Synergy of mTOR and SGLT-2 Inhibitors in Aging

A recent review published in the International Journal of Molecular Sciences has proposed a compelling hypothesis regarding the intersection of two important molecular inhibitors in the context of aging: mTOR and SGLT-2 inhibitors. These molecules are suggested to affect overlapping cellular processes that may influence age-related phenomena.

Inhibition of Two Molecules is Better than One

mTOR (mechanistic target of rapamycin) has been a prominent focus in aging research due to its critical role in regulating lifespan across multiple organisms, including Caenorhabditis elegans, yeast, fruit flies, and mammals. Research indicates that mTOR inhibition potentially extends human lifespan as well [2].

Similarly, SGLT-2 inhibitors (sodium-glucose co-transporters) have gained attention for their roles in age-related processes, particularly in preventing the accumulation of senescent cells [3]. While SGLT-2 inhibitors are primarily recognized for their glucose-reducing properties, recent findings suggest they impact nutrient signaling pathways, thereby contributing to reduced mTOR activity. The synergy of mTOR and SGLT-2 inhibition could mimic the metabolic state akin to caloric restriction, providing a potential therapeutic strategy against aging-related conditions.

Two Molecules, Multiple Processes

One significant characteristic of senescent cells is the senescence-associated secretory phenotype (SASP), which involves the secretion of pro-inflammatory cytokines and various soluble factors. Evidence suggests that mTOR contributes to SASP development, and its inhibition subsequently reduces SASP marker secretion. Additionally, SGLT-2 inhibitors exhibit anti-inflammatory properties that may further mitigate age-related chronic inflammation, or inflammaging [4].

Inhibition of mTOR and SGLT-2 may also provide benefits for the aging immune system (immunosenescence), vital in countering diminished immune responses in elderly populations. Notably, studies suggest SGLT-2 inhibitors may positively influence immune functions, while mTOR inhibitors like rapamycin are shown to enhance aged immune system performance in preclinical and clinical settings.

Mitochondrial Function and Microbiome Interactions

Maintaining mitochondrial function is also crucial for healthy aging. mTOR plays a vital role in regulating mitophagy—the selective removal of damaged mitochondria. In vitro studies have demonstrated that mTOR inhibitors can promote effective mitophagy, aiming to reduce mitochondrial mutations [10]. Likewise, SGLT-2 inhibitors have been shown to enhance mitochondrial morphology and efficacy.

Moreover, age-related declines in microbial diversity, particularly in the gut microbiome, can influence a range of bodily functions. The mTOR pathway is implicated in the communication between the gut microbiota and host metabolism, demonstrating the potential for therapeutic interventions. Preliminary evidence indicates that both mTOR and SGLT-2 inhibition can reshape microbial composition and metabolite profiles to favor health and support healthy aging [11].

Potential Side Effects and Future Directions

Despite the promising benefits of combining mTOR and SGLT-2 inhibition, the authors of the review caution against possible side effects and limitations. Current data relating to their use in the aging population is limited, though it suggests comparable efficacy and safety between older and younger individuals. Still, risks like urinary tract infections and hypoglycemia persist, especially in elderly patients.

mTOR inhibition can also result in adverse effects, including an increased likelihood of developing type 2 diabetes, proteinuria, and blood dyslipidemia. However, SGLT-2 inhibitors may mitigate some of these risks. Future research should aim to elucidate the molecular mechanisms of SGLT-2 and mTOR inhibition in cellular senescence, optimizing treatments while addressing factors like sex and pre-existing health conditions.

Literature Cited

[1] Troise, D. et al. (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. et al. (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. et al. (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. et al. (2019). mTOR and Aging: an old fashioned dress. International Journal of Molecular Sciences, 20(11), 2774.

[6] Gohari, S. et al. (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. et al. (2019). Rapamycin improves healthspan but not inflammaging in nfκb1-/- mice. Aging Cell, 18(1), e12882.

[8] Masclaux-Daubresse, C. et al. (2017). Regulation of nutrient recycling via autophagy. Current Opinion in Plant Biology, 39, 8–17.

[9] Fukushima, K. et al. (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. et al. (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 & Aging, 18(1), 2.

[12] Lifespan.io