Small molecule conjugates with selective estrogen receptor 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) can cause major safety concerns due to the enrichment of ER in female tissues and certain malignancies. In contrast, ER is more broadly expressed in metabolic tissues and the skin. Thus, it is desirable to generate selective ER agonist conjugates for maximizing the therapeutic effects of ERs while minimizing the risks of ER activation. Here, we report the design and production of small molecule conjugates containing selective non-steroid ER 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 . We further uncovered the benefits of ER 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-selective agonist conjugates offer novel therapeutic potential to improve aging-associated conditions and aid in rejuvenating skin health.