Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice

Yildirim, Gozde; Bergamo, Edmara Tatiely Pedroso; Poudel, Sher Bahadur; Ruff, Ryan Richard; Dixit, Manisha; Hu, Bin; Mijares, Dindo Q.; Witek, Lukasz; Chlebek, Carolyn; Harrison, David E.; Strong, Randy; Miller, Richard A.; Ladiges, Warren; Bromage, Timothy G.; Rosen, Clifford J.; Yakar, Shoshana

doi:10.1007/s11357-023-00803-8

Cited by 5 publications

(3 citation statements)

References 72 publications

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“…Micro-CT was done in accordance with the American Society for Bone and Mineral Research (ASBMR) guidelines [20]. Bones were scanned using a high-resolution SkyScan micro-CT system (SkyScan 1172, Kontich, Belgium) containing 10-M digital detector set at a 10W energy level (100kV and 100 μA), with a 0.5 mm aluminum filter with a 9.7μm image voxel size as described in our recent papers [21-23]. Data reconstruction was done using NRecon software (version 1.7.3.0; Bruker micro-CT, Kontich, Belgium), data analysis was done using CTAn software (version 1.17.7.2+; Bruker micro-CT, Kontich, Belgium) and 3D images were done using CT Vox software (version 3.3.0 r1403; Bruker micro-CT, Kontich, Belgium).…”

Section: Methodsmentioning

confidence: 99%

Deletion of absent in melanoma (AIM) 2 gene alters bone morphology

Gong,

Dixit,

Poudel

et al. 2024

Preprint

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Absent in Melanoma (AIM) 2 is a gene that is induced by interferon and acts as a cytosolic sensor for double-stranded (ds) DNA. It forms the AIM2 inflammasome, leading to the production of interleukin (IL)-1β and IL-18. Our previous research demonstrated that mice lacking AIM2 exhibit spontaneous obesity, insulin resistance, and inflammation in adipose tissue. In this study, we aimed to explore the impact of AIM2 gene deletion on bone structure in adult and aged mice. Utilizing micro-computed tomography (micro-CT), we discovered that female mice lacking AIM2 showed an increase in the total cross-sectional area at 5 months of age, accompanied by an increase in cortical thickness in the mid-diaphysis of the femur at both 5 and 15 months of age. At 15 months of age, the cortical bone mineral density (BMD) significantly decreased in AIM2 null females compared to wild-type (WT) mice. In AIM2 null mice, both trabecular bone volume and BMD at the distal metaphysis of the femur significantly decreased at 5 and 15 months of age. Similarly, micro-CT analysis of the L4 vertebra revealed significant decreases in trabecular bone volume and BMD in aged AIM2 null females compared to WT mice. Histological examination of femurs from aged mice demonstrated increased bone marrow adiposity in AIM2 null mice, accompanied by a significant increase in CD45-/CD31-/Sca1+/Pdgfa+ adipose progenitor cells, and a decrease in the ratio of CD31-/CD31+ osteogenic progenitor cells, as determined by flow cytometry of bone marrow cells. Our findings suggest that AIM2 deficiency affects bone health by promoting adipogenesis in bone marrow cells and inducing a pro-inflammatory environment, potentially contributing to the decreased bone mineral density.

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Section: Methodsmentioning

confidence: 99%

Deletion of absent in melanoma (AIM) 2 gene alters bone morphology

Gong,

Dixit,

Poudel

et al. 2024

Preprint

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“…In the ITP, dietary canagliflozin (180 ppm) started at 7 months of age extended the lifespan of UM-HET3 male mice by 14% with no effect on females despite lower fasting glucose and improved glucose tolerance in both sexes [52]. Concerningly, canagliflozin use in patients with T2DM, UM-HET3 mice, and rats report adverse effects on bone health as evident by decreased bone mineral density and increased risk of fracture [185][186][187][188][189].…”

Section: Sglt2 Inhibitorsmentioning

confidence: 99%

“…More work is needed exploring the interaction between various exercise modalities and SGLT2i to determine if SGLTi can have favorable effects on exercise adaptations. Furthermore, there is a need to understand whether the osteogenic effects of exercise can protect against the decline in bone health with SGLT2i use [185][186][187][188][189]. The limited data to date in humans suggests SGLT2i may interfere with glucose control and insulin sensitivity but do not negatively impact several other health benefits of exercise.…”

Section: Sglt2i + Exercisementioning

confidence: 99%

Geroprotector drugs and exercise: friends or foes on healthy longevity?

Elliehausen,

Anderson,

Diffee

et al. 2023

BMC Biol

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Physical activity and several pharmacological approaches individually combat age-associated conditions and extend healthy longevity in model systems. It is tantalizing to extrapolate that combining geroprotector drugs with exercise could extend healthy longevity beyond any individual treatment. However, the current dogma suggests that taking leading geroprotector drugs on the same day as exercise may limit several health benefits. Here, we review leading candidate geroprotector drugs and their interactions with exercise and highlight salient gaps in knowledge that need to be addressed to identify if geroprotector drugs can have a harmonious relationship with exercise.

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Anti-aging interventions in geriatric mice: insights into the timing of treatment, benefits, and limitations

Malavolta

2024

GeroScience

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Long-term effects of canagliflozin treatment on the skeleton of aged UM-HET3 mice

Cited by 5 publications

References 72 publications

Deletion of absent in melanoma (AIM) 2 gene alters bone morphology

Deletion of absent in melanoma (AIM) 2 gene alters bone morphology

Geroprotector drugs and exercise: friends or foes on healthy longevity?

Anti-aging interventions in geriatric mice: insights into the timing of treatment, benefits, and limitations

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