The reintroduction of estrogen hormonal therapy (HRT) may go down in history as one of the biggest blunders medicine has ever made. Not only have breast cancer (and other cancer) deaths reversed their decline since doctors started recommending estrogen again as HRT for aging women (and even men), but aging-related functional decline has also accelerated over the same time period. One of the lesser known members of the estroge family is the so called estrogen-related receptor gamma (ERRy). It is a nuclear receptor and and part of the ERa/ERb group, but medicine claims that ERRy has no known endogenous ligand and that major estrogens such as estradiol or estrone do not activate it. However, ERRy expression is increased whenever another one of the estrogen receptors is activated. So, if/when estradiol activates ERa, for example, that results in downstream transcription cascade that increases the expression of ERRy as well. Conversely, estrogen antagonists such as fulvestrant and SERM drugs such as tamoxifen are known antagonists of ERRy, confirming that ERRy behaves very much like the rest of the estrogen receptors. Interestingly enough, the bisphenol family of high estrogenic endocrine distuptors from plastic, also potently activate ERRy. A number of studies have also found that ERRy is overexpressed in many cancers and that activating ERRy is a major driver of the cancerization of normal tissue, characterized by the well-known metabolic shifts (e.g. Warburg Effect) seen in cancer. Conversely, blocking ERRy has shown great promise as a treatment even for cancers medicine claims are hormone-independent.
https://doi.org/10.1002/adtp.202400192
“…Several independent studies have implicated ERR isoforms like ERRα, ERRβ, and ERRγ in the pathways of cancer development and progression. The construction of tissue-specific ERR transgenic or knockout mice and the application of synthetic ligands have precisely indicated the critical and diverse role of ERRγ than other isoforms. ERRγ, plays a critical and diverse role, enabling switching metabolism to oncometabolism in favor of cancer cells, making it a “hot target” in cancer therapy. ERRγ expression is correlated with the clinical status of diverse cancer types and various cancer tissue treatments.”
Now, a new study has shown that ERRy is solely responsible for the well-known muscle remodeling effect seen in aging. Namely, the switch of muscles fibers from the fast-twitch type II to the slow-twitch type I. The former type is predominant in young people and allows quick bursts of explosive power, and relies primarily on glucose metabolism for its function. The latter type is seen primarily in old people an endurance athletes and produces much lower levels of power but over extended periods of time, and oxidizes primarily fat as fuel. The evidence available so far suggests that the loss of the fast-twitch fibers seen in aging is largely responsible for the frailty and sarcopenia seen in advanced age and various chronic conditions. Just as in cancer, the role of ERRy is crucial for this muscle process as well, and blocking ERRy fully prevented this undesirable muscle remodeling. Interestingly enough, the effects of ERRy were mediated through decline in the levels of cardiolipin – the crucial respiratory complex lipid that Ray mentioned in several of his articles. Thus, once again, decline in oxidative metabolism is found to play a central role in a completely “structural” issue, which is something medicine to this day denies could be the case. While there is currently no evidence that progesterone or the androgens act directly as antagonists at ERRy, they do antagonize the rest of the estrogen receptor family and as such lead to decreased expression of ERRy. This effects would also explain, at least partially, the ability of those steroids to preserve the fast-twitch fiber morphology even in advanced age. Finally, several studies have demonstrated that supplementing with lipids devoid of PUFA restored cardiolipin levels back to youthful levels, so this could be another method for inhibiting the muscle decline seen in aging.
https://dx.doi.org/10.1038/s43587-026-01227-7
https://medicalxpress.com/news/2026-09-hidden-biggest-paradoxes-aging-muscle.html
“…The scientists found that cardiolipin levels decline in mouse and human muscle mitochondria with age and disease, leaving the mitochondria distorted and unable to operate properly. To test whether falling cardiolipin was a cause rather than a consequence, the scientists lowered cardiolipin levels in young mice to mimic the drop seen in aging. They saw the same shift from fast-twitch to slow-twitch muscle fibers that occurs naturally in aged mice and humans. When cardiolipin levels were partially restored to roughly two-thirds of normal, the muscle wasting began to reverse, and the animals’ early deaths were prevented entirely.”
“…As cardiolipin levels decline, strained mitochondria generate far more reactive oxygen species (ROS), which damage cells. But ROS also serves as a signal: When the researchers used an antioxidant to mop up ROS in cardiolipin-depleted muscle cells, the shift toward slow-twitch fibers was blunted. The switch itself runs through a protein called ERRγ, which triggers the cells to remodel their mitochondria and change fiber type from fast-twitch to slow-twitch. When the scientists blocked ERRγ in cultured muscle cells, the fiber switch was completely shut down.”
