mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes

Abstract

The aging process contributes significantly to the onset of chronic diseases, which are the primary causes of global mortality, morbidity, and healthcare costs. Numerous studies have shown that the removal of senescent cells from tissues extends lifespan and reduces the occurrence of age-related diseases. Consequently, there is growing momentum in the development of drugs targeting these cells. Among them, mTOR and SGLT-2 inhibitors have garnered attention due to their diverse effects: mTOR inhibitors regulate cellular growth, metabolism, and immune responses, while SGLT-2 inhibitors regulate glucose reabsorption in the kidneys, resulting in various beneficial metabolic effects. Importantly, these drugs may act synergistically by influencing senescence processes and pathways. Although direct studies on the combined effects of mTOR inhibition and SGLT-2 inhibition on age-related processes are limited, this review aims to highlight the potential synergistic benefits of these drugs in targeting senescence.

Keywords: SGLT-2 inhibitors; aging; inflammaging; mTOR inhibitors; senescence; senomorphic compounds; senotherapeutic strategies.

Figure 1

mTOR and SGLT-2 inhibitors synergistic effects. mTOR and SGLT-2 inhibitors play a significant role in many cellular processes considered hallmarks of aging. mTORi enhance autophagy, promoting the removal of dysfunctional or unnecessary cellular components, reduce the age-related increase of proinflammatory cytokines by dampening immune responses, and have a positive effect on mitochondrial dynamics. SGLT-2i improve metabolic health, which indirectly supports autophagy and reduces inflammation. Additionally, they have been shown to have potential immunomodulatory properties. Furthermore, these drugs can influence gut microbiota composition, mitigating dysbiosis, a condition linked to age-related diseases. Collectively, these effects contribute to healthier aging by targeting key cellular processes. Created with https://www.BioRender.com (accessed on 23 July 2024).

Figure 2

mTOR and SGLT-2 inhibition on senescence pathways. Cellular stress factors activate signaling pathways correlated with senescence (black lines). The p53–p21 and p16–Rb pathways are considered major players in the DNA damage cellular response. Modulating these pathways has been shown to increase lifespan and improve age-related processes. Both mTORi and p53 suppress mTOR through distinct mechanisms. Additionally, SGLT-2i have been shown to inhibit mTOR signaling by upregulating energy deprivation sensors like AMPK. The evidence that SGLT-2i and mTORi reduce senescence markers suggests they might have complementary mechanisms and, together, they could reduce the burden of senescence (red lines). Created with https://www.BioRender.com (accessed on 20 June 2024).