Effect of a GLP-1 analogue on different models of cellular senescence

Abstract

Introduction

Aging is a gradual and irreversible decline of biological functions at the systemic level, which is influenced by various genetic and environmental factors for its development. It is mainly characterized by various marks at the cellular and molecular level such as cellular senescence, which is an irreversible state, in which cells remain metabolically active, but without entering the replicative cycle, in addition to releasing inflammatory factors that damage the surrounding tissues. Senescent cells (SCs) exhibit alterations in mitochondrial functioning, metabolism, and genomic structure. Aging correlates with the accumulation of CS in the tissues of living things. Glucagon-like peptide 1 (GLP-1) is key to cellular homeostasis as it is involved in glucose metabolism, mitochondrial function, and its role in cellular senescence has recently been proposed. Semaglutide is a synthetic analogue of GLP-1, this drug is hyperglycemic extended-release belonging to the family of synthetic incretins, which are characterized by being GLP-1 receptor (GLP-1R) agonists. Semaglutide has been observed to be involved in the activation of several pathways that decrease during aging. Therefore, it is important to investigate the molecular mechanisms of semaglutide's effects on senescent cells. This work aims to evaluate the repositioning of the drug semaglutide as a new therapeutic alternative in various functional targets related to aging and cellular senescence.

Objective

To evaluate the effects of GLP-1 analogue (semaglutide) on different marks of aging, including cellular senescence in three models of senescent fibroblasts. 

Methods

The proposed cell model is through primary fibroblasts from: a 20-year-old individual (GM03440), a 96-year-old individual (AG04059), an individual with Hutchinson-Gilford progeria syndrome (HGPS) (AG11513). Treatments of 10 nM and 50 nM of semaglutide were performed for 24, 72 and 120 hours in the different models of senescent patients, after the treatment cell viability and proliferation were analyzed using the MTT technique. To evaluate the effect of semaglutide during the senescence induction process, the effect of the drug during H2O2 exposure in primary dermal fibroblasts was evaluated.

Results

We found that the administration of semaglutide in fibroblasts significantly increases their viability and cell proliferation (Image 1). On the other hand, we found that the concentration of 50 μM of H2O2 is adequate to test the induction of cellular senescence in dermal fibroblasts.

In addition, our results show that semaglutide treatments are able to attenuate marks of cellular senescence such as B-galactosidase and lamina B1.

Conclusions

The administration of semaglutide considerably improved the cell viability of primary dermal fibroblasts. Likewise, treatment with semaglutide managed to attenuate some marks of cellular senescence compared to the control.