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Targeting impaired nutrient sensing with novel interventions to prevent or treat age-related dementia: a systematic review in relation to sirtuins

S. Perera (1, 3), D. Heard (1, 2, 3), T. Rego (1, 2, 3), C. Tuttle (3) and A. Maier (1, 2, 3, 4)

  1. The Royal Melbourne Hospital, Melbourne, Victoria, Australia

  2. North West Mental Health, Melbourne Health, Melbourne, Victoria, Australia

  3. @AgeMelbourne, Department of Medicine and Aged Care, University of Melbourne, Melbourne, Victoria, Australia

  4. @AgeAmsterdam, Department of Human Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, Netherlands

Background

Age-related dementia is currently an untreatable condition that is detrimental to the quality of life of its sufferers. Impaired nutrient sensing pathways found in Alzheimer’s and Parkinson’s Disease brains suggest that these pathways may be involved in dementia pathogenesis. Sirtuins are a key protein involved in this pathway, and as such could be a potential therapeutic target in treating dementia. This review aims to collate all current interventional study evidence for targeting these pathways with novel drugs and compounds as an intervention for age-related dementia and cognitive decline.


Methods

PubMed, Web of Science and Embase databases were searched from inception until 29th March 2019. Interventional studies of novel drugs which modulate nutrient sensing pathways in Alzheimer’s disease, Parkinson’s disease, Lewy Body disease, vascular dementia and cognitive aging, in either animal models or humans with change in cognition as the outcome were included. The SYRCLE and Cochrane tools were used to assess risk of bias.

Results

Overall 22 trials, 19 animal and 3 human, were isolated for inclusion in this review. Drugs tested in animals and humans included resveratrol, nicotinamide adenine dinucleotide, and ketogenic compounds. Drugs tested only in animals included a variety of novel compounds such as: chemical relations to resveratrol, beta-lapachone, pyruvate, reverse transplantation of human stem cells, monoclonal antibodies, and caloric restriction.  Nicotinamide and their modulators (n= 6 animal, n= 2 human) and Resveratrol (n = 4 animal, n= 1 human)  were the most studied nutrient sensing modifying drugs influencing cognition.

Conclusion

Overall, the collective findings support the hypothesis that targeting impaired nutrient sensing for the treatment of dementia may be beneficial. For these therapeutic interventions to be translated into clinical practice, however, larger human clinical trials will have to occur.