The Rhyothemis princeps Brain Externalization Project

 I don't even have time today to post links to references and  hope I can find them again at some point in future ... {update 2021-07-18 - I'm working on it} A commenter on YT that I had previously discussed how methionine restriction can actually cause an increase in homocysteine levels asked me what I thought about the apparent paradox - since methionine restriction (MR) lengthens lifespan, but high homocysteine / hyperhomocysteinemia (HHcy) should cause an increase in mortality from CVD (and other things). In lab animals HHcy is induced by feeding excess met and restricting B12, folate and B6. But low met decreases CBS activity, which can also cause HHcy. Chronic HHcy can cause hypermethylation of the CBS gene, reducing its expression. I'm guessing that's why clinical trials to lower Hcy with vitamin B6 etc. don't necessarily result in improvement in cardiovascular health - CBS is still not working and H2S signalling is still impaired. Maybe not the case, though,...

  A brief review on how statins could be used to treat immune thrombocytopenia (ITP), an autoimmune disease: Nazy and Cuker (2018) - Statins for high cholesterol … and for low platelets? - https://doi.org/10.1182/blood-2018-01-824888 "Megakaryocytes in ITP patients show impaired maturation and signs of degradation due to defects in the megakaryocytes and their environment. 7   Among the cells in the BM [bone marrow] niche implicated in supporting megakaryopoiesis and thrombopoiesis are the BM EPCs [endothelial progenitor cells], ... Treatments that induce platelet production by enhancing the BM microenvironment could be beneficial for corticosteroid-resistant ITP. Atorvastatin is a widely used drug for the treatment of primary hypercholesterolemia and mixed dyslipidemia by inhibiting 3-hydroxy-3methyl-glutaryl-coenzyme A reductase. Among its activities, it is known to improve the mobilization and function of EPCs. Recently, Shi et al showed the effectiveness of atorv...

Two mind-blowing articles on the effects of geomagnetic field fluctuations on human health, published in highly ranked peer-reviewed journals. Otsuka et al. (2019) Anti-aging effects of long-term space missions, estimated by heart rate variability  https://www.nature.com/articles/s41598-019-45387-6 "Exposure to variable magnetic fields in space resulted in an increase in several HRV endpoints, suggesting that aging may also be slowed down in astronauts in space, as it was for Caenorhabditis elegans 18 . By contrast, our previous 1998–2000 studies (during solar cycle 23) in a subarctic area indicated that magnetic storms, which involved larger magnetic disturbances than those observed during ISS01 and ISS02, suppressed HRV indices in 19 clinically healthy subjects 24 . The decrease in HRV was statistically validated for TF (−18.6%, P = 0.00009), primarily contributed to by VLF (−21.9%, P < 0.000001) in conjunction with ULF (−15.5%, P = 0.00865) and LF (−14.2%, P = 0.001...

Modern Healthspan released a video on an article that reports that shikimic acid reduced markers of  UV light induced cellular senescence in cultured dermal fibroblasts, increased SIRT1 activity and restored proteostasis . As MH suggests in the video, these findings could have much broader implications. Video: https://youtu.be/m_qaZSsFiT8 Research article:  Martinez-Gutierrez et al. (2021) https://www.aging-us.com/article/203010/text "SA reverted misfolded protein accumulation upon senescence, an effect that was abrogated by EX-527. Consistently, SA induced an increase in the levels of the chaperone BiP, resulting in a downregulation of unfolded protein response (UPR) signaling and UPR-dependent autophagy, avoiding their abnormal hyperactivation during senescence. SA did not directly activate SIRT1 in vitro, suggesting that SIRT1 is a downstream effector of SA signaling specifically in the response to cellular senescence. Our study not only uncovers a shikimic acid/SIRT1 signa...

Yesterday Lifespan.io reported on a finding by Wen et al. (2021) that vibration at 90 Hz reduced cellular senescence in bone marrow mesenchymal stem cells; from the news article's conclusion: https://www.lifespan.io/news/vibration-reduces-cellular-senescence-in-the-bones-of-rats/ "Further, while maintaining bone density is crucial to extending healthspan, vibration does not seem to be a great candidate as an anti-aging therapy. One of the greatest advantages of a longevity-based approach is its application to all the tissues in the body, and while the authors of this study did not investigate the effect of vibration on other organs, it seems logical that these effects would apply only to bone tissue."  Original research article: https://www.aging-us.com/article/202907/text  However - https://pubmed.ncbi.nlm.nih.gov/16364518/ “Longstanding evidence that bone formation and resorption are required for the development of haemopoietic marrow strongly suggests that ost...

 Someone on a forum asked about carnosine ... Carnosine is interesting since it can quench reactive carbonyl species such as acrolein. Acrolein can cause the formation of methemoglobin in red blood cells, which reduces oxygen delivery and can cause fatigue. Later stage PD patients have elevated levels of methemoglobin in RBCs. RBCs actually have a dopamine transporter and it may function to clear excess dopamine (maybe, not really known at this point). Oxidized dopamine can also interact with hemoglobin to form methemoglobin. Carnosine was found to reduce acrolein-induced methemoglobin in the following paper - which is unfortunately paywalled. The abstract says the carnosine had no effect on metHb formed by dopamine, but in the article it shows that the carnosine had an overall effect of greatly lowering the amount of metHb in the RBCs. The same group also put out a meeting abstract (so not peer -reviewed) that reported a lowering of the metHb caused by dopamine with spermidine. ...

Journal articles: Association of sleep duration in middle and old age with incidence of dementia (2021) https://www.nature.com/articles/s41467-021-22354-2 - an epidemiological study followed people for 25 years and found those who reported sleeping 6 hours or less per night had 30% higher risk of dementia relative to those who reported sleeping at least 7 hours, on average Sleep arousal burden is associated with long-term all-cause and cardiovascular mortality in 8001 community-dwelling older men and women (2021) https://academic.oup.com/eurheartj/advance-article/doi/10.1093/eurheartj/ehab151/6239256 - a polysomnography study found higher all-cause and cardiovascular disease associated with higher arousal burden (a measure of unconscious wakefulness) for women, associations were less strong for men; potential for arousal burden as a biomarker & modifiable risk factor News articles: Sleeping Too Little in Middle Age May Increase Dementia Risk, Study Finds (2021) https://www.nytime...

 Lemon balm ( Melissa officinalis ) was found to improve sleep in a fly model of Alzheimer's disease. Screening of sleep assisting drug candidates with a Drosophila model (2020) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390450/   "Overall, female flies were more vulnerable to DD stimulation considering total sleep time, but not in the sleep frequency. Therefore, female flies were chosen for the following drug screening study. ... the administration of melatonin shortened sleep latency but did not increase the total sleep time during sleep deprivation ( Fig 4A, 4B and 4F ), indicating that melatonin may only induce flies to sleep faster but not longer. Such results are consistent with human clinical trials that have reported that the prescription of melatonin helps induce sleep but does not enhance total sleep time [ 4 ]. Moreover, the activity index shows no change after melatonin treatment ( Fig 4G ), suggesting that melatonin has a limited effect on activity during wake...

Notes on: Histidine in Health and Disease: Metabolism, Physiological Importance, and Use as a Supplement  (2020) https://www.mdpi.com/2072-6643/12/3/848 "According to several studies, dietary [histidine] HIS affects histamine concentrations in immune cells, the stomach, and the brain [ 58 , 59 , 60 , 61 ]. Altered function of the immune system, allergic reactions, and/or peptic ulcers have not been reported after HIS administration. ... In the skin, filaggrin, a skin barrier protein with high HIS content, is the main HIS source for histidase to generate ammonia and urocanate [40]. Because most of the ammonia produced in the splanchnic region is detoxified to urea in the liver, the skin should be considered a significant source of blood ammonia in the systemic circulation. ... Although HIS is a precursor of histamine, allergic reactions or peptic ulcers caused by increased gastric acid secretion have not been reported. Practically important might be reduced folate status [ 45 ,...

  https://academic.oup.com/brain/advance-article/doi/10.1093/brain/awab054/6242260  "Animal studies suggest that noradrenergic fibres from the locus coeruleus play a key role in providing trophic support for both astrocytes and neurons, and in suppressing inflammation and oxidative stress. 19 Control of microvascular flow by the noradrenergic locus coeruleus might provide part of this trophic support by helping to match oxygen availability to cellular oxidative phosphorylation in brain tissue."   https://pubmed.ncbi.nlm.nih.gov/23426667/ "Our data demonstrate that stimulation of the LC activates a broad network of cortical pyramidal cells and interneurons and concomitantly increases cortical perfusion. The hyperemic response virtually disappeared after selective lesioning of the LC–NA system and required activation of α- and β-adrenoreceptors. In addition, the evoked CBF response to the LC–NA system required the release of glutamate and GABA likely from the...

Someone on a forum asked why iNOS inhibitors (e.g., agmatine, anatabine) would be beneficial and my reply follows: Too much NO generates peroxyynitrite and can cause nitrosative and oxidative stress, causing production of nitrated/oxidized alpha synuclein and oxidized dopamine. NO generated by iNOS in glial cells is particularly problematic for neurons. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408780/ This is in contrast with NO generated by the endothelium during exercise, which acts on the endothelium (autocrine signalling) which in turn produces good things like BDNF (the vascular endothelium can be thought of as an endocrine organ). https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791344/ https://youtu.be/lhZZS6_-Cg4 There are lots of studies on iNOS inhibitors in models of Parkinson's and other neurodegenerative disease. https://pubmed.ncbi.nlm.nih.gov/31192483/ Tobacco use and Solanaceae vegetable consumption are associated with reduced risk of PD. If causal, the relations...

Hydrogen sulfide (H2S) signalling is involved in the central regulation of breathing / ventilatory response. If the enzyme that makes H2S, cystathionine beta synthase, (CBS) is blocked, the neural network that controls breathing in the brain  breaks down and gasping results.  https://www.nature.com/articles/s42003-020-01312-6 Dopamine and serotonin upregulate CBS activity. CBS has a heme moiety and needs vitamin B6 as a cofactor. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022568 "Cystathionine-β-synthase (CBS) is the most likely endogenous candidate enzyme to increase H 2 S production. Endogenous H 2 S is mainly synthesized by CBS and cystathionine-γ-lyase [8] , [9] . Both enzymes depend on pyridoxal 5′-phosphate (PLP) as a cofactor [10] . However, only CBS contains a heme moiety, which may bind oxygen and make the enzyme function dependent on oxygen levels, as demonstrated in recombinant human CBS [11] . In addition, a range of biogenic amines, in...