Canagliflozin retards age-related lesions in heart, kidney, liver, and adrenal gland in genetically heterogenous male mice

Abstract

Canagliflozin (Cana), a clinically important anti-diabetes drug, leads to a 14% increase in median lifespan and a 9% increase in the 90th percentile age when given to genetically heterogeneous male mice from 7 months of age, but does not increase lifespan in female mice. A histopathological study was conducted on 22-month-old mice to see if Cana retarded diverse forms of age-dependent pathology. This agent was found to diminish incidence or severity, in male mice only, of cardiomyopathy, glomerulonephropathy, arteriosclerosis, hepatic microvesicular cytoplasmic vacuolation (lipidosis), and adrenal cortical neoplasms. Protection against atrophy of the exocrine pancreas was seen in both males and females. Thus, the extension of lifespan in Cana-treated male mice, which is likely to reflect host- or tumor-mediated delay in lethal neoplasms, is accompanied by parallel retardation of lesions, in multiple tissues, that seldom if ever lead to death in these mice. Canagliflozin thus can be considered a drug that acts to slow the aging process and should be evaluated for potential protective effects against many other late-life conditions.

Keywords: Age-related pathology; Canagliflozin; ITP; Lifespan; Sexual dimorphism.

Fig. 1

The incidence or severity of age-related lesions was decreased in 22-month-old HET3 male mice treated with canagliflozin starting at 7 months of age. A Adrenal gland – cortical neoplasm, B Heart – arteriosclerosis, C Heart – cardiomyopathy, D Kidney – glomerulonephropathy, E Liver – microvesicular cytoplasmic vacuolation (lipidosis), and F Pancreas – exocrine atrophy

Fig. 2

Histology of the kidney and liver. Kidney (A–D). Representative histology images consistent with minimal glomerulonephropathy (A, grade 1); mild glomerulonephropathy (B, grade 2); and moderate glomerulonephropathy (C, grade 3) with increased mesangial matrix (asterisk) are shown. HE, original magnification 40 × . Arrows indicate the glomerulus. D Masson’s trichrome staining of a kidney with moderate glomerulonephropathy shows an irregular and focally depressed capsular surface (asterisk) and increased collagen deposition (blue staining, arrows) within the interstitium. Original magnification 10 ×. Liver (E-F). Microvesicular cytoplasmic vacuolation in male mice. E Normal liver without cytoplasmic vacuolation is shown (histologic grade 0). F Minimal centrilobular cytoplasmic microvesicular vacuolation (histologic grade 1)

Fig. 3

Histology of the heart and myocardial vessels. Heart (A–E) (HE, original magnification 20 ×) and F (Masson’s trichrome, original magnification 10 ×). A Normal myocardium (grade 0). B Minimal cardiomyopathy (grade 1). C Mild cardiomyopathy (grade 2). D Moderate cardiomyopathy (grade 3). E Severe cardiomyopathy with Masson’s trichrome (F) demonstrating regions of increased collagen deposition (blue staining, arrows) within the myocardium. G–J Myocardial vessels. G–H HE (G and I, original magnification 40 ×) and Masson’s trichrome (H and J, original magnification 20 ×). Normal myocardial vessels (arteriosclerosis grade 0) stained with HE (G) and Masson’s trichrome (H). I–J Arteriosclerosis (grade 2) stained with HE (I) and Masson’s trichrome (J)

Fig. 4

Histology of the pancreas demonstrating increasing severity of exocrine pancreatic atrophy and replacement with fat (asterisks). HE, original magnification 10 × . Islets indicated with “i.” A Normal pancreas (grade 0). B Grade 1, with minimal focal exocrine atrophy and replacement with adipose tissue (asterisk). Islet cell hyperplasia is also present. C Grade 2, mild exocrine atrophy. D Grade 3, moderate exocrine atrophy. E, F Grade 4, severe exocrine atrophy with regionally extensive near total loss of exocrine pancreatic tissue. Islets (i) and pancreatic ducts remain

Fig. 5

Canagliflozin influenced histologic lesions in female mice. A Adrenal gland – cortical neoplasm. B Pancreas – exocrine atrophy. C Thyroid – adenoma

Fig. 6

Canagliflozin affects bladder size in male but not female mice