Abstract

Metformin is a widely accepted first-line hypoglycemic agent in current clinical practice, and it has been applied to the clinic for more than 60 years. Recently, researchers have identified that metformin not only has an efficient capacity to lower glucose but also exerts anti-aging effects by regulating intracellular signaling molecules. With the accelerating aging process and mankind’s desire for a long and healthy life, studies on aging have witnessed an unprecedented boom. Osteoporosis, sarcopenia, degenerative osteoarthropathy, and frailty are age-related diseases of the musculoskeletal system. The decline in motor function is a problem that many elderly people have to face, and in serious cases, they may even fail to self-care, and their quality of life will be seriously reduced. Therefore, exploring potential treatments to effectively prevent or delay the progression of aging-related diseases is essential to promote healthy aging. In this review, we first briefly describe the origin of metformin and the aging of the movement system, and next review the evidence associated with its ability to extend lifespan. Furthermore, we discuss the mechanisms related to the modulation of aging in the musculoskeletal system by metformin, mainly its contribution to bone homeostasis, muscle aging, and joint degeneration. Finally, we analyze the protective benefits of metformin in aging-related diseases of the musculoskeletal system.

Highlights

  • Metformin is a widely used oral hypoglycemic agent originally extracted from Galega officinalis, a traditional European herb, and was first reported in 1957 for the treatment of diabetes (Marshall, 2017; Flory and Lipska, 2019)

  • AKT is a protein kinase associated with cell survival and apoptosis, and in vitro experiments suggest that metformin reverses oxidative stress damage induced by a high glucose environment through the ROS-AKT-mTOR axis and promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts (Zhou et al, 2020)

  • Reduced the risk of both osteoporosis and vertebral fracture by 30–40% Femoral neck bone mineral density was higher in the metformin compared to the placebo group Metformin treatment has a small but positive effect on the mineral content and density of peripheral bone lower risk of osteoporosis in adult women regardless of the presence of type 2 diabetes or obesity Reduced risk of sarcopenia in patients with type 2 diabetes Anti-oxidative stress; promoted skeletal muscle differentiation and myotubular maturation by regulating signaling molecules such as ERKs and AKT; prevented sedentariness damages Impaired muscle function by modulating myostatin in skeletal muscle cells via the AMPK-FoxO3a-HDAC6 pathway The combination of exercise and metformin prevented strength and muscle mass loss Inhibited the hypertrophic response to resistance training (Continued on following page)

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Summary

Introduction

Metformin is a widely used oral hypoglycemic agent originally extracted from Galega officinalis, a traditional European herb, and was first reported in 1957 for the treatment of diabetes (Marshall, 2017; Flory and Lipska, 2019). Metformin can play a pro-osteoclastogenic role by activating AMPK/BMP/Smad signaling pathway (Sun et al, 2021) Another similar study confirms that metformin promotes the osteogenic function of pro-osteoblasts in type 2 diabetic patients through the BMP-4/ Smad/Runx2 axis (Liang et al, 2020).

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