![]() Moreover, signaling pathways have evolved to respond to cellular stresses in aging, with the AMPK and mTOR pathways being widely studied in cellular development and ageing 11, 12, 13, 14. For example, caloric restriction and intermittent fasting retard structural and functional decline during aging in laboratory rodents and monkeys 8, 9, 10. Metabolites affect key steps in cellular pathways where they act as substrates for enzymes or as signaling molecules for the activation of biochemical pathways. In turn, this system is part of a wider cellular homeostasis system, which includes a variety of other components, including the metabolite homeostasis system 6, 7. Although the molecular origins of this disease are still to be firmly established, it is generally recognized that the presence of protein deposits is associated with the dysregulation of the protein homeostasis network 4, 5. ![]() Taken together, our findings provide a link between metabolite homeostasis and protein homeostasis, which could inspire preventative interventions against neurodegenerative disorders.Īlzheimer’s disease (AD) is a complex disorder characterized by the presence of aberrant protein deposits in brain tissues 1, 2, 3. ![]() These results help rationalise previous observations regarding the possible anti-ageing benefits of these metabolites by providing a mechanism for their action. We found that these metabolites act by triggering a cytosolic unfolded protein response through the transcription factor HSF-1 and downstream chaperones HSP40/J-proteins DNJ-12 and DNJ-19. By computationally analysing the Human Metabolome Database, we identified two endogenous metabolites, carnosine and kynurenic acid, that inhibit the aggregation of the amyloid beta peptide (Aβ) and rescue a C. Although the roles of metabolites have been extensively studied with regard to cellular signaling pathways, their effects on protein aggregation remain relatively unexplored. Age-related changes in cellular metabolism can affect brain homeostasis, creating conditions that are permissive to the onset and progression of neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. ![]()
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