Junk food mouse
Researchers publishing in Nature Aging have discovered that inhibiting a glucose transporter leads to a decrease in senescent cells.
Forcing a reduction in calories
Why we Age: Cellular SenescenceAs your body ages, more of your cells become senescent. Senescent cells do not divide or support the tissues of which they are part; instead, they emit potentially harmful chemical signals, collectively known as the senescence-associated secretory phenotype (SASP), which encourages nearby cells to enter the same senescent state. Their presence causes many problems: they degrade tissue function, increase chronic inflammation, and can even eventually raise the risk of cancer and other age-related ... Read More
This paper begins with a discussion of the well-known problems with widespread cellular senescence and its connections with other aspects of aging. Previous work has found that inhibiting sodium–glucose co-transporter 2 (SGLT2) leads to reduced glucose uptake by cells, causing it to be excreted in the urine [1], and that it reduces cellular senesence in the kidneys [2, 3].
However, previous experiments were relatively limited and consisted of cells and diabetic model mice. These researchers decided to advance their understanding of this particular transporter by conducting a study in wild-type mice.
Effective against high-fat diets
The mice in this study were fed a high-fat diet for 8 to 10 weeks, and the treatment group was given a week of canagliflozin, which inhibits SGLT2. This treatment didn’t have any impact on body weight, fat mass, oxygen use, or food intake, but the treatment group had reduced diabetic phenotypes: less insulin resistance and better glucose metabolism. These benefits continued even after the treatment was stopped for a week and canagliflozin no longer had a significant presence in the mice’s systems.
ADVERTISEMENT
Eterna is a clothing company with a focus on longevity.
This treatment also significantly reduced senesence. Biomarkers of senescent cells were significantly reduced throughout the mice’s bodies, including in atherosclerotic plaques. Evidence of inflammation and cellular stress was also significantly decreased, as were SASP factors. Ongoing 4-week treatment of canagliflozin led to a long-term reduction of cellular senescence.
These changes were not mirrored with insulin. Insulin, as expected, restored metabolic biomarkers, but it did not affect the senescent cell burden in the way that canagliflozin did. Similarly, feeding the mice a normal diet instead of a high-fat diet restored metabolic biomarkers, but the senescent cells remained.
Additional benefits were found in a mouse model of progeria. Progeroid mice fed canagliflozin lived significantly longer than progeroid mice that were not, and these results were confirmed for both sexes.
A key pathway
The researchers investigated exactly what canagliflozin might be doing to impact senesence. They discovered that SGLT2 inhibition upregulated AICAR, a compound that activates AMPK. The AMPK pathway is well-known in metabolism and was previously found to downregulate cellular senescence [4]. Further experimentation with AICAR and AMPK found that this was indeed the case, as interfering with this chain of events blocked the beneficial effects of canagliflozin.
Inhibiting SGLT2 was also found to downregulate programmed cell death ligand 1 (PD-1), which is associated with cellular senescence and encourages pathological aging [4]. The AMPK chain that was discovered to inhibit cellular senescence was directly linked to this downregulation of PD-1.
An advertisement banner for PartiQular supplements.
All of this work was done on mice fed a high-fat diet or on progeric mice. It is not clear if SGLT2 inhibition works on wild-type mice fed more normal diets. However, given the prevalence of unhealthy dietary practices among Western populations, it is conceivable that this approach may have clinical benefit. A clinical trial would need to be conducted to determine if inhibiting SGLT2 would provide benefits related to inhibiting cellular senescence, particularly when accompanied by diabetes or metabolic syndrome.
Literature
[1] Ferrannini, E. (2017). Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell metabolism, 26(1), 27-38.
[2] Kim, M. N., Moon, J. H., & Cho, Y. M. (2021). Sodium‐glucose cotransporter‐2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body‐induced NRF2 activation. Diabetes, Obesity and Metabolism, 23(11), 2561-2571.
[3] Eleftheriadis, T., Pissas, G., Filippidis, G., Efthymiadi, M., Liakopoulos, V., & Stefanidis, I. (2022). Dapagliflozin Prevents High-Glucose-Induced Cellular Senescence in Renal Tubular Epithelial Cells. International Journal of Molecular Sciences, 23(24), 16107.
[4] Wang, T. W., Johmura, Y., Suzuki, N., Omori, S., Migita, T., Yamaguchi, K., … & Nakanishi, M. (2022). Blocking PD-L1–PD-1 improves senescence surveillance and ageing phenotypes. Nature, 611(7935), 358-364.
