The Rhyothemis princeps Brain Externalization Project

Stomach acid suppression can result in deficiencies of B12, calcium and other important nutrients. B12 is needed for tetrahydrobiopterin production which is in turn a cofactor for nitric oxide [NO] synthesis by nitric oxide synthase [NOS]. Also, nitrite is converted in the presence of stomach acid to nitrous acid, which then forms NO. So it seems plausible that the association of cardiovascular disease with long-term proton pump inhibitor [PPI] use could be due to lowered production of NO as the result of acid reduction. However, other mechanisms may be at work, and may be more significant -  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864131/   "The evidence obtained in the aforementioned studies suggest that the underlying mechanism for cardiovascular effects of PPIs are not directly related to acid suppression, since H2-receptor antagonists are not associated with the cardiovascular risk [45, 46]. " Another explanation for the association is that PPIs inhibit PON1 ( in

Stuff I wrote on YT comments in response to a question of mosaicism and aging: "Interesting question, especially with respect to neurodegeneration (may partly explain the phenomenon of selective vulnerability as well as some sporadic cases of neurodegenerative diseases). There is a related article I would like to link to, but YT does not seem to allow that anymore. The article can be found by googling "Brain discovery explains a great mystery of Alzheimer's, Parkinson's" (February 15, 2019) about research conducted by Michael McConnell of UVA." { But I can link to it here (stupid YT) } https://www.sciencedaily.com/releases/2019/02/190215135835.htm Then found some YT videos on the topic ... "This one is technical - https://youtu.be/y-XWoEjsg5Y   The main takeaways for me were that there are distinct signatures for somatic mutations acquired during development and for those accrued during aging, and that chromothr

Last notes were about intracellular pH and senescent cell clearance, cancer and neurodegeneration. Just a few days later, an article on Nrf2 appeared in my news feed: https://medicalxpress.com/news/2021-01-nrf2-magic-molecule-eternal-youth.html "At the risk of overstating the obvious, if a little extra NRF2 is good for every cell in your body, and every cell in your body is good, then NRF2 must be good for your body. The weak link in that argument, however, is that all cells are not good. Nobody wants harmful bacterial cells to flourish, and nobody wants cancer cells to flourish. A paper recently published in Nature now suggests that inhibiting NRF2 can block the migration and invasion of non-small-cell lung cancer cells through the body. If anyone is going to derive benefit from NRF2, they may need to be smart about it. The main reason NRF2, or Nuclear factor-erythroid 2-related factor 2, is so highly sought, is because it is a key transcriptional regulator of several an

New article on kidney type glutaminase and senescent cell clearance: https://science.sciencemag.org/content/371/6526/265   related:   Simultaneously Targeting Tissue Transglutaminase and Kidney Type Glutaminase Sensitizes Cancer Cells to Acid Toxicity and Offers New Opportunities for Therapeutic Intervention https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291776/   It's interesting that this all hinges on intracellular pH; there was a good talk on intracellular pH and neurodegeneration a while back: https://youtu.be/OUmFkfTFm_o

The topic of low dose doxycycline (DOX) for Parkinson's came up on a forum. Rationale for its use in PD is typically based inhibition of a-syn aggregation , however DOX is a matrix metalloproteinase inhibitor (2 and 9). Matrix metalloproteinases are a group of enzymes that break down collagen and some other extracellular matrix proteins. White tea is supposed to be good for preventing skin aging since it contains a substance that inhibits one or two matrix metalloproteinases (can't remember which ones). The extracellular matrix is the stuff in between cells and it is mostly collagen. A lot of TGF-beta, a signalling molecule involved in the immune system, is localized in the ECM and engages in 'solid state' signalling - it is not dissolved in fluid, it stays put and interacts with cells as they come in contact when the tissue is deformed by mechanical pressure or cells migrate . People with connective tissue disorders often have immune system problems because

Got into a discussion about the U-shaped or J-shaped mortality curve for serum urate. U or J, there's an inflection point, and the lowest mortality is not at the extreme lower end. Could this be due to impaired kidney function causing both high mortality and low serum urate levels? Or is it because very low levels are harmful? People with mutations in the urate transporter (URAT1) gene SLC22A12 have low levels of serum urate due to low resorption rate and have endothelial dysfunction, likely due to oxidative stress. - Extremely Low Levels of Serum Uric Acid Are Associated With Endothelial Dysfunction in Humans https://www.jstage.jst.go.jp/article/circj/79/5/79_CJ-15-0232/_pdf/-char/en Primates have evolved higher serum urate levels as the result of positive selection pressure through loss of the uricase gene and also increase in efficiency of the urate transporter.  - Coevolution of URAT1 and Uricase during Primate Evolution:Implications for Serum Urate Homeostasis and Gout https

This morning brought me a rather disturbing story about squirrels aggressively attacking residents of a Queens, New York neighborhood. The attacks were unprovoked. The story is reported in detail here: https://patch.com/new-york/ foresthills/vicious-squirrel- attacks-rattle-rego-park- residents   What could cause the squirrels to behave this way? It could be due to food scarcity; there have been a lot of restaurant closures due the pandemic - so fewer scraps around and less garbage to raid. There have been cases of people feeding meth (methamphetamine) to squirrels in order to make them more aggressive: https://www.newsweek.com/man- accused-feeding-squirrel-meth- 1485460 The other thought that comes to mind is that the behavior change could be due to SARS-CoV-2 infection. It is at least theoretically possible for squirrels to become infected and there is some preliminary evidence linking covid with onset of mental illness in humans. https://www.medscape.com/viewarticle/940922 The m

A clinical trial [ Veterans Affairs Topical Tretinoin Chemoprevention Trial (VATTC)] of topical all-trans retinoic acid (tretinoin, Retin-A) had to be halted because the intervention arm experienced higher mortality. The authors indicate that a causal relationship is unlikely, but the finding is a bit troubling nonetheless. The increase in mortality was not attributable to any one specific cause of death. https://jamanetwork.com/journals/jamadermatology/fullarticle/711869 "We considered the possibility that topical tretinoin applied to the face and ears might be a cause of death. One study that was published during our trial involved systemic administration of isotretinoin, a closely related compound. That trial found a significant interaction between the medication and smoking in their effect on mortality, with isotretinoin therapy associated with increased mortality among smokers. 4 Studies involving a less closely related compound, beta carotene, have also suggested an

Glucosamine (credit: AndresJS )   Sometimes I lurk on various life extension message boards and am perplexed that many (most?) people do not list glucosamine in their pro-longevity 'stack' even though its use is associated with reduction in all-cause mortality. Glucosamine is cheap and relatively well-tolerated. While association does not mean causation, the relationship has been found in several large epidemiological studies and holds up when controlling for various demographic factors; similar associations have not been found for other supplements - not even fish oil or vitamin D. There are some plausible mechanisms, which I don't have time to really get into, unfortunately. In brief, glucosamine inhibits glucose metabolism (see Ristow interview linked below) - which could have direct effects and also effects via the gut microbiome, increases hyaluronic acid production, and may have other effects relating to O-GlcNAcylation (that's what I'm most interested i

Fucoidan is a sulfated polysaccharide found in brown seaweed that varies in molecular weight and composition. Wakame ( Undaria pinnatifida ) is a brown seaweed commonly consumed in Japan and is a main ingredient in miso soup and is also served as a salad.  Recently it as been reported that fucoidan can inhibit SARS-CoV-2 replication in vitro: https://www.nature.com/articles/s41421-020-00192-8 Of course it remains to be demonstrated in humans, but it's a start.  ~ Wakame fucoidan could be useful for Covid-19 since it inhibits thrombosis without increasing bleeding time: https://pubmed.ncbi.nlm.nih.gov/22084059/ The  Min et al. (2011) study also found in comparison to wakame fucoidan, fucoidan from bladder wrack inhibited thrombus formation, but bleeding time was prolonged (but not as much as for heparin).  An important caveat when considering the therapeutic potential of seaweed/fucoidan is that there are differences in biological activities in fucoidans from different species as we

 4-aminopyridine (4-AP, fampridine, dalfampridine) has been used to treat episodic ataxia 2 and downbeat nystagmus; so far it does not seem to have been trialed or even suggested for use in multiple system atrophy: "In recent years, advance has been made in the pharmacological treatment of cerebellar disorders, for example episodic ataxia type 2 (EA2) and in adition downbeat nystagmus (DBN), specifically because of the utilization of aminopyridines (AP) [ 10 - 13 ]. This agent is a nonselective blockers of the Kv family, mainly the Kv1.5 voltage-activated potassium channels, thereby prolonging the duration of action potentials in axons because of delayed repolarization [ 14 ]. In vitro studies showed that 4-aminopyridine (4-AP) increases the resting discharge rate and excitability of cerebellar Purkinje cells (PCs) of the guinea pig cerebellum [ 15 ], and regulates the PC firing in brain slices of the rat [ 16 , 17 ], Due to an increased activity of PC [ 13 ] the GABAe

  Some news on metformin - a study of C. elegans (worms) and human cell cultures found that older individuals had deleterious effects while younger individuals benefited. Co-administering rapamycin alleviated the toxic effects in older individuals: https://medicalxpress.com/news/2020-11-age-decisive-positive-negative-effects.html   Original research article: https://doi.org/10.1038/s42255-020-00307-1 I am curious to know if boosting NAD+ would also mitigate the toxicity. Related: https://www.sciencedaily.com/releases/2018/12/181211113024.htm Coincidentally I also saw yesterday a video presentation on the effects of aging on microRNA production in response to exercise. An enzyme called DICER is involved in RNA processing and it increased in activity in response to exercise; the effect size was found to be much lower in older individuals and the effect is AMPK dependent. https://youtu.be/lN_wJT-EkuA 10:54 there's one young individual at the bottom of the graph - what's up