Researchers publishing in Nature Ageing have found that inhibiting a glucose transporter leads to a decrease in senescent cells.
Forcing a discount in energy
This paper begins with a dialogue of the well-known issues with widespread mobile senescence and its connections with different points of growing older. Earlier work has discovered that inhibiting sodium–glucose co-transporter 2 (SGLT2) results in diminished glucose uptake by cells, inflicting it to be excreted within the urine [1], and that it reduces mobile senesence within the kidneys [2, 3].
Nevertheless, earlier experiments have been comparatively restricted and consisted of cells and diabetic mannequin mice. These researchers determined to advance their understanding of this specific transporter by conducting a examine in wild-type mice.
Efficient towards high-fat diets
The mice on this examine have been fed a high-fat weight loss plan for 8 to 10 weeks, and the therapy group was given per week of canagliflozin, which inhibits SGLT2. This therapy didn’t have any impression on physique weight, fats mass, oxygen use, or meals consumption, however the therapy group had diminished diabetic phenotypes: much less insulin resistance and higher glucose metabolism. These advantages continued even after the therapy was stopped for per week and canagliflozin now not had a major presence within the mice’s techniques.
This therapy additionally considerably diminished senesence. Biomarkers of senescent cells have been considerably diminished all through the mice’s our bodies, together with in atherosclerotic plaques. Proof of irritation and mobile stress was additionally considerably decreased, as have been SASP elements. Ongoing 4-week therapy of canagliflozin led to a long-term discount of mobile senescence.
These adjustments weren’t mirrored with insulin. Insulin, as anticipated, restored metabolic biomarkers, but it surely didn’t have an effect on the senescent cell burden in the best way that canagliflozin did. Equally, feeding the mice a standard weight loss plan as an alternative of a high-fat weight loss plan restored metabolic biomarkers, however the senescent cells remained.
Extra advantages have been present in a mouse mannequin of progeria. Progeroid mice fed canagliflozin lived considerably longer than progeroid mice that weren’t, and these outcomes have been confirmed for each sexes.
A key pathway
The researchers investigated precisely what canagliflozin could be doing to impression senesence. They found that SGLT2 inhibition upregulated AICAR, a compound that prompts AMPK. The AMPK pathway is well-known in metabolism and was beforehand discovered to downregulate mobile senescence [4]. Additional experimentation with AICAR and AMPK discovered that this was certainly the case, as interfering with this chain of occasions blocked the helpful results of canagliflozin.
Inhibiting SGLT2 was additionally discovered to downregulate programmed cell demise ligand 1 (PD-1), which is related to mobile senescence and encourages pathological growing older [4]. The AMPK chain that was found to inhibit mobile senescence was straight linked to this downregulation of PD-1.
All of this work was finished on mice fed a high-fat weight loss plan or on progeric mice. It isn’t clear if SGLT2 inhibition works on wild-type mice fed extra regular diets. Nevertheless, given the prevalence of unhealthy dietary practices amongst Western populations, it’s conceivable that this strategy might have medical profit. A medical trial would should be carried out to find out if inhibiting SGLT2 would supply advantages associated to inhibiting mobile senescence, notably when accompanied by diabetes or metabolic syndrome.
Literature
[1] Ferrannini, E. (2017). Sodium-glucose co-transporters and their inhibition: medical physiology. Cell metabolism, 26(1), 27-38.
[2] Kim, M. N., Moon, J. H., & Cho, Y. M. (2021). Sodium‐glucose cotransporter‐2 inhibition reduces mobile senescence within the diabetic kidney by selling ketone physique‐induced NRF2 activation. Diabetes, Weight problems and Metabolism, 23(11), 2561-2571.
[3] Eleftheriadis, T., Pissas, G., Filippidis, G., Efthymiadi, M., Liakopoulos, V., & Stefanidis, I. (2022). Dapagliflozin Prevents Excessive-Glucose-Induced Mobile Senescence in Renal Tubular Epithelial Cells. Worldwide Journal of Molecular Sciences, 23(24), 16107.
[4] Wang, T. W., Johmura, Y., Suzuki, N., Omori, S., Migita, T., Yamaguchi, Ok., … & Nakanishi, M. (2022). Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes. Nature, 611(7935), 358-364.
