INTRODUCTION
A multifactorial and complex process, aging is defined as the culmination over time of damage in cells and tissues resulting in altered function of an organism. Intrinsic and inevitable, the aging process impacts every organ of the human body, including the skin, leading to age-related diseases and ultimately death. Oxidative stress, cellular senescence, chronic inflammation, and the accumulation of metabolic waste products are major contributing factors to aging.1 Skin aging affects not only its protective mechanical and immunological functions but also its aesthetic appearance. Two antihyperglycemic drugs, metformin and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have garnered interest for their geroprotective properties.2,3 The review herein will summarize the mechanisms underlying how these drugs may be protective specifically against skin aging.
Pathogenesis of Skin Aging
Defining features of aged skin are decreased elasticity, epidermal atrophy, dyschromia, and xerosis.4 A main intrinsic factor of skin aging is the decline of estrogen and androgen levels over time, while the primary extrinsic factor is exposure to ultraviolet radiation (UVR).5 Common to both intrinsic (chronological) and UVR-induced skin aging is the increased generation of reactive oxygen species (ROS) and DNA damage. Both products lead to increased induction of matrix metalloproteinases (MMPs), thereby increasing degradation of collagen and other extracellular matrix components and inhibiting neocollagenesis.5
Advanced glycation end products (AGEs) are increasingly implicated in age-related diseases.6 AGEs are free amino acids of nucleic acids, proteins, or lipids covalently bonded together under high-glucose conditions.7 Accumulating in the skin throughout aging and during high-glycemic states, AGEs lead to the transcription of proinflammatory genes through activation of the nuclear factor kappa B (NF-kB), induce oxidative stress, and impair the biomechanical properties of skin through deleterious modification of collagen, elastin, and fibronectin.6,8 Reducing the accumulation of AGEs and thus activation of the receptor for AGE (RAGE) through anti-hyperglycemic medications therefore may protect against skin aging. A summary of putative anti-aging mechanisms can be found in the Table.
Antihyperglycemic Medications and Skin Aging
Metformin
Metformin is a synthetic biguanide used as a first-line treatment for type 2 diabetes. By enhancing insulin sensitivity, decreasing glucose production in the liver, increasing GLP-1, and reducing intestinal absorption of glucose, metformin effectively lowers basal and post-prandial blood glucose levels.9,10 Metformin has been associated with a reduction in early mortality due to age-related diseases and this effect is theorized to be a result of its antihyperglycemic actions.2 Studies specifically investigating the impact of metformin on skin aging have been conducted in vitro and using animal models. Treatment of human foreskin fibroblasts with 100 microM metformin
