Drug synergy as a strategy for compression of morbidity in a Caenorhabditis elegans model of Alzheimer ’s disease

AbstractAlzheimer ’s disease (AD) is the most common cause of dementia worldwide. AD is a multifactorial disease with simultaneous occurrence of several connected pathological processes including mitochondrial dysfunction and impaired proteostasis. Most of these are also implicated in organismal aging per se. The p resence of separable pathological conditions poses the opportunity to try combination treatments that target these different processes separately. This approach may provide an effective strategy to target AD; therefore, we investigated whether a combination of metformin (targeting mitochondria and e nergy metabolism) and lithium (targeting proteostasis) could result in synergistic benefits. In this perspective paper, we looked for benefits in lifespan and healthspan using a transgenic nematode strain, GRU102, which expresses pan-neuronal human amyloid-beta (Aβ). Individually, metformin and lit hium extended the lifespan of both non-transgenic GRU101 controls and GRU102. Combination treatment using metformin and lithium did not result in any synergistic increase in GRU102 lifespan, but this treatment did result in a significant compression of morbidity when compared with each individual dr ug, resulting in relative and absolute extension of healthspan. Despite over-expressing pathogenic human Aβ in their neurons, GRU102 worms treated with the combination treatment enjoyed longer lifespans and significantly compressed morbidity, even compared with untreated non-t...

Source: AGE - February 21, 2020 Category: Geriatrics Source Type: research