Effects of pharmaceutical modulation of protein aggregation on lifespan in Caenorhabditis elegans

Abstract

Aging is accompanied by a disruption in various homeostatic networks including those devoted to maintaining protein conformation and integrity. Collectively this maintenance is referred to protein homeostasis or proteostasis. Growing evidence suggests that promoting proteostasis may not only be beneficial for protein aggregation-related disorders but may also influence normal aging. We have investigated various pharmacological means of promoting the proteostatic network and the effects on healthspan and longevity in the nematode Caenorhabditis elegans.

Here we show that known amyloid binding compounds can prevent protein aggregation and extend lifespan in C. elegans. We report that the widely used amyloid-binding compound, Thioflavin-T not only adheres to Amyloid- β (A β) but also inhibits its misfolding or aggregation, thereby delaying the accompanying disease state in a C. elegans model of Alzheimer’s Disease (AD). Our data suggests that Thioflavin-T can prolong the vitality and lifespan of wild type (WT) C. elegans by stabilizing the proteostatic machinery. Additionally, we identified three other compounds related to Thioflavin-T that also extend lifespan. Interestingly, these other compounds are known to chelate copper and iron, two metals implicated in several aggregation-related disorders (Paper I).

Many age-related protein aggregation neurodegenerative disorders (NDs) are accompanied by alterations in levels of various metals such as iron and copper. Whether these metals are a cause or consequence of ND is not well understood. In a characterization of metal composition (the metallome) with age we show that normal aging of C. elegans is accompanied by accumulation of calcium, iron, copper and manganese. Additionally, we found that increased dietary iron enhances toxicity in both A β and PolyQ-associated models of protein aggregation. We were able to reduce endogenous iron levels in C. elegans and found that this ameliorated various models of proteotoxic disease. Moreover, we show that CaEDTA exposure increases healthspan and lifespan in WT animals. Taken together, our findings suggest that metal accumulation is an inherent part of the aging process and likely destabilizes the proteostasis of the organism (Paper II).

By using a C. elegans model for proteotoxicity we were able to screen a large natural library for additional drugs that could potentially enhance the healthspan and lifespan of C. elegans. Subsequently, we investigated the effects of 5-fluoro-2-deoxyuridine (FUdR) in models of protein aggregation. We have found that inhibiting reproduction with FUdR at standard laboratory concentrations improves protein homeostasis, stress resistance and healthspan of C. elegans (paper III).