The authors of a recent review propose that there may be positive synergistic effects from combining mTOR inhibitors and sodium-glucose co-transporter-2 (SGLT-2) inhibitors [1].
Inhibition of two molecules is better than one
mTOR is a well-known molecule in aging research. Inhibition of mTOR has been shown to extend lifespan in multiple organisms, including worms, yeast, flies, and mammals. Further investigation has suggested that it can also prolong human lifespan [2].
mTOR is involved in many cellular processes, like growth, metabolism, proliferation, and protein synthesis. SGLT-2 is also involved in aging processes, and SGLT-2 inhibitors play a role in preventing the accumulation of senescent cells [3]. However, SGLT-2 inhibitors are currently more known for their role in regulating glucose reabsorption in the kidneys and excretion through urine. Since they lower glucose levels, they are used as therapeutics in type 2 diabetes.
SGLT-2 inhibitors impact nutrient signaling, which leads to a reduction of mTOR activation and activation of different proteins related to nutrient sensing. Those changes simulate the state of caloric restriction. This, in addition to other molecular changes associated with SGLT-2 inhibition, made these researchers speculate about using SGLT-2 inhibitors alongside mTOR inhibitors in conditions that are related to aging or mTOR activation.
The authors of this review note that there are few studies that directly test combinations of mTOR and SGLT-2 inhibitors and their impacts on age-related processes. However, there is enough data to discuss potential synergistic benefits, as the pathways affected by the inhibition of those two molecules appear to be complementary.
Two molecules, multiple processes
One of the most well-known features of senescent cells is the senescence-associated secretory phenotype (SASP), which is the release of pro-inflammatory cytokines and other factors. mTOR has been found to be involved in the development of the SASP, and its inhibition has, accordingly, been found to inhibit the production of some of its factors. SGLT-2 inhibition has also been shown to reduce these molecules [4].
SGLT-2 inhibition’s anti-inflammatory properties are also useful in reducing the factors involved in chronic, age-related inflammation (inflammaging). The expression of some of those pro-inflammatory factors is regulated through SGLT-2 inhibitors and proteins in the mTOR network, and lowering mTOR activity can reduce their expression [5, 6]. However, the authors also mention that some research shows that using the mTOR inhibitor rapamycin doesn’t impact chronic inflammation, but it reduces cellular senescence markers [7]. Future work is needed to better reconcile those two observations.
The authors also discuss that mTOR and SGLT-2 inhibition can help with the aging of the immune system (immunosenescence), which leads to the weakening of immune responses in the elderly. Recent studies suggest the potential for SGLT-2 inhibition in immunomodulatory processes and that mTOR inhibition improves “the performance of the aging immune system in both mice and humans.”
The authors also discuss the consumption of a cell’s own parts (autophagy), a maintenance process that has effects on lifespan [8]. mTOR is one of the major regulators of autophagy, and SGLT-2 inhibition also has been shown to improve autophagy in several organs [9].
Mitochondrial function also declines with age. mTOR is essential for regulating the selective consumption of dysfunctional mitochondria through mitophagy, a quality control process that reduces mutations. Using one of the mTOR inhibitors was shown “to significantly induce mitophagy and reduce mitochondrial mutation frequency in vitro” [10]. SGLT-2 inhibitors also have a positive impact on mitochondria and have been shown to restore mitochondrial morphology and function.
The authors also discuss the microbes that live in the body, mostly the gut (the microbiome), which plays an essential function in many bodily processes. Aging leads to a decrease in microbial diversity.
The mTOR pathway plays an essential role in the communication between microbes and the host organism and can be utilized in therapies. mTOR and SGLT-2 inhibition have been shown to have an impact on microbial composition and microbial metabolites and increase the abundance of microbial species that are associated with health benefits and healthy aging [11]. However, there is still a lack of understanding of the molecular processes behind those connections.
Beneficial combination with some side effects
Even though there might be benefits of combining mTOR and SGLT-2 inhibition, the authors also point to its possible side effects and limitations in its clinical applications.
As of now, there is limited data in the aging population regarding the use of the SGLT-2 inhibitors. Existing evidence suggests similarities in efficacy and safety for older and younger populations. Still, there is a risk of adverse effects, such as urinary tract infections, renal-related adverse events, and hypoglycemia, which is higher in the elderly. That being said, the authors point to a “favorable benefit–risk balance in elderly patients” for SGLT-2 inhibitors.
mTOR inhibition comes with its own challenges and side effects. Rapamycin use was linked to an increase in the risk of developing type 2 diabetes, high levels of protein in the urine (proteinuria), and abnormalities in blood lipid levels (dyslipidemia). The authors note that SGLT-2 inhibitors can be potentially used to mitigate some of the mTOR side effects.
The authors also believe there is a need to understand the molecular mechanism behind how the inhibition of SGLT-2 and mTOR regulates cellular senescence. This will allow for optimizing those treatments while considering variables such as sex or pre-existing conditions. They also highlight the need for long-term clinical trials to test such combinations in the elderly.
Literature
[1] Troise, D., Mercuri, S., Infante, B., Losappio, V., Cirolla, L., Netti, G. S., Ranieri, E., & Stallone, G. (2024). mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes. International journal of molecular sciences, 25(16), 8676.
[2] Johnson, S. C., Rabinovitch, P. S., & Kaeberlein, M. (2013). mTOR is a key modulator of ageing and age-related disease. Nature, 493(7432), 338–345.
[3] Ferrannini E. (2017). Sodium-Glucose Co-transporters and Their Inhibition: Clinical Physiology. Cell metabolism, 26(1), 27–38.
[4] Scisciola, L., Cataldo, V., Taktaz, F., Fontanella, R. A., Pesapane, A., Ghosh, P., Franzese, M., Puocci, A., De Angelis, A., Sportiello, L., Marfella, R., & Barbieri, M. (2022). Anti-inflammatory role of SGLT2 inhibitors as part of their anti-atherosclerotic activity: Data from basic science and clinical trials. Frontiers in cardiovascular medicine, 9, 1008922.
[5] Stallone, G., Infante, B., Prisciandaro, C., & Grandaliano, G. (2019). MTOR and Aging: an old fashioned dress. International Journal of Molecular Sciences, 20(11), 2774.
[6] Gohari, S., Ismail-Beigi, F., Mahjani, M., Ghobadi, S., Jafari, A., Ahangar, H., & Gohari, S. (2023). The effect of sodium-glucose co-transporter-2 (SGLT2) inhibitors on blood interleukin-6 concentration: a systematic review and meta-analysis of randomized controlled trials. BMC endocrine disorders, 23(1), 257.
[7] Correia-Melo, C., Birch, J., Fielder, E., Rahmatika, D., Taylor, J., Chapman, J., Lagnado, A., Carroll, B. M., Miwa, S., Richardson, G., Jurk, D., Oakley, F., Mann, J., Mann, D. A., Korolchuk, V. I., & Passos, J. F. (2019). Rapamycin improves healthspan but not inflammaging in nfκb1-/- mice. Aging cell, 18(1), e12882.
[8] Masclaux-Daubresse, C., Chen, Q., & Havé, M. (2017). Regulation of nutrient recycling via autophagy. Current Opinion in Plant Biology, 39, 8–17.
[9] Fukushima, K., Kitamura, S., Tsuji, K., Sang, Y., & Wada, J. (2020). Sodium Glucose Co-Transporter 2 Inhibitor Ameliorates Autophagic Flux Impairment on Renal Proximal Tubular Cells in Obesity Mice. International journal of molecular sciences, 21(11), 4054.
[10] Twig, G., Hyde, B., & Shirihai, O. S. (2008). Mitochondrial fusion, fission and autophagy as a quality control axis: The bioenergetic view. Biochimica Et Biophysica Acta (BBA) – Bioenergetics, 1777(9), 1092–1097.
[11] Ragonnaud, E., & Biragyn, A. (2021). Gut microbiota as the key controllers of “healthy” aging of elderly people. Immunity & ageing : I & A, 18(1), 2.
