Date Published: February 10, 2019
Publisher: John Wiley and Sons Inc.
Author(s): Michael Garratt, Danielle Leander, Kaitlyn Pifer, Brian Bower, Jonathan J. Herrera, Sharlene M. Day, Oliver Fiehn, Susan V. Brooks, Richard A. Miller.
Pharmacological treatments can extend mouse lifespan, but lifespan effects often differ between sexes. 17‐α estradiol (17aE2), a less feminizing structural isomer of 17‐β estradiol, produces lifespan extension only in male mice, suggesting a sexually dimorphic mechanism of lifespan regulation. We tested whether these anti‐aging effects extend to anatomical and functional aging—important in late‐life health—and whether gonadally derived hormones control aging responses to 17aE2 in either sex. While 17aE2 started at 4 months of age diminishes body weight in both sexes during adulthood, in late‐life 17aE2‐treated mice better maintain body weight. In 17aE2‐treated male mice, the higher body weight is associated with heavier skeletal muscles and larger muscle fibers compared with untreated mice during aging, while treated females have heavier subcutaneous fat. Maintenance of skeletal muscle in male mice is associated with improved grip strength and rotarod capacity at 25 months, in addition to higher levels of most amino acids in quadriceps muscle. We further show that sex‐specific responses to 17aE2—metabolomic, structural, and functional—are regulated by gonadal hormones in male mice. Castrated males have heavier quadriceps than intact males at 25 months, but do not respond to 17aE2, suggesting 17aE2 promotes an anti‐aging skeletal muscle phenotype similar to castration. Finally, 17aE2 treatment benefits can be recapitulated in mice when treatment is started at 16 months, suggesting that 17aE2 may be able to improve aspects of late‐life function even when started after middle age.
With an increased proportion of individuals living to older ages, a greater proportion of the human population suffers from frailty and impaired physical function. Demographic models predict that the number of people living to old ages in high‐income countries will increase (Colby & Ortman, 2017; Robine & Cubaynes, 2017), which presents a potentially substantial burden for healthcare and economic systems. Interventions that can slow age‐related physical decline and improve health later in life would help to ameliorate this burden, while improving the quality of life for elderly adults. Pharmacological treatments are increasingly being recognized as potential methods to slow functional declines during aging in humans (Longo et al., 2015), in addition to reducing the incidence of age‐associated morbidities and neurological decline.
Pharmacological treatments that extend the lifespan of laboratory organisms deserve consideration as guides to interventions that could improve healthy aging in humans (Longo et al., 2015). A key criterion is that lifespan extension should be associated with improved physical function and health, which has not always been met when functional tests have been performed on long‐lived animals (Bansal, Zhu, Yen, & Tissenbaum, 2015; Richardson et al., 2015). In this study, we show that the lifespan extension observed with 17aE2 is associated with reduced age‐associated sarcopenia and improved late‐life physical function, benefits that can be gained even from a 6‐month treatment period beginning at middle age. However, these effects largely occur in a sex‐specific manner, matching the lifespan response seen with this treatment (Strong et al., 2016). Among the outcomes we tested, only elevations in skeletal muscle fiber size and altered body weight occurred to a similar degree in both sexes. The similar changes in body weight with 17aE2 in both sexes are particularly notable, since reductions in body weight with the onset of 17aE2 treatment have been linked to reduced feeding behavior as a consequence of actions at hypothalamic pro‐opiomelanocortin (POMC) expressing neurons (Steyn et al., 2018). The observation that body weight declines in both sexes with 17aE2, but functional benefits occur only in males, could suggest that the beneficial anti‐aging effects of 17aE2 are not purely a consequence reduced body weight and consumption of fewer calories, because we would expect this to benefit both sexes. Ultimately, normalization of food intake between controls and 17aE2 is required to definitively test this, either via a controlled feeding approach or by using a mouse model without functional POMC expression. Previous use of mice lacking POMC expression has shown some metabolic responses to 17aE2 can occur without changes in weight and feeding (Steyn et al., 2018), supporting the hypothesis that health benefits of 17aE2 are independent of reductions in calorie intake.
A detailed outline of all experimental procedures and statistical approaches is found in the supplementary information. UM‐HET3 mice were produced and maintained as previously described (Miller et al., 2014; Strong et al., 2008). Mice were given free access to water and were fed Purina 5LG6 after weaning. Mice were group housed in ventilated cages and were transferred to fresh cages every 14 days. Temperature was maintained within the range of 21–23°C. At 3 months of age, all animals in cohort 1 went through castration, ovariectomy or a sham procedure as previously described (Garratt, Bower et al., 2017; Garratt et al., 2018). Cohort 2 did not go through surgeries and had normal gonadal hormone production.