Impact of metformin, resveratrol and rapamycin on mouse liver proteome

Research shows that diet and macronutrients can influence the cellular machinery – effects can be dampened by three drugs: metformin, rapamycin and resveratrol.

Aging is an irreversible process that is associated with several physiological changes across multiple organ systems. A complex process, human aging is associated with genetic factors and epigenetic factors, as well as environmental factors.

Aging is most often associated with a wide range of age-related diseases such as Alzheimer’s disease, cardiovascular diseases, cancer, hypertension, diabetes and arthritis. Therefore, it is important to come up with new strategies to slow the rate of aging in humans; one prominent mechanism to slow aging apart from nutritional, genetic and pharmacological interventions is caloric restriction [1].

Nutrient sensing pathways are cellular pathways that link aging with caloric restriction. These pathways are associated with aging since many genes that have been reported to play important roles in lifespan have also been found in the nutrient-sensing pathways. The nutrient-sensing pathways that are associated with longevity include the kinase target of rapamycin (TOR), sirtuins, AMP kinase (AMPK) as well as insulin and insulin/insulin-like growth factor (IGF-1) signalling. Several studies have indicated that reducing the activity of these pathways could help to promote longevity in humans [2].

Protein restriction has been found to increase lifespan while high fat and high protein diets have been found to reduce lifespan; additionally, the replacement of dietary proteins with carbohydrates has been found to increase lifespan in invertebrates and mice. Recently, several drugs have been reported to act on these nutrient-sensing pathways that could in turn influence the normal physiological responses to various types of diets.

Longevity. Technology: The liver is the main organ that responds to nutrient changes; the pathways that respond to changes in nutrients include those that are involved in storage or use for energy, synthesis and degradation of nutrients and their transformation into other substrates. Studies have highlighted that caloric restriction or the action of drugs in the liver impacts pathways that are involved in aging such as mitochondria, autophagy and inflammation.

A new study from the University of Sydney, University of Melbourne and the ANZAC research institute aimed to determine how drugs and diet impacted the specific nutrient-sensing pathways and whether diet and drugs interact in their effects using mice models. The results reported that diets with high fat and protein concentrations were associated with the highest body weight, insulin resistance and body fat percentage while drugs such as metformin, resveratrol and rapamycin had no impact on the phenotype [3].

Several proteins were identified that correlated with energy uptake either positively or negatively. Proteins that positively correlated with energy uptake were involved in nutrient metabolism while those that negatively correlated were spliceosome-related proteins. The drugs metformin, rapamycin and resveratrol were found to reduce the pathways that were associated with energy intake as well as reduce the abundance of proteins that were either positively or negatively associated with energy uptake. However, these drugs were not found to act on aging and nutrient-sensing pathways.

Furthermore, high protein diets have been reported to be associated with an increase in the number and size of mitochondria as well as an increase in the number of genes that influence mitochondria. High protein intake also leads to oxidative stress that was found to be reduced by rapamycin and metformin.

High protein intake was also found to upregulate the mitochondrial NAD+ transporter, SLC25A51. Protein intake was found to have a negative correlation with a neurotrophic factor, NENF which is expressed in the liver, endoplasmic reticulum and mitochondria and is a potential regulator of appetite. Rapamycin on the other hand was reported to lead to high levels of NENF.

The results also reported that protein intake had a positive correlation with amino acid metabolic pathways, fat intake had a similar correlation with fat metabolic pathways and carbohydrate intake with carbohydrate metabolic pathways. Additionally, the effect of the three drugs on the proteome was found to be quite less compared to the dietary components.

Resveratrol was found to be the most effective in dampening the correlations between protein abundance and protein or carbohydrate intake. Resveratrol was also found to increase the slope of the association between macronutrients and protein abundance as well as play a role in the regulation of transcription. Additionally, metformin and rapamycin were found to play important roles as compared to resveratrol in reducing the abundance of mitochondrial proteins in response to protein intake.

Therefore, several pathways were found to be influenced by diets that could lead to an abundance of spliceosome proteins and an increase in oxidative stress. Metformin, rapamycin and resveratrol could reduce the responses to the diets leading to suppression of protein synthesis thereby promoting the longevity of individuals.

[1] https://immunityageing.biomedcentral.com/articles/10.1186/1742-4933-9-9
[2] https://www.pnas.org/doi/10.1073/pnas.1913212116
[3] https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00528-3

Photograph: Pixabay/Pexels

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