Heinze Stefan S, Hodgins Maddison L, Howlett Susan E
Department of Pharmacology, Dalhousie University, Halifax, NS, Canada.
Department of Medicine (Geriatric Medicine), Dalhousie University, Halifax, NS, Canada.
Mech Ageing Dev. 2025 Jun;225:112054. doi: 10.1016/j.mad.2025.112054. Epub 2025 Mar 28.
Androgen receptors (AR) are promising therapeutic targets for mechanisms of aging, including chronic inflammation, lean mass loss, and worsening bone health. We investigated the impact of RAD140, a selective AR modulator that activates ARs, on frailty and underlying mechanisms in older C57BL/6 mice.
Mice (23.7-25.5 months; N = 21 males; 15 females) received RAD140 (5 mg/kg/day) or placebo (DMSO) daily for 6-weeks. Frailty (clinical and lab-based), body composition, circulating inflammatory markers, grip strength, and genes relating to function/hypertrophy in quadriceps femoris muscles were assessed.
Despite no differences in frailty between treatment and control, there were positive effects in male, but not female mice. RAD140 treated male mice had preserved lean mass (p = 0.024) and bone mineral density (p = 0.004) and lower serum interleukin-6 (p = 0.043) versus controls. In contrast, benefits to body composition and inflammatory markers were not seen in females. In either sex, grip strength, fat mass, and skeletal muscle genes were unaffected.
Six-weeks of RAD140 treatment did not affect frailty in older male or female mice. The beneficial effects in lean mass, bone mineral density, and systemic inflammation warrant longer treatments to explore any positive impact on frailty in males. RAD140 may not be ideal for achieving these in females.
雄激素受体（AR）是衰老机制中很有前景的治疗靶点，包括慢性炎症、瘦体重流失和骨骼健康恶化。我们研究了一种激活AR的选择性AR调节剂RAD140对老年C57BL/6小鼠衰弱及潜在机制的影响。
小鼠（23.7 - 25.5个月；21只雄性；15只雌性）每天接受RAD140（5毫克/千克/天）或安慰剂（二甲亚砜），持续6周。评估衰弱情况（临床和基于实验室指标）、身体成分、循环炎症标志物、握力以及股四头肌中与功能/肥大相关的基因。
尽管治疗组和对照组在衰弱方面没有差异，但RAD140对雄性小鼠有积极作用，对雌性小鼠则没有。与对照组相比，接受RAD140治疗的雄性小鼠保留了瘦体重（p = 0.024）和骨矿物质密度（p = 0.004），血清白细胞介素 - 6水平较低（p = 0.043）。相比之下，雌性小鼠在身体成分和炎症标志物方面未观察到益处。无论雄性还是雌性，握力、脂肪量和骨骼肌基因均未受影响。
为期6周的RAD140治疗对老年雄性或雌性小鼠的衰弱情况没有影响。RAD140在瘦体重、骨矿物质密度和全身炎症方面的有益作用值得进行更长时间的治疗，以探索其对雄性衰弱的任何积极影响。RAD140可能并非实现雌性这些效果的理想药物。
