Canagliflozin enhances senescent cell clearance, improving aging-related conditions

In a recent study published in Nature Aging, researchers investigated whether sodium-glucose co-transporter 2 (SGLT2) inhibitors induce senolysis.

Study: SGLT2 inhibition eliminates senescent cells and alleviates pathological aging. Image Credit: tomertu/Shutterstock.comStudy: SGLT2 inhibition eliminates senescent cells and alleviates pathological aging. Image Credit: tomertu/Shutterstock.com

Background

Senescent cells, responsible for aging, amass in tissues and endure permanent growth stops, leading to age-associated illnesses.

However, blocking senescence regulators can induce cancer. Senolysis, or senescent cell removal, improves aging symptoms such as metabolic illness, cardiovascular disease, bone loss, and renal failure while prolonging life without raising cancer risk.

Caloric restriction can lengthen organisms' lifespans, and some research indicates that SGLT2 inhibitor drugs may have senolytic impacts.

About the study

In the present study, researchers evaluated the senolytic effects of SGL2 inhibition. Researchers investigated the impact of SGLT2 inhibitors on the senescent cellular load in vivo. They fed mice high-fat diets (HFD) for eight to ten weeks, followed by treatment with canagliflozin, an SGL2 inhibitor, for seven days.

The team compared glucose metabolism following seven days of canagliflozin and insulin therapy to one week without canagliflozin administration.

The researchers used transgenic mice to study the senolytic impact of canagliflozin. They administered canagliflozin to mice for a week, with or without diphtheria toxins (DT). They evaluated the effect of restoring metabolic processes by HFD-fed mice returning to regular chow on senescent cell accumulation.

They also examined the function of 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR), an adenosine monophosphate-activated protein kinase (AMPK) activator, in senolysis induction by canagliflozin.

The team developed a paradigm in which they drove fibroblasts from CAG-tdTomato reporter mice into cellular senescence, combined with Matrigel, and transplanted into the subcutaneous tissue of wild-type mice.

They examined senescent cell clearance from Matrigel to evaluate the effects of canagliflozin and AMPK deletion on senescent cell removal.

The researchers investigated the impact of canagliflozin on premature aging development in ApoE-knockout mice. Starting at 12 weeks of age, they administered canagliflozin or vehicle to Zmpste24 KO mice and measured survival.

They also administered canagliflozin to wild-type murine animals over 20 weeks to investigate pathological aging characteristics.

They measured canagliflozin concentrations in serum using ultra-performance liquid chromatography/tandem mass spectrometry and tested canagliflozin's in vitro protein binding by equilibrium dialysis.

Results

Inhibiting SGLT2 with canagliflozin increased senescent cell clearance, which improved age-related phenotypic alterations.

In a murine dietary adiposity model, short-term therapy with canagliflozin decreased senescence loads in visceral fat while improving inflammation and metabolic dysregulation. However, insulin therapy to normalize plasma glucose did not affect senescent cells.

Canagliflozin increased the longevity of murine animals with accelerated aging, even in the case of therapy commencing in the middle age group. Short-term canagliflozin therapy increased AICAR levels, improved immunologically related senescent cell clearance, and decreased programmed cell death ligand 1 (PD-L1) expression.

Short-term canagliflozin therapy did not impact body weight, gonadal white adipose tissues (gWAT), oxygen consumption, or dietary intake. However, the drug dramatically lowered insulin resistance, reducing glucose intolerance compared to controls.

In vivo, fluorescence imaging revealed that canagliflozin and DT dramatically reduced ARF tumor suppressor protein (p19Arf)-expressing cell accumulation in HFD-fed mice.

In the animals, short-term treatment with insulin decreased insulin resistance and glucose intolerance while not altering the gonadal white adipose tissue weight or body weight compared to controls. However, canagliflozin therapy did not alter HFD-inflicted senescence-resembling alterations or inflammatory reactions in the gonadal white adipose tissue.

Returning HFD-fed murine animals to regular chow for a week improved blood glucose and marginally lowered body weight without impacting the gonadal white adipose tissue weight. Canagliflozin's benefits were not the result of normalized glucose metabolism.

AICAR treatment raised fasting blood glucose and decreased senescence-associated β-galactosidase (SA-β-gal) activities in the gonadal white adipose tissues compared to controls.

The study showed that canagliflozin has senolytic effects due to T-cell activation and that clusters of differentiation 3 (CD3)-neutralizing antibodies reduce its impact on senescent cells.

SGLT2 inhibition decreased tdTomato-positive senescent cells, reversed by AMPK knockdown. Inhibiting SGLT2 increased mice's longevity while improving senescence-like alterations in the aorta, lowering inflammatory marker expression, and eliminating senescent cells from atherosclerotic plaques.

The findings indicated that inhibiting SGLT2 might help eradicate senescent cells from atherosclerotic plaques.

Conclusion

The study findings revealed that inhibiting SGLT2 improves senescent cell immunosurveillance associated with heart failure, diabetes, and chronic renal disease. SGLT2 inhibition causes a systemic metabolism comparable to fasting and calorie restriction.

Short-term therapy with the AMPK activator, AICAR, produced senolytic effects comparable to canagliflozin. However, inhibiting AMPK reduced the senolytic action of canagliflozin.

The findings imply that AMPK-activating medications, such as biguanides, may provide comparable effects.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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