17‐α estradiol ameliorates age‐associated sarcopenia and improves late‐life physical function in male mice but not in females or castrated males

Abstract

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.

Canagliflozin extends life span in genetically heterogeneous male but not female mice

“…Both acarbose and 17aE2 reduce mid-life hypothalamic inflammation in male mice only (20). More work will be needed to work out the molecular and physiological explanation(s) for these sex-specific effects, but it is notable that at least some of these effects are blocked by castration of young adult male mice before the initiation of treatment by acarbose or 17aE2 (31,32), suggesting that levels of male hormones, even in postpubertal adults, sensitize mice to life span extension by these drugs.…”

Canagliflozin Extends Lifespan in Genetically Heterogeneous Male But Not Female Mice

“…Only one other tested agent, the amino acid glycine, produced significant lifespan extension in both male and female mice, and the effect, though seen at each of the three ITP test sites, was quite small, yielding less than a 5% increase in median longevity (14). Effects of acarbose, including an increase glucose tolerance and mTORC2 function (27) and a reduction of subscapular fat depots (15), were seen principally in males, and the effects of 17aE2 on metabolite profiles, glucose control, grip strength, and rotarod performance were also male-specific (28). Both acarbose and 17aE2 reduce mid-life hypothalamic inflammation in males only (17).…”

“…Both acarbose and 17aE2 reduce mid-life hypothalamic inflammation in males only (17). More work will be needed to work out the molecular and physiological explanation(s) for these sex-specific effects, but it is notable that at least some of these effects are blocked by castration of young adult male mice prior to the initiation of treatment by acarbose or 17aE2 (27,28), suggesting that levels of male hormones, even in post-pubertal adults, sensitize mice to lifespan extension by these drugs.…”

Sex hormones underlying 17a-Estradiol effects on neuroinflammation

“…Improvements in glucose tolerance and enhanced hepatic mTORC2 signaling with 17aE2 treatment are observed in male mice only, and these effects are inhibited in castrated males. Furthermore, 17aE2 treatment improves male grip strength and capacity to balance on a rotarod, and these improvements are not seen in castrated male mice treated with 17aE2 (Garratt et al 2019). The hypothalamus is a major central regulator of peripheral metabolism, and the regulation of metabolism via this region is influenced by inflammatory responses (Zhang et al 2013).…”