Targeting impaired nutrient sensing via the sirtuin pathway with novel compounds to prevent or treat dementia: A...

Dementia is prevalent in aged populations and is associated with disability and distress for those affected. Therapeutic benefits of drugs targeting dementia are small. Impaired nutrient sensing pathways have been implicated in the pathogenesis of dementia and may offer a novel treatment target.

This systematic review collated evidence for novel therapeutic compounds that modify nutrient sensing pathways, particularly the sirtuin pathway, in preventing cognitive decline or improving cognition in normal ageing, mild cognitive impairment (MCI), and dementia.

PubMed, Embase and Web of Science databases were searched using key search terms. Articles were screened using Covidence systematic review software. The risk of bias was assessed using the Systematic Review Center for Laboratory animal Experimentation (SYRCLE)'s risk of bias tool for animal studies and Cochrane Risk of Bias tool v 2.0 for human studies.

Out of 3841 articles, 68 were included describing 38 different novel therapeutic compounds that modulate the nutrient sensing pathway via the sirtuin pathway. In animal models (58 studies), all investigated novel therapeutic compounds showed cognitive benefits. Ten studies were human intervention trials targeting normal ageing (1 study) and dementia populations (9 studies). Direct sirtuin (silent mating type information regulation 2 homolog) 1 (SIRT1) activators Resveratrol and Nicotinamide derivatives improved cognitive outcomes among human subjects with normal cognition and MCI.

Animal studies support that modulation of the sirtuin pathway has the potential to improve cognitive outcomes. Overall, there is a clear lack of translation from animal models to human populations.