Novel frame-shift mutation in Slc5a2 encoding SGLT2 in a strain of senescence-accelerated mouse SAMP10.

The senescence-accelerated mouse prone10 (SAMP10) strain, a model of aging, exhibits cognitive impairments and cerebral atrophy. We noticed that SAMP10/TaSlc mice, a SAMP10 substrain, have developed persistent glucosuria over the past few years. In the present study, we characterized SAMP10/TaSlc mice and further identified a spontaneous mutation in the Slc5a2 gene encoding sodium-glucose co-transporter (SGLT) 2. The mean concentration of urine glucose was high in SAMP10/TaSlc mice and increased further with advancing age, whereas other strains of senescence-accelerated mice, including SAMP1/SkuSlc, SAMP6/TaSlc and SAMP8/TaSlc or normal aging control SAMR1/TaSlc mice, exhibited no detectable glucose in urine. SAMP10/TaSlc mice consumed increasing amounts of food and water compared to SAMR1/TaSlc mice, suggesting the compensation of polyuria and the loss of glucose. Oral glucose tolerance tests showed decreased glucose reabsorption in the kidney of SAMP10/TaSlc mice. In addition, blood glucose levels decreased in an age-dependent fashion. The kidney was innately larger than that of control mice with no histological alterations. We examined the expression levels of glucose transporters in the kidney. Among SGLT1, SGLT2, glucose transporter (GLUT) 1 and GLUT2, we found a significant decrease only in the level of SGLT2. DNA sequencing of SGLT2 in SAMP10/TaSlc mice revealed a single nucleotide deletion of guanine at 1236, which resulted in a frameshift mutation that produced a truncated protein. We designate this strain as SAMP10/TaSlc-Slc5a2(slc) (SAMP10-ΔSglt2). Recently, SGLT2 inhibitors have been demonstrated to be effective for the treatment of patients with type 2 diabetes (T2D). SAMP10-ΔSglt2 mice may serve as a unique preclinical model to study the link between aging-related neurodegenerative disorders and T2D.

Beta-cryptoxanthin, plentiful in Japanese mandarin orange, prevents age-related cognitive dysfunction and oxidative damage in senescence-accelerated mouse brain.

Increased oxidative stress is known to accelerate age-related pathologies. Beta-cryptoxanthin (ß-CRX, (3R)-ß,ß-caroten-3-ol) is a potent antioxidant that is highly rich in Satsuma mandarin orange (mandarin), which is the most popular fruit in Japan. We investigated the antioxidative and anti-aging effects of ß-CRX and mandarin using senescence-accelerated mice (SAMP10), which were characterized by a short lifespan, high generation of superoxide anions in the brain and poor learning ability with aging. ß-CRX (0.5-5.0 µg/ml) or mandarin juice (3.8-38.0%) was added to drinking water of SAMP10 one to 12 months of age. ß-CRX was dose-dependently incorporated into the cerebral cortex and the contents were similar to the concentration of ß-CRX in the human frontal lobe. These mice also had higher learning ability. The level of DNA oxidative damage was significantly lower in the cerebral cortex of mice that ingested ß-CRX and mandarin than control mice. In addition, the mice that ingested ß-CRX (>1.5 µg/ml) and mandarin (>11.3%) exhibited a higher survival when 12 month-old, the presenile age of SAMP10, than control mice. These results suggest that ß-CRX is incorporated into the brain and has an important antioxidative role and anti-aging effect.