Effects of Low Testosterone on Frailty and a Selective Androgen Receptor Modulator on Frailty, Frailty Mechanisms, and Cardiac Structure and Function in Older Mice

Abstract

Frailty is a state of increased risk to health issues and can arise in older age and during disease. Low circulating levels of testosterone, especially in older men, are thought to predispose toward a frail state due to links between low testosterone and mechanisms of frailty, including chronic inflammation, muscle wasting, and cardiac disease. However, results from a 6-month longitudinal study presented in this thesis suggested that chronic low levels of testosterone in older male C57BL/6 mice do not strongly predispose toward frailty, suggesting that low testosterone may correlate with frailty in older men but may not potently drive it. On the other hand, testosterone treatment improves aspects of frailty. An emerging class of drugs called selective androgen receptor modulators (SARMs) offer an exciting alternative to testosterone therapy due to their tissue selectivity in muscle and bone. A SARM was given (5 mg/kg/day of RAD140) to older male and female C57BL/6 mice for 6-weeks to investigate the impact on frailty, body composition, and chronic inflammation compared to vehicle treated mice. Not much is known about how SARMs affect the heart, but because low testosterone levels correlate with poor cardiac function, this also was assessed using echocardiography. Frailty levels were unchanged between treatment groups after 6-weeks, but SARM treated male mice had improvements in lean mass, bone mineral density, chronic inflammation, and cardiac function compared to control mice. SARM treated females only had better cardiac function, while demonstrating increased circulating levels of three pro-inflammatory cytokines compared to controls. These results suggested that the SARM RAD140 was able to beneficially change several bodily systems related to frailty in males, but not females. Future studies investigating RAD140 as a treatment for frailty are warranted, especially in males.