Community Research and Development Information Service - CORDIS



Project ID: 281010
Funded under: FP7-IDEAS-ERC
Country: Israel

Final Report Summary - LATELIFEHEALTH (Mapping the late-life health promoting mechanisms in worms and mammals)

Aging manipulation is an emerging strategy aimed to postpone the manifestation of late-onset maladies which stem from protein misfolding and aggregation (proteotoxicity) and to slow their progression once emerged. These illnesses include neurodegenerative disorders such as Alzheimer's (AD), Huntington's diseases (HD) and prion disorders. The alteration of aging can be achieved by several interventions including by reducing the activity of the Insulin/IGF signaling cascade (IIS). The IIS is a prominent aging-regulating pathway that is highly conserved among worms and mammals. Previously we have shown that IIS reduction protects worms from AD-associated proteotoxicity. Similarly, IGF1 signaling reduction protects mice from AD-like disease. Furthermore, IIS reduction late in life was shown to protect worms from toxicity without affecting lifespan. These discoveries strongly suggest that IIS inhibition has the potential to delay the emergence of neurodegenerative maladies and alleviate their symptoms without affecting lifespan. Accordingly, this project has been designed to elucidate the mechanism that regulates proteotoxicity in late life stages and to test whether pharmaceutical IIS inhibitors are capable to mitigate disease-linked phenotypes. Employing various technologies we identified a subset of genes that are regulated by the IIS in midlife but not in young ages. We also recognized aging-associated protein modifications which have led us to identify proteins whose activities are required to prevent proteotoxicity is the elderly. Finally we tested whether NT219, a new highly efficient IGF signaling inhibitor, is capable to mitigate proteotoxicity and found that it alleviates the toxic effects of AD and HD-associated aggregative proteins. Preliminary data suggest that NT219 can also protect mice from AD-like disease. The discoveries that have been already obtained during this ERC-funded project, provide important new insights as they point at new targets for counter-neurodegeneration therapeutic interventions. NT219 is the first compound that has the potential to delay the onset of different late onset devastating disorders by a selective manipulation of the aging process.

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