MTFHRT@groups.io | HRT and brain

CRISPR–Cas9 screens reveal regulators of ageing in neural stem cells

https://www.nature.com/articles/s41586-024-07972-2

"Ageing impairs the ability of neural stem cells (NSCs) to transition from quiescence to proliferation in the adult mammalian brain. Functional decline of NSCs results in the decreased production of new neurons and defective regeneration following injury during ageing1,2,3,4. Several genetic interventions have been found to ameliorate old brain function5,6,7,8, but systematic functional testing of genes in old NSCs—and more generally in old cells—has not been done. Here we develop in vitro and in vivo high-throughput CRISPR–Cas9 screening platforms to systematically uncover gene knockouts that boost NSC activation in old mice. Our genome-wide screens in primary cultures of young and old NSCs uncovered more than 300 gene knockouts that specifically restore the activation of old NSCs. The top gene knockouts are involved in cilium organization and glucose import. We also establish a scalable CRISPR–Cas9 screening platform in vivo, which identified 24 gene knockouts that boost NSC activation and the production of new neurons in old brains. Notably, the knockout of Slc2a4, which encodes the GLUT4 glucose transporter, is a top intervention that improves the function of old NSCs. Glucose uptake increases in NSCs during ageing, and transient glucose starvation restores the ability of old NSCs to activate. Thus, an increase in glucose uptake may contribute to the decline in NSC activation with age. Our work provides scalable platforms to systematically identify genetic interventions that boost the function of old NSCs, including in vivo, with important implications for countering regenerative decline during ageing."

Sex hormones and diseases of the nervous system

https://genomicpress.kglmeridian.com/view/journals/brainmed/aop/article-10.61373-bm025w.0008/article-10.61373-bm025w.0008.xml

Introduction
This paper is dedicated with heartfelt gratitude to Dr. Seymour (Si) Reichlin whose mentorship during a fellowship in neuroendocrinology at Tufts (1987–1988) continues to inform my career. For neurologists such as myself, the scope of clinical neuroendocrinology broadens significantly when considering the pervasive influences of circulating gonadal hormones on neurological disease expression. This article examines the diverse range of central and peripheral nervous system disorders affected by reproductive hormone fluctuations. The review focuses predominantly on steroid–neural interactions in women, given that the relatively stable (tonic) pattern of androgen secretion in men makes it more challenging to delineate the roles of testicular hormones in the natural history of neurological disorders.

Hormonal changes associated with specific stages of the menstrual cycle, pregnancy, menopause, and exposure to exogenous sex hormones can impact the release and metabolism of neurotransmitters and neuromodulators, potentially triggering or altering the semiology of various neurological and neuropsychiatric conditions. This review covers the major categories of human neurological disease—vascular, metabolic, inflammatory, degenerative, and others—with emphasis on how these conditions manifest in women. Neurological disorders that respond to specific hormonal and antihormonal therapies are highlighted. The involvement of gonadal hormones in psychiatric conditions such as depression, psychosis, and premenstrual syndrome is covered in other sources (1).

Seems there is positive effect of estradiol produced specifically in the brain, not just systemic estradiol in blood. In this case, the effect is on appetite control. For this to work (at least in the mouse model), you need to have aromatase working, and to have feedstock, which is testosterone. This action is not duplicated with just blood estradiol.

https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.17426

Estrogen synthesized in the central nervous system enhances MC4R expression and reduces food intake

Estrogen is synthesized throughout various tissues in the body, and its production is regulated by the rate-limiting enzyme aromatase (encoded by the Cyp19a1 gene). Notably, aromatase is also expressed in central nervous system cells, allowing for localized estrogen synthesis in regions such as the hypothalamus. Estrogens produced within these neurons are referred to as neuroestrogens. In this study, we investigated the role of neuroestrogens in the regulation of appetite through modulation of hypothalamic pathways in OVX, ArKO, and aromatase-restored mice. Estrogen suppresses appetite by influencing the expression of appetite-regulating peptides, including POMC and NPY, via MC4R. We explored the direct effects of neuroestrogens, independent from ovarian estrogen, on appetite suppression and the underlying molecular mechanisms. We monitored body weight and food intake and evaluated the expression of Cyp19a1, Mc4r, and other appetite-related genes. Our findings indicate that OVX and ArKO mice exhibited increased body weight and food consumption, which correlated with altered expression of Mc4r and Cyp19a1. Conversely, restoration of Cyp19a1 expression in a neuron specific manner significantly decreased food intake and increased Mc4r expression in the hypothalamus. Furthermore, neuroestrogens enhanced leptin responsiveness. Our results imply that neuroestrogens likely contribute to appetite regulation and may be relevant for body weight reduction.

Well that's kind of a bummer.
Or is there a way to get my brain into producing those neuroestrogens?

I actually tried using bovine ovaries from Swanson myself for over a year. The idea behind it is to stimulate aromatase activity, enabling the conversion of testosterone into estrogen. Of course, this only works if you still have your testicles. Personally, I didn’t notice any significant changes, but I also wasn’t doing regular blood monitoring. That said, there are people who report noticeable effects, so it seems to work for some—especially at relatively high doses.

Whether the effect is permanent, I can’t say for sure, but according to the manufacturer, it should be. After Brexit, though, it became really difficult to get hold of the product, as it was constantly sold out and quite expensive. That’s ultimately why I stopped using it.

03.05.2025 22:42:04 Zoe Vee via groups.io <stephenie.vee@...>: