Small molecule conjugates with selective estrogen receptor β agonism promote anti-aging benefits in metabolism and skin recovery.

Estrogen is imperative to mammalian reproductivity, metabolism, and aging. However, the hormone activating estrogen receptor (ERs) α can cause major safety concerns due to the enrichment of ER α in female tissues and certain malignancies. In contrast, ER β is more broadly expressed in metabolic tissues and the skin. Thus, it is desirable to generate selective ER β agonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ER α activation. Here, we report the design and production of small molecule conjugates containing selective non-steroid ER β agonists Gtx878 or genistein. Treatment of aged mice with our synthesized conjugates improved aging-associated declines in insulin sensitivity, visceral adipose integrity, skeletal muscle function, and skin health, with validation in vitro. We further uncovered the benefits of ER β conjugates in the skin using two inducible skin injury mouse models, showing increased skin basal cell proliferation, epidermal thickness, and wound healing. Therefore, our ER β -selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health. The use of selective estrogen receptor β conjugate agonists in mice provides anti-aging benefits in metabolism and skin health. [Display omitted] [ABSTRACT FROM AUTHOR]