Right now, there is a lot of excitement over a new study showing that the SGLT2 inhibitor canagliflozin eliminates senescent cells and relieves pathological aging phenotypes. This is an exciting finding as flozins have an excellent safety profile and have shown remarkable improvements in CVD, CHF, CKD and other age-related diseases in the last few years. This new study identifies SGLT2i as a novel class of senolytic drugs and provides a mechanism for their senolytic activity which is independent of their ability to regulate glucose.
These findings are ground-breaking for two reasons. First, they show that there are FDA approved drugs with excellent safety profiles that could be senolytic. This sets them apart from other therapies currently used as a senolytic (e.g., D+Q, fisetin). Second, the mechanism of senolysis involves improvement of the patient’s immune system (cytotoxic T cells), naturally increasing immunosurveillance of senescent cells. As senescent cells have physiologic functions (e.g. tumor suppression), it is not clear what the long-term effects of targeting senescent cells directly may be. Improving immune system immunosurveillance could provide a natural defense against accumulation of senescent cells and may be less likely to cause adverse events related to low senescent cell load.
In this Nature Aging study, the authors show that canagliflozin improves immune system function, at least partly through AMPK activation and a decrease in T cell exhaustion. Mice treated with canagliflozin showed a remarkable decrease in senescent cell load independently of normalization of serum glucose levels. In addition, canagliflozin decreased the size of atherosclerotic plaque and decreased cellular senescence in arteries, suggesting that the drug’s cardioprotective ability may at least in part rely on senolysis. The authors also used a progeroid mouse model to show that canagliflozin treatment improves survival.
In the Clinic
We are looking forward to hearing your thoughts about how you are using SGLT2i in longevity medicine and how these data impact your thinking. Some early thoughts from us, the authors, and some of our KOLs:
SGLT2i vs metformin vs exercise?
The authors suggest that drugs that activate AMPK (metformin) may have a similar senolytic effect. Of course, the most potent activator of AMPK is exercise
Males vs females?
In this study, primarily male mice were used. ITP studies also showed extension of lifespan and decrease in aging pathology with canagliflozin in males but not females.
Canagliflozin vs other SGLT2i?
While all drugs in this class have affinity for SGLT2, they have different selectivities for SGLT1 vs SGLT2. Canagliflozin has a selectivity ratio of ~ 160–410 for SGLT2 over SGLT1. In comparison, dapagliflozin’s ratio is 1,200 and empagliflozin 2,600. Due to canagliflozin’s lesser SGLT2 to SGLT1 selectivity, it is known to have effects on not only renal glucose reabsorption, but intestinal glucose absorption and metabolism as well. Thus, canagliflozin may work as a local and low-potency SGLT1 inhibitor as well as an SGLT2 inhibitor and it is possible that its effect on SGLT1 is important for senolytic function.
Other considerations?
SGLT2 inhibitors can cause hypoglycemia in non-diabetics and UTI/yeast infections in women, affecting benefit-risk analysis
SGLT2 inhibitors have been shown to be more effective in people over age 65 compared to those under age 65. This may reflect a higher senescent cell load in these individuals, suggesting that SGLT2i may also benefit patients with higher senescent load regardless of chronological age
Pathway targets?
AICAR could be an interesting intervention but is much less studied than SGLT2 inhibitors. While AICAR can be acquired, it is banned by the US anti-doping agency, not approved in any country, and is lacking data on dosing and safety in humans
How can SapereX help?
SapereX measures cellular senescence and T cell immune function. Our strategy of measuring both components is vital for understanding senescent cell load, guiding patient selection, and monitoring treatment efficacy.
SapereX reports cellular senescence to identify patients who could most benefit from senolytic interventions
SapereX reports a composite metric of immune function to identify patients who may be accumulating senescent cells due to impairment in clearance and may be poised to benefit from therapies that improve immune clearance of senescent cells
SapereX also reports T cell exhaustion, a metric that in particular may help stratify patients for a novel senolytic treatment like SGLT2i
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