highly conserved from worms to mammals. First, knocking down one copy of the mouse IGF-1 receptor (Igf1r), the closest daf-2 orthologue in mammals,29 results
in longevity Inhibitors,research,lifescience,medical and elevated oxidative stress resistance of the animals compared to their selleck kinase inhibitor litter-mates which carry two Igf1r copies.30 Similarly, the knock-out of the insulin receptor in the adipose tissues of mice (FIRKO mice) leads to extended longevity,31 and mice lacking the insulin receptor substrate 1 (IRS1) are also long-lived.32 The findings that the regulation of aging by the insulin and IGF-1 signaling pathways are conserved in Inhibitors,research,lifescience,medical the mouse raised the question of whether these mechanisms also regulate the aging program of humans.
To address that, the activity of the IGF-1 signaling pathway was examined in centenarians (humans who lived more than a century) of different ethnicities. In a seminal study, Suh and colleagues identified mutations Inhibitors,research,lifescience,medical in the IGF-1 receptor that are correlated with decreased IGF-1 signaling to be more abundant among Jewish Ashkenazi centenarians compared to control individuals, members of families that do not exhibit extreme longevity.33 Similarly, mutations which hyper-activate FOXO3a (the DAF-16 mammalian orthologue) have been found to be linked with extreme longevity in two centenarian groups Inhibitors,research,lifescience,medical of distinct ethnicities, Japanese-Hawaiian34 and German.35 IRS2 variants were also reported to correlate with extreme longevity in an Italian subpopulation.36 Together, these studies strongly suggest that the aging-regulating mechanisms downstream of the IIS are conserved from worms to humans. SLOWING AGING PROTECTS MODEL ORGANISMS FROM NEURODEGENERATION-LINKED PROTEOTOXICITY
Inhibitors,research,lifescience,medical The developments in the research of aging and the molecular tools that enable us to alter the aging program of invertebrates and mammals opened the way to address the question of whether aging-associated processes allow protein aggregation to become toxic and initiate neurodegeneration PDK4 late in life. Several proteotoxicity models have been developed in C. elegans, and toxicity assays have been established. If the development of conformational diseases was an aging-independent progressive process, it was expected that slowing aging will show no effect on the rate of proteotoxicity over time. However, if an aging-associated decline in the activity of protective mechanisms exposes the aged organism to proteotoxicity it was anticipated that the alteration of aging protects from proteotoxicity.