4019 replies to this topic

[lostfalco]

BieraK mentioned mitohormesis the other day and I thought I'd post a little abstract with some info on it in case you guys were interested. Hormesis is HUGELY important in human adaptive responses to the environment and mitohormesis is an up and coming theory worth paying attention to imo. 

 

 

 

 

http://www.ncbi.nlm....pubmed/26654757

 

Free Radic Biol Med. 2015 Nov 30. pii: S0891-5849(15)01141-7. doi: 10.1016/j.freeradbiomed.2015.11.032. [Epub ahead of print]

Mitohormesis in exercise training.

Merry TL1, Ristow M2.

Author information

Abstract

Hormesis is a process whereby exposure to a low dose of a potentially harmful stressor promotes adaptive changes to the cell that enables it to better tolerate subsequent stress. In recent years this concept has been applied specifically to the mitochondria (mitohormesis), suggesting that in response to a perturbation the mitochondria can initiate and transduce a signal to the nucleus that coordinates a transcriptional response resulting in both mitochondrial and non-mitochondrial adaptations that return and maintain cellular homeostasis. In this review we summarize the evidence that mitohormesis is a significant adaptive-response signaling pathway, and suggest that it plays a role in mediating exercise-induced adaptations. We discuss potential mitochondrial emitters of retrograde signals that may activate known exercise-sensitive transcription factors to modulate transcription responses to exercise, and draw on evidence from mitochondrial dysfunction animal models to support a role for mitohormesis in mitochondrial biogenesis. Studies directly linking mitohormesis to the exercise training response are lacking, however mounting evidence suggests numerous signals are emitted from the mitochondria during exercise and have the potential to induce a nuclear transcription response, with reactive oxygen species (ROS) being the primary candidate.

 

Edited by lostfalco, 18 December 2015 - 12:55 AM.

[lostfalco]

Sigma-1 receptors have very complicated effects but also have some serious potential for learning and memory enhancement. Definitely check out the video below if you have time (the relationship between mitochondria and endoplasmic reticulum is especially interesting (MAM)).

 

Pregnenolone sulfate (PregS) is a possibility here (see the last study below) and also see here. http://www.longecity...-83#entry741089

 

Oral pregnenolone is converted to PregS. 

 

 

 

 

 

http://www.ncbi.nlm....pubmed/25143613

 

J Neurosci. 2014 Aug 20;34(34):11325-38. doi: 10.1523/JNEUROSCI.0458-14.2014.

NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus.

Pabba M1, Wong AY1, Ahlskog N1, Hristova E1, Biscaro D1, Nassrallah W1, Ngsee JK2, Snyder M1, Beique JC2, Bergeron R3.

Author information

Abstract

Sigma-1 receptors (σ-1Rs) are endoplasmic reticulum resident chaperone proteins implicated in many physiological and pathological processes in the CNS. A striking feature of σ-1Rs is their ability to interact and modulate a large number of voltage- and ligand-gated ion channels at the plasma membrane. We have reported previously that agonists for σ-1Rs potentiate NMDA receptor (NMDAR) currents, although the mechanism by which this occurs is still unclear. In this study, we show that in vivo administration of the selective σ-1R agonists (+)-SKF 10,047 [2S-(2α,6α,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (N-allylnormetazocine) hydrochloride], PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate hydrochloride), and (+)-pentazocine increases the expression of GluN2A and GluN2B subunits, as well as postsynaptic density protein 95 in the rat hippocampus. We also demonstrate that σ-1R activation leads to an increased interaction between GluN2 subunits and σ-1Rs and mediates trafficking of NMDARs to the cell surface. These results suggest that σ-1R may play an important role in NMDAR-mediated functions, such as learning and memory. It also opens new avenues for additional studies into a multitude of pathological conditions in which NMDARs are involved, including schizophrenia, dementia, and stroke.

 

 

http://www.ncbi.nlm....pubmed/25420607

 

Psychopharmacology (Berl). 2015 May;232(10):1779-91. doi: 10.1007/s00213-014-3809-6. Epub 2014 Nov 26.

Sigma 1 receptor activation regulates brain-derived neurotrophic factor through NR2A-CaMKIV-TORC1 pathway to rescue the impairment of learning and memory induced by brain ischaemia/reperfusion.

Xu Q1, Ji XF, Chi TY, Liu P, Jin G, Gu SL, Zou LB.

Author information

Abstract

RATIONALE: 

Sigma-1 receptor (Sig-1R) agonists showed anti-amnesic properties in Alzheimer's disease models and anti-inflammatory properties in cerebrum ischaemia models. The agonist of Sig-1R was reported to up-regulate brain-derived neurotrophic factor (BDNF) levels in the hippocampus of mice. Here, we investigate whether the activation of Sig-1R attenuates the learning and memory impairment induced by ischaemia/reperfusion and how it affects the expression of BDNF.

OBJECTIVES: 

Bilateral common carotid artery occlusion (BCCAO) was induced for 20 min in C57BL/6 mice.

MATERIALS AND METHODS: 

Sig-1R agonist, PRE084, sigma 1/2 non-selective agonist, DTG, Sig-1R antagonist and BD1047 were injected once daily throughout the experiment. Behavioural tests were performed from day 8. On day 22 after BCCAO, mice were sacrificed for biochemical analysis.

RESULTS: 

PRE084 and DTG ameliorated learning and memory impairments in the Y maze, novel object recognition, and water maze tasks and prevented the decline of synaptic proteins and BDNF expression in the hippocampus of BCCAO mice. Furthermore, PRE084 and DTG up-regulated the level of NMDA receptor 2A (NR2A), calcium/calmodulin-dependent protein kinase type IV (CaMKIV) and CREB-specific co-activator transducer of regulated CREB activity 1 (TORC1). Additionally, the effects of PRE084 and DTG were antagonised by the co-administration of BD1047.

CONCLUSIONS: 

Sig-1R activation showed an attenuation in the ischaemia/reperfusion model and the activation of Sig-1R increased the expression of BDNF, possibly through the NR2A-CaMKIV-TORC1 pathway, and Sig-1R agonists might function as neuroprotectant agents in vascular dementia.

 

http://www.ncbi.nlm....pubmed/22884465

 

Neuropharmacology. 2012 Nov;63(6):1042-50. doi: 10.1016/j.neuropharm.2012.07.035. Epub 2012 Jul 31.

Anti-amnesic effect of neurosteroid PREGS in Aβ25-35-injected mice through σ1 receptor- and α7nAChR-mediated neuroprotection.

Yang R1, Chen L, Wang H, Xu B, Tomimoto H, Chen L.

Author information

Abstract

A single intracerebroventricular injection of β-amyloid 25-35 peptide (Aβ(25-35)) (9 nmol/mouse) induces the spatial cognitive deterioration and approximately 50% loss of pyramidal cells in hippocampal CA1 region within 1 week. The present study focused on exploring the effects of neurosteroid pregnenolone sulfate (PREGS), in comparison with the selective agonists of sigma-1 receptor (σ(1)R) and α7 nicotinic acetylcholine receptor (α7nAChR), on the cognitive deficits and the death of pyramidal cells in Aβ(25-35)-mice. Herein, we reported that the administration of PREGS (1-100 mg/kg) for 7 days after Aβ(25-35)-injection could dose-dependently ameliorate the cognitive deficits and attenuate the apoptosis of pyramidal cells. Either the σ(1)R antagonist NE100 or the α7nAChR antagonist MLA could block the neuroprotection of PREGS in Aβ(25-35)-mice. Both the σ(1)R agonist PRE084 and the α7nAChR agonist DMXB could mimic the PREGS-neuroprotection against the Aβ(25-35)-neurotoxicity. The neuroprotection of PRE084 was attenuated by MLA, but the DMXB-action was insensitive to NE100. The neuroprotection of PREGS, PRE084 or DMXB was blocked by the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, whereas only the effect of PREGS or PRE084 was sensitive to the MAPK/ERK kinase (MEK) inhibitor U0126. PREGS prevented Aβ(25-35)-inhibited Akt (Serine/threonine kinase) phosphorylation leading to increase in caspase-3 activity, which was σ(1)R- and α7nAChR-dependent. By contrast, PREGS-rescued reduction of extracellular signal-related kinase-2 (ERK2) phosphorylation in Aβ(25-35)-mice only required the activation of σ(1)R. Blockage of PREGS-neuroprotection by LY294002 significantly attenuated its anti-amnesic effect in Aβ(25-35)-mice. The findings indicate that the anti-amnesic effects of PREGS in Aβ(25-35)-mice depend on the σ(1)R- and α7nAChR-mediated neuroprotection.

 

Edited by lostfalco, 24 December 2015 - 08:49 PM.

[lostfalco]

http://www.ncbi.nlm....pubmed/26401706

 

J Alzheimers Dis. 2015;47(3):715-28. doi: 10.3233/JAD-150307.

Central Nervous System Delivery of Intranasal Insulin: Mechanisms of Uptake and Effects on Cognition.

Salameh TS1,2, Bullock KM1, Hujoel IA1, Niehoff ML3,4, Wolden-Hanson T1, Kim J3, Morley JE3, Farr SA3,4, Banks WA1,2.

Author information

Abstract

Intranasal insulin has shown efficacy in patients with Alzheimer's disease (AD), but there are no preclinical studies determining whether or how it reaches the brain. Here, we showed that insulin applied at the level of the cribriform plate via the nasal route quickly distributed throughout the brain and reversed learning and memory deficits in an AD mouse model. Intranasal insulin entered the blood stream poorly and had no peripheral metabolic effects. Uptake into the brain from the cribriform plate was saturable, stimulated by PKC inhibition, and responded differently to cellular pathway inhibitors than did insulin transport at the blood-brain barrier. In summary, these results show intranasal delivery to be an effective way to deliver insulin to the brain.

 

http://www.ncbi.nlm....les/PMC3709085/

 

CNS Drugs. 2013 Jul;27(7):505-14. doi: 10.1007/s40263-013-0076-8.

Intranasal insulin as a treatment for Alzheimer's disease: a review of basic research and clinical evidence.

Freiherr J1, Hallschmid M, Frey WH 2nd, Brünner YF, Chapman CD, Hölscher C, Craft S, De Felice FG, Benedict C.

Author information

Abstract

Research in animals and humans has associated Alzheimer's disease (AD) with decreased cerebrospinal fluid levels of insulin in combination with decreased insulin sensitivity (insulin resistance) in the brain. This phenomenon is accompanied by attenuated receptor expression of insulin and insulin-like growth factor, enhanced serine phosphorylation of insulin receptor substrate-1, and impaired transport of insulin across the blood-brain barrier. Moreover, clinical trials have demonstrated that intranasal insulin improves both memory performance and metabolic integrity of the brain in patients suffering from AD or its prodrome, mild cognitive impairment. These results, in conjunction with the finding that insulin mitigates hippocampal synapse vulnerability to beta amyloid, a peptide thought to be causative in the development of AD, provide a strong rationale for hypothesizing that pharmacological strategies bolstering brain insulin signaling, such as intranasal administration of insulin, could have significant potential in the treatment and prevention of AD. With this view in mind, the review at hand will present molecular mechanisms potentially underlying the memory-enhancing and neuroprotective effects of intranasal insulin. Then, we will discuss the results of intranasal insulin studies that have demonstrated that enhancing brain insulin signaling improves memory and learning processes in both cognitively healthy and impaired humans. Finally, we will provide an overview of neuroimaging studies indicating that disturbances in insulin metabolism--such as insulin resistance in obesity, type 2 diabetes and AD--and altered brain responses to insulin are linked to decreased cerebral volume and especially to hippocampal atrophy.

 

 

http://www.ncbi.nlm....pubmed/17643054

 

Neuroendocrinology. 2007;86(2):136-42. Epub 2007 Jul 20.

Intranasal insulin to improve memory function in humans.

Benedict C1, Hallschmid M, Schultes B, Born J, Kern W.

Author information

Abstract

BACKGROUND: 

Compelling evidence indicates that central nervous insulin enhances learning and memory and in particular benefits hippocampus-dependent (i.e., declarative) memory. Intranasal administration of insulin provides an effective way of delivering the compound to the central nervous system, bypassing the blood-brain barrier and avoiding systemic side effects.

METHODS: 

Here we review a series of recent studies on the effects of intranasally administered insulin on memory functions in humans. In accordance with the beneficial effects of intravenously administered insulin on hippocampus-dependent declarative memory observed in hyperinsulinemic-euglycemic clamp studies, intranasal insulin administration similarly improves this type of memory, but in the absence of adverse peripheral side effects.

RESULT AND CONCLUSION: 

Considering that cerebrospinal fluid insulin levels are reduced in patients suffering from Alzheimer's disease, these results may be of considerable relevance for future clinical applications of insulin in the treatment of memory disorders.

 

http://www.ncbi.nlm....pubmed/15288712

 

Psychoneuroendocrinology. 2004 Nov;29(10):1326-34.

Intranasal insulin improves memory in humans.

Benedict C1, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J, Kern W.

Author information

Abstract

Previous studies have suggested an acutely improving effect of insulin on memory function. To study changes in memory associated with a prolonged increase in brain insulin activity in humans, here we used the intranasal route of insulin administration known to provide direct access of the substance to the cerebrospinal fluid compartment. Based on previous results indicating a prevalence of insulin receptors in limbic and hippocampal regions as well as improvements in memory with systemic insulin administration, we expected that intranasal administration of insulin improves primarily hippocampus dependent declaration memory function. Also, improvements in mood were expected. We investigated the effects of 8 weeks of intranasal administration of insulin (human regular insulin 4 x 40 IU/d) on declarative memory (immediate and delayed recall of word lists), attention (Stroop test), and mood in 38 healthy subjects (24 males) in a double blind, between-subject comparison. Blood glucose and plasma insulin levels did not differ between the placebo and insulin conditions. Delayed recall of words significantly improved after 8 weeks of intranasal insulin administration (words recalled, Placebo 2.92 +/- 1.00, Insulin 6.20 +/- 1.03, p < 0.05). Moreover, subjects after insulin reported signs of enhanced mood, such as reduced anger (p < 0.02) and enhanced self-confidence (p < 0.03). Results indicate a direct action of prolonged intranasal administration of insulin on brain functions, improving memory and mood in the absence of systemic side effects. These findings could be of relevance for the treatment of patients with memory disorders like in Alzheimer's disease.

 

[lostfalco]

Hypertension and atherosclerosis are significantly detrimental to cognition. PDE5i's have shown great promise in ameliorating both. Get hard, study hard. =) 

 

http://www.ncbi.nlm....pubmed/26696017

 

Curr Pharm Biotechnol. 2015 Dec 23. [Epub ahead of print]

Novel Therapeutic Targets for Phosphodiesterase 5 Inhibitors: current state-of-the-art on systemic arterial hypertension and atherosclerosis.

Vasquez EC1, Gava AL, Graceli JB, Balarini CM, Campagnaro BP, de Melo C Pereira T, Meyrelles SS.

Author information

Abstract

The usefulness of selective inhibitors of phosphodiesterase 5 (PDE5) is well known, first for the treatment of male erectile dysfunction and more recently for pulmonary hypertension. The discovery that PDE5 is present in the systemic artery endothelium and smooth muscle cells led investigators to test the extra sexual effects of sildenafil, the first and most investigated PDE5 inhibitor, in diseases affecting the systemic arteries. Cumulative data from experimental and clinical studies have revealed beneficial effects of sildenafil on systemic arterial hypertension and its target organs, such as the heart, kidneys and vasculature. An important effect of sildenafil is reduction of hypertension and improvement of endothelial function in experimental models of hypertension and hypertensive subjects. Interestingly, in angiotensin-dependent hypertension, its beneficial effects on endothelial and kidney dysfunctions seem to at least in part be caused by its ability to decrease the levels of angiotensin II and increase angiotensin 1-7, in addition to improving nitric oxide bioavailability and diminishing reactive oxygen species. Another remarkable finding on the effects of sildenafil comes from studies in apolipoprotein E knockout mice, a model of atherosclerosis that closely resembles human atherosclerotic disease. In this review, we focus on the promising beneficial effects of sildenafil for treating systemic high blood pressure, especially resistant hypertension, and the endothelial dysfunction that is present in hypertension and atherosclerosis.

 

http://www.ncbi.nlm....pubmed/26615558

 

Eur Radiol. 2015 Nov 28. [Epub ahead of print]

Disrupted white matter structure underlies cognitive deficit in hypertensive patients.

Li X1,2, Ma C1,2, Sun X2, Zhang J1,2, Chen Y1,2, Chen K2,3, Zhang Z4,5.

Author information

Abstract

OBJECTIVES: 

Hypertension is considered a risk factor of cognitive impairments and could result in white matter changes. Current studies on hypertension-related white matter (WM) changes focus only on regional changes, and the information about global changes in WM structure network is limited.

METHODS: 

We assessed the cognitive function in 39 hypertensive patients and 37 healthy controls with a battery of neuropsychological tests. The WM structural networks were constructed by utilizing diffusion tensor tractography and calculated topological properties of the networks using a graph theoretical method. The direct and indirect correlations among cognitive impairments, brain WM network disruptions and hypertension were analyzed with structural equation modelling (SEM).

RESULTS: 

Hypertensive patients showed deficits in executive function, memory and attention compared with controls. An aberrant connectivity of WM networks was found in the hypertensive patients (P Eglob = 0.005, P Lp = 0.005), especially in the frontal and parietal regions. Importantly, SEM analysis showed that the decline of executive function resulted from aberrant WM networks in hypertensive patients (p = 0.3788, CFI = 0.99).

CONCLUSIONS: 

These results suggest that the cognitive decline in hypertensive patients was due to frontal and parietal WM disconnections. Our findings highlight the importance of brain protection in hypertension patients.

KEY POINTS: 

• Hypertension has a negative effect on the performance of the cognitive domains • Reduced efficiencies of white matter networks were shown in hypertension • Disrupted white matter networks are responsible for poor cognitive function in hypertension.

 

http://www.ncbi.nlm....pubmed/26106116

 

Stroke. 2015 Aug;46(8):2190-6. doi: 10.1161/STROKEAHA.115.008994. Epub 2015 Jun 23.

Intima-Media Thickness and Cognitive Function in Stroke-Free Middle-Aged Adults: Findings From the Coronary Artery Risk Development in Young Adults Study.

Zeki Al Hazzouri A1, Vittinghoff E2, Sidney S2, Reis JP2, Jacobs DR Jr2, Yaffe K2.

Author information

Abstract

BACKGROUND AND PURPOSE: 

The relationship between carotid artery intima-media thickness (IMT) and cognitive function in midlife remains relatively unexplored. We examined the association between IMT and cognitive function in a middle-aged epidemiological cohort of 2618 stroke-free participants.

METHODS: 

At the year 20 visit (our study baseline), participants from the Coronary Artery Risk Development in Young Adults study had IMT measured by ultrasound at the common carotid artery. Five years later, participants completed a cognitive battery consisting of the Rey Auditory-Verbal Learning Test of verbal memory, the Digit Symbol Substitution Test of processing speed, and the Stroop test of executive function. We transformed cognitive scores into standardized z scores, with negative values indicating worse performance.

RESULTS: 

Mean age at baseline was 45.3 years (SD, 3.6). Greater IMT (per 1 SD difference of 0.12 mm) was significantly associated with worse performance on all cognitive tests (z scores) in unadjusted linear regression models (verbal memory, -0.16; 95% confidence interval [CI], -0.20 to -0.13; processing speed, -0.23; 95% CI, -0.27 to -0.19; and executive function, -0.17; 95% CI, -0.20 to -0.13). In models adjusted for sociodemographics and vascular risk factors that lie earlier in the causal pathway, greater IMT remained negatively associated with processing speed (-0.06; 95% CI, -0.09 to -0.02; P, 0.003) and borderline associated with executive function (-0.03; 95% CI, -0.07 to 0.00; P, 0.07) but not with verbal memory.

CONCLUSIONS: 

We observed an association between greater IMT and worse processing speed-a key component of cognitive functioning-at middle age above and beyond traditional vascular risk factors. Efforts targeted at preventing early stages of atherosclerosis may modify the course of cognitive aging.

 

Edited by lostfalco, 25 December 2015 - 08:29 PM.

[lostfalco]

A Quick Update (unknown/high risk warning)

 

Ghrelin/MK-677 -- this is very powerful stuff; much stronger than hydrogen water for ghrelin enhancement (hydrogen water also has MANY other benefits). It increased energy, mood, clarity of thought, and....hunger; significantly. I was able to counteract the hunger increase easily with 50mg of modafinil (histamine was my theoretical reason for taking it). This stuff was strong enough that I'm diving into as much research as I can to determine how dangerous it is to take chronically (IGF-1 is a legitimate concern). I bought mine here (no affiliation). http://www.ceretropi...k-677-solution/

 

Nyles7 also sells the powder and is a reliable vendor in my experience (no affiliation). http://www.ebay.com/...1-/181499559038

 

MC4R/MSH -- again, powerful stuff. Increased motivation, mood, clarity of thought...and sex drive. I didn't get terribly tan from this stuff but it's also winter so I didn't get a huge amount of sun. This stacked very well with MK-677 although it seemed to have a short half-life. I'm currently looking into making my own Melanotan II nasal spray to try out. http://www.antiaging...om/256-msh2-pro

 

ITPP -- I've only taken a few doses of this so far. Nothing to report yet but I'll keep you guys updated. http://www.nyles7.co...20-31eb53b1e048

 

Edited by lostfalco, 27 December 2015 - 04:27 PM.

[mettmett]

A Quick Update (unknown/high risk warning)

 

Ghrelin/MK-677 -- this is very powerful stuff

I agree with that.  I like the hunger though  I used superior peptide's version since they frequently have 50% off sales.

 

MC4R/MSH -- again, powerful stuff. Increased motivation, mood, clarity of thought...and sex drive

 

You had me at increased motivation

How would you describe the motivation...more physical or more mental?  

 

Different things that have increased my motivation usually lean towards one or the other...so I'm curious

 

 I'm sitting on some MT-II but I am trying to figure out how I want to dose so I can avoid gaining new moles - if anyone has had success with getting rid of moles I'd be interested in that as well.

I've read that people anywhere from 25ug to 500ug to 1mg usually EOD

Also, if anyone goes with pt-141 you shouldn't do it nasally because for some reason that ROA increases blood pressure -https://en.wikipedia...i/Bremelanotide

 

ITPP

I've been dosing 100mg daily a couple weeks now.

My experience hasn't been as glowing as some other anecdotes I've read, but it has still been positive.

 

I notice it the most during my warmup on the treadmill.  I've been able to increase the speed and it still feels like I'm running at the slower speed.  Example: a speed of 8 units now feels like 6.5 units did before I started ITPP.

 

Maybe I'll do a sprint workout to really test its power.

 

I've also stacked it with Methylene Blue at a 35mg dose, but nothing much to report there either.

 

But that's ok, because I'm not really into enhancement for an immediate benefit.  I'm more interested in sustainable approaches.

 

Because more often than not, substances that provide an immediate benefit aren't sustainable.  That's my theory anyways...

[lostfalco]

I agree with that.  I like the hunger though  I used superior peptide's version since they frequently have 50% off sales.

 

 

How would you describe the motivation...more physical or more mental?  

 

 I'm sitting on some MT-II but I am trying to figure out how I want to dose so I can avoid gaining new moles - if anyone has had success with getting rid of moles I'd be interested in that as well.

I've read that people anywhere from 25ug to 500ug to 1mg usually EOD

 

I've been dosing 100mg daily a couple weeks now.

My experience hasn't been as glowing as some other anecdotes I've read, but it has still been positive.

 

Just ordered some of superior peptide's MK-677 for the same reason...it'll be interesting to compare. 

 

MSH motivation was mental for me...bordered on aggression but 'extreme confidence' is also apt. Luckily it was combined with a positive mood so I didn't (foolishly) try to whoop everyone's ass. ha  Seriously though, sex on this stuff is fun...very fun. My gf humbly requested that I stay on it forever (that punk). There is almost certainly an oxytocin and/or dopamaine relationship here.  http://www.ncbi.nlm....pubmed/25652247

 

Misteryouaresodumb discusses melanotan ii intranasal here. https://www.reddit.c...v0h/melanotan2/  Ceretropic is not going to carry it due to their recent legal issues so we'll have to make our own...but it seemed to work when they tested it. 

 

Thanks for the ITPP info! I'll have to increase my dose. I've been conservative due to its long half-life and the fact that I only bought 1 gram. Gonna have to step it up. Appreciate the feedback, Matt. These are some pretty cool enhancements, imo. 

Edited by lostfalco, 28 December 2015 - 04:02 PM.

[mettmett]

Good to hear about MSH.  Think I'll start my trial soon...

 

Yeah I ordered 2 grams ITPP.  I'm dosing similar to that reddit post I linked earlier.

 

I'm using the 1st gram at 100mg/day, then using the 2nd gram at 100mg/once a week for maintenance.  

[lostfalco]

New white paper from Jeff Hawkins and Numenta on Hierarchical Temporal Memory. They are attempting to build software based on the neuroscience of how the neocortex works. I am NOT saying this is the 'true' model of learning and memory...but it is a VERY informative one. I've been following their work for a number of years now and their recent AI partnership with IBM to build intelligent machines will be interesting to watch. http://arxiv.org/pdf...2.05463v1.pdf  

 

"IBM is testing a contentious idea for making computers more intelligent by trying to copy mechanisms from the human brain."

http://www.technolog...ain-algorithms/

[mettmett]

Hey guys, I finished Part II of my mitochondria series: http://remedyrising....ial-biogenesis/

 

Let me know what you think!

[Lsdium]

Hey guys, I finished Part II of my mitochondria series: http://remedyrising....ial-biogenesis/

 

Let me know what you think!

 

Damn mettmett, keep going with your work!

 

Nice, clean and very details about mitochondria, loved it   

[mettmett]

Damn mettmett, keep going with your work!

 

Nice, clean and very details about mitochondria, loved it   

 

Thank you so much Lsdium!

[lostfalco]

 

Hey guys, I finished Part II of my mitochondria series: http://remedyrising....ial-biogenesis/

 

Let me know what you think!

 

Damn mettmett, keep going with your work!

 

Nice, clean and very details about mitochondria, loved it   

 

Agreed! Well done, mettmett. I'm honored to have been mentioned in your article. =)

 

 

[mettmett]

Agreed! Well done, mettmett. I'm honored to have been mentioned in your article. =)

Thanks LostFalco!  Of course I had to have you in there, you are the one responsible for advancing my advancements after all!

[BieraK]

Hello guys, sorry for not appearing was very busy.

I will try to experiment with oxygenation and methylene blue, with fasting+methylene blue+oxygenation and other nice things, Like LLLT+Methylene blue+PQQ.

Finally today arrived two bottles of 98% oxygen. I took 30 mg of methylene blue today and delivered oxygen to my blood. Results: Nice boosting of energy, happy feeling like smoking low dose of marijuana or like a low dose of a dopaminergic drug, concentration was better. Today I sleep like 5 hours but the oxygen and the MB cleared all the fatigue.

This looks highly interesting, I will try to increase the dose in the next days and try to do comparisons of Oxygen alone with Oxygen+MB.

On the otherhand Mitohormesis looks interesting also, I want to do a 3 day fasting but with methylene blue+oxygen, methylene blue activates Sirt1, AMPK, PGC-1alpha, Nrf2 genes and all the complex bla bla bla of the caloric restriction:
http://www.anti-agin...5/mitohormesis/.
Perhaps methylene blue combined with fasting could produce better mitochondria, with more resistance to stress, the Nrf2 gene plays a key role in mitohormesis, and this is a gene that is touched by MB.

Spoiler

 

BieraK mentioned mitohormesis the other day and I thought I'd post a little abstract with some info on it in case you guys were interested. Hormesis is HUGELY important in human adaptive responses to the environment and mitohormesis is an up and coming theory worth paying attention to imo. 

 

 

 

 

http://www.ncbi.nlm....pubmed/26654757

 

Free Radic Biol Med. 2015 Nov 30. pii: S0891-5849(15)01141-7. doi: 10.1016/j.freeradbiomed.2015.11.032. [Epub ahead of print]

Mitohormesis in exercise training.

Merry TL1, Ristow M2.

Author information

Abstract

Hormesis is a process whereby exposure to a low dose of a potentially harmful stressor promotes adaptive changes to the cell that enables it to better tolerate subsequent stress. In recent years this concept has been applied specifically to the mitochondria (mitohormesis), suggesting that in response to a perturbation the mitochondria can initiate and transduce a signal to the nucleus that coordinates a transcriptional response resulting in both mitochondrial and non-mitochondrial adaptations that return and maintain cellular homeostasis. In this review we summarize the evidence that mitohormesis is a significant adaptive-response signaling pathway, and suggest that it plays a role in mediating exercise-induced adaptations. We discuss potential mitochondrial emitters of retrograde signals that may activate known exercise-sensitive transcription factors to modulate transcription responses to exercise, and draw on evidence from mitochondrial dysfunction animal models to support a role for mitohormesis in mitochondrial biogenesis. Studies directly linking mitohormesis to the exercise training response are lacking, however mounting evidence suggests numerous signals are emitted from the mitochondria during exercise and have the potential to induce a nuclear transcription response, with reactive oxygen species (ROS) being the primary candidate.

 

Edited by BieraK, 01 January 2016 - 01:11 AM.

[BieraK]

In this study, the guys talks about the properties of MB of enhancing oxygen consumption, enhancing of OXPHOS, and the reduction of the Warburg effects... the study looks highly interesting, http://www.sciencedi...301008215300605
 

 

Alternative mitochondrial electron transfer for the treatment of neurodegenerative diseases and cancers: Methylene blue connects the dots Abstract  

Brain has exceptional high requirement for energy metabolism with glucose as the exclusive energy source. Decrease of brain energy metabolism and glucose uptake has been found in patients of Alzheimer's, Parkinson's and other neurodegenerative diseases, providing a clear link between neurodegenerative disorders and energy metabolism. On the other hand, cancers, including glioblastoma, have increased glucose uptake and rely on aerobic glycolysis for energy metabolism. The switch of high efficient oxidative phosphorylation to low efficient aerobic glycolysis pathway (Warburg effect) provides macromolecule for biosynthesis and proliferation. Current research indicates that methylene blue, a century old drug, can receive electron from NADH in the presence of complex I and donates it to cytochrome c, providing an alternative electron transfer pathway. Methylene blue increases oxygen consumption, decrease glycolysis, and increases glucose uptake in vitro. Methylene blue enhances glucose uptake and regional cerebral blood flow in rats upon acute treatment. In addition, methylene blue provides protective effect in neuron and astrocyte against various insults in vitro and in rodent models of Alzheimer's, Parkinson's, and Huntington's disease. In glioblastoma cells, methylene blue reverses Warburg effect by enhancing mitochondrial oxidative phosphorylation, arrests glioma cell cycle at s-phase, and inhibits glioma cell proliferation. Accordingly, methylene blue activates AMP-activated protein kinase, inhibits downstream acetyl-coA carboxylase and cyclin-dependent kinases. In summary, there is accumulating evidence providing a proof of concept that enhancement of mitochondrial oxidative phosphorylation via alternative mitochondrial electron transfer may offer protective action against neurodegenerative diseases and inhibit cancers proliferation.

 

Then I foud this other study:

Mitochondrial complex I inhibitors and forced oxidative phosphorylation synergize in inducing cancer cell death.  

Palorini R1, Simonetto T, Cirulli C, Chiaradonna F.

Author information  

 

Abstract  

Cancer cells generally rely mostly on glycolysis rather than oxidative phosphorylation (OXPHOS) for ATP production. In fact, they are particularly sensitive to glycolysis inhibition and glucose depletion. On the other hand mitochondrial dysfunctions, involved in the onset of the Warburg effect, are sometimes also associated with the resistance to apoptosis that characterizes cancer cells. Therefore, combined treatments targeting both glycolysis and mitochondria function, exploiting peculiar tumor features, might be lethal for cancer cells. In this study, we show that glucose deprivation and mitochondrial Complex I inhibitors synergize in inducing cancer cell death. In particular, our results reveal that low doses of Complex I inhibitors, ineffective on immortalized cells and in high glucose growth, become specifically cytotoxic on cancer cells deprived of glucose. Importantly, the cytotoxic effect of the inhibitors on cancer cells is strongly enhanced by forskolin, a PKA pathway activator, that we have previously shown to stimulate OXPHOS. Taken together, we demonstrate that induction in cancer cells of a switch from a glycolytic to a more respirative metabolism, obtained by glucose depletion or mitochondrial activity stimulation, strongly increases their sensitivity to low doses of mitochondrial Complex I inhibitors. Our findings might be a valuable approach to eradicate cancer cells.

 

Basically Methylene Blue+Complex I inhibitors like Metformin+Forskolin+Oxygen concentrator or Bottled Oxygen Could be an excellent approach for CA therapy.
I wrote a bit about that in this post: http://www.longecity...ndpost&p=756379
I think that a cheap drug like Mebendazole that looks highly effective for killing cancer cells could be another part of the stack.

So this is the time for the stimulation of OXPHOS, doing some 3 day fasting with MB+Oxygen+HIIT+c60 ... and perhaps low dose metformin with forskolin?

Edited by BieraK, 01 January 2016 - 01:12 AM.

[Groundhog Day]

 

According to wikipedia article oxygen toxicity is a concern with hyperbaric oxygen therapy also, so Hyperbaric oxygen chamber+methylene blue does not sound like a good idea?.

You have the reason the dose makes the poison here...

 

In the book I read they used injectable glutathione which is a strong antioxidant.  In theory this should counter the possible oxygen damage that could occur from excessive oxygen treatment.

So to be clear, with my current knowledge I think that methylene blue + oxygen is a good idea.

But as always proceed with caution and start with a low dose of each.  

 

The only reason I posted that link to oxygen toxicity is because you asked for a possible side effect.  I don't think you will actually reach that toxic level as long as you stay within therapeutic doses.
 

 

but this makes think in Myo-inositol tryspyrophosphate:
http://www.longecity...-supply-to-tis/
http://www.longecity...ve-enhancement/

 

I'll have to check that out!

 

A small dose of methylene blue like 10 mg could be a good starting point, This really intrigues me.... Why not to try first with bottled oxygen like this? http://mlc-s1-p.mlst...49_032015-F.jpg

 

 

 

I haven't done much research on bottled oxygen water but I feel like you would run into similar problems with it as you do with Hydrogen infused water.  I think earlier in this thread someone, maybe falco, discovered that only certain metals can retain Hydrogen in liquid. So by the time the drink made it out of the factory and into your hands, there is likely to be little left. I could be wrong though.  

 

If they do work, these drinks would definitely be a more convenient way to give oxygen a test drive..but the machine would save you money in the long run.

 

 

 

I have MB and a mild hyperbaric chamber, Solace 210. What's a good low starting point? 6-7mg of MB and 30 minutes in the chamber?

[mettmett]

Start at 0.5mg/kg. For 165lb person this is ~38mg of Methylene Blue.

Not sure about the time for the chamber

Edited by mettmett, 01 January 2016 - 09:46 PM.

[lostfalco]

Disclaimer: Very High Risk

 

As some of you may remember, I've been working on "The God Stack" for some time now. The basic theory behind it is this: supranormal cognition will be caused by making MANY small changes simultaneously. I've been focusing for the past year on as many different systems as I possibly can. We've talked about MC4R, A7nAChR, ghrelin, ampakines, kynurenic acid, the cholinergic anti-inflammatory pathway, pgc-1a, gap junctions, glutamate, histamine, orexin, dopamine, norepinephrine, PDE5i, HDACi, sigma-1 receptors, the microbiome, the suprachiasmatic nucleus, allosteric modulation of red blood cells, GSK3i, NMDA/AMPA receptor trafficking, mitochondrial enhancement, calcium gradients/signaling, the endoplasmic reticulum, etc.

 

I think we are getting close to something very profound here, but there are a few more systems that still need a little tweaking. One of those adjustments relates to neuroinflammation. The heavy hitters here are asthma medications (leukotriene modifiers) that are already available by prescription and that have shown great promise in preventing neurodegeneration, enhancing neurogenesis, and ameliorating memory deficits in Alzheimer rodent models: zileuton and montelukast.

 

I have some montelukast on the way and I'll let you guys know once I try it out.

 

 

 

 

 

 

http://www.ncbi.nlm....les/PMC3737232/

 

PLoS One. 2013 Aug 7;8(8):e70991. doi: 10.1371/journal.pone.0070991. eCollection 2013.

Zileuton improves memory deficits, amyloid and tau pathology in a mouse model of Alzheimer's disease with plaques and tangles.

Chu J¹, Li JG, Praticò D.

Author information

Abstract

The 5-lipoxygenase (5LO) enzyme is widely distributed within the central nervous system. Previous works showed that this protein is up-regulated in Alzheimer's disease (AD), and plays an active role in the development of brain amyloidosis in the APP transgenic mice. In the present paper, we studied the effect of its pharmacological inhibition on the entire AD-like phenotype of a mouse model with plaques and tangles, the 3 × Tg mice. Compared with mice receiving placebo, the group treated with zileuton, a specific 5LO inhibitor, manifested a significant improvement of their memory impairments. The same animals had a significant reduction in Aβ levels and deposition, which was secondary to a down-regulation of the γ-secretase pathway. Additionally, while total tau levels were unchanged for both groups, zileuton-treated mice had a significant reduction in its phosphorylation state and insoluble forms, secondary to a decreased activation of the cdk5 kinase. These data establish a functional role for 5LO in the pathogenesis of the full spectrum of the AD-like phenotype and represent the successful completion of the initial step for the preclinical development of 5LO inhibitors as viable therapeutic agents for AD.

 

http://www.ncbi.nlm....les/PMC4639806/

 

Nat Commun. 2015 Oct 27;6:8466. doi: 10.1038/ncomms9466.

Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug.

Marschallinger J^1,2, Schäffner I³, Klein B^1,2, Gelfert R^1,2, Rivera FJ^1,2, Illes S^1,2, Grassner L^1,2,4, Janssen M^1,2, Rotheneichner P^1,2,5, Schmuckermair C⁶, Coras R⁷, Boccazzi M⁸, Chishty M⁹, Lagler FB¹⁰, Renic M¹¹, Bauer HC^2,12, Singewald N⁶, Blümcke I⁷, Bogdahn U¹³, Couillard-Despres S^2,5, Lie DC³, Abbracchio MP⁸, Aigner L^1,2.

Author information

Abstract

As human life expectancy has improved rapidly in industrialized societies, age-related cognitive impairment presents an increasing challenge. Targeting histopathological processes that correlate with age-related cognitive declines, such as neuroinflammation, low levels of neurogenesis, disrupted blood-brain barrier and altered neuronal activity, might lead to structural and functional rejuvenation of the aged brain. Here we show that a 6-week treatment of young (4 months) and old (20 months) rats with montelukast, a marketed anti-asthmatic drug antagonizing leukotriene receptors, reduces neuroinflammation, elevates hippocampal neurogenesis and improves learning and memory in old animals. By using gene knockdown and knockout approaches, we demonstrate that the effect is mediated through inhibition of the GPR17 receptor. This work illustrates that inhibition of leukotriene receptor signalling might represent a safe and druggable target to restore cognitive functions in old individuals and paves the way for future clinical translation of leukotriene receptor inhibition for the treatment of dementias.

 

Edited by lostfalco, 02 January 2016 - 06:10 AM.

[lostfalco]

The God Stack (in progress)

 

In case you were wondering where to buy. =)

 

MC4R  http://www.antiaging...om/256-msh2-pro

A7nAChR  http://www.powdercit...antamine-powder

ghrelin   http://www.ceretropi...k-677-solution/

ampakines  http://www.ceretropi...idra-21-powder/

kynurenic acid inhibition -- galantamine + phenylalanine + tyrosine + glutamine

the cholinergic anti-inflammatory pathway  http://www.powdercit...antamine-powder

pgc-1a    http://www.amazon.co.../dp/B00C1E7SHQ/

gap junctions/histamine/orexin/dopamine/norepinephrine   https://www.modafinilcat.com/

MAOB   http://www.antiaging...com/50-deprenyl

PDE5i  http://www.superiorp...e.com/tadalafil

HDACi  http://www.powdercit...nitine-benefits

sigma-1 receptors   https://smartpowders...enolone-powder/

the microbiome   http://www.amazon.co.../dp/B0013JOKBC/

the suprachiasmatic nucleus   http://www.amazon.co...e/dp/B000W8Y7FY

allosteric modulation of red blood cells   http://www.nyles7.co...20-31eb53b1e048

GSK3i    http://www.swansonvi...ium-60-veg-caps

mitochondrial enhancement   http://www.amazon.co...V/dp/B014GLEM5W

mitochondrial enhancement II   http://www.nyles7.co...55-ea8e7e6bfd4c

calcium gradients/ryanodine receptors  caffeine + tadalafil/NO  http://www.powdercit...nhydrous-powder

norepinephrine   ephedrine -- go to Walgreens, ask pharmacist for Bronkaid, kept behind pharmacy counter, no prescription required  http://www.bronkaid.com/home.php

Spaced Repetition Learning   http://ankisrs.net/

The 20/10 Method    http://www.ncbi.nlm....les/PMC3782739/

 

Upcoming Experiments: ibudilast (PDE4i), montelukast (leukotriene receptor inhibition), atomoxetine (norepinephrine), dihexa (renin-angiotensin system), more ITPP experiments, T4 (enhances f-actin), testosterone/dht (enhance spinogenesis)

 

Note: remember that "The Big Six" come before ALL of the aforementioned enhancements: diet, exercise, sleep, fasting, meditation, and standing

Note 2: Inspired by UCI neuroscientist Gary Lynch. Read this! =)  http://www.ncbi.nlm....les/PMC4033242/

Note 3: Yes, I have taken low doses of all of the above linked substances at the same time. Do NOT do this unless you know what you are doing and ALWAYS start with very low doses before working up. Intelligence is all about balance. Megadosing leads to imbalances and never works long term.

Edited by lostfalco, 02 January 2016 - 07:29 AM.

[BieraK]

Montelukast is cheap in my country, pharmacies sell it without prescription, I was thinking on take it but first I want to experiment with other things.
I will buy it in the next month, was most impressed me is that  according to this the rats showed a "rejuvenation" in the brain.

 

 "We've restored learning and memory 100 per cent, to a level comparable with youth." When the team studied the brains of the animals, they found that old rats that had been given montelukast had 80 per cent less inflammation. They also had an enhanced level of new neuron growth compared with untreated old rats - about 50 per cent of that seen in young rats. The team also found that the blood-brain barrier - which stops infectious agents reaching the brain and which weakens in old age - was stronger in treated old rats. "Structurally, the brain had rejuvenated."

https://www.fightagi...ive-decline.php

Edited by BieraK, 02 January 2016 - 08:47 AM.

[Lsdium]

Damn Lostfalco, and your still alive 

 

No vibration or oxygen add to your god stack?'

 

Please, share your experience with that stack, how do you feel? God himself? Planing on world domination 

 

 

[lostfalco]

 

Montelukast is cheap in my country, pharmacies sell it without prescription

Damn, I'm jealous!

 

Yeah, montelukast looks very promising but, of course, it didn't help young rats (equivalent to 17 year old humans) in the study. The mechanism of action was too interesting for me to pass up though. I think it might actually be something that could be taken in low doses over the long term in order to prevent cognitive decline. We'll see if I notice anything when I try it in a few weeks. If you end up testing it out, let us know how it goes!

[lostfalco]

Damn Lostfalco, and your still alive 

 

No vibration or oxygen add to your god stack?'

 

Please, share your experience with that stack, how do you feel? God himself? Planing on world domination 

Haha...I think so. =)

 

It was really tempting to add them but I'm leaving them off for now. It was also a difficult choice to leave off hydrogen water. They're all still in the mix but I'm not ready to include them quite yet.

 

Regarding oxygen, I haven't tested it much recently and I've intentionally avoided it while taking ITPP. I set my concentrator back up again a few weeks ago and didn't have time to get it up and running before leaving for vacation...so I'll be messing around with it again soon.

 

To be honest, I feel pretty damn good. It's difficult for me to see how I could feel much better but I can see all of these interconnected pathways that I haven't tried yet...and I really want to know how the pieces fit, or don't fit, together. At the very least, I think all of this experimentation will give me a better idea how to help people when I ultimately turn my focus to anti-aging and curing diseases. My goal is world amelioration, not world domination. =)
 

[di36]

What are your results with "god stack" lostfalco?

[Groundhog Day]

Start at 0.5mg/kg. For 165lb person this is ~38mg of Methylene Blue.

Not sure about the time for the chamber

 

I've been messing around with it at much lower doses, 10mg max but I upped it today.

 

Going to try an experiment:

 

Fasting for 14 hours

600-700mg vit. C early morning

30mg MB just now with 1000mg niacinamide

1 hour of HBOT (about to jump in)

 

If I don't respond back, I'm dead.

[magta39]

Anyone know if LLLT might help restore color to gray hair on your scalp, or prevent further graying haha?

[BieraK]

Anyone know if LLLT might help restore color to gray hair on your scalp, or prevent further graying haha?

http://heelspurs.com/led.html

4/7/2014:

Notes from a phone conversation with son: After the initial month of using the helmet at 7 to 15 minutes twice a day as described above, he was more social and confident with words. Before using the helmet, his "mini-mental state" examinations had shown deterioration from 27 to 25 during about 4 tests over the course of a year (mild dementia), then improved to 28 (which is technically borderline normal) for 2 tests after the first month of using the helmet. His son's impression as of this date is that it has helped him from getting worse quicker, but nothing miraculous. However, only the first month was used at the strong dose, and he went on vacation and then into a methylene blue trial during which the helmet was not used. His hair got noticebly and definitely thicker and darker according to son, wife, and sister. His son estimates 15% to 20% thicker and 10% darker, and the sister noticed a difference in the hair before she knew about the helmet. We agreed on the phone that if the helmet had been used consistently for 6 months at the higher dose, then the results might have been very beneficial, if the mini-mental state exam results are "accurately indicative". The reason it was not consistently used at the longer treatment times is due to heat and comfort. So I recommended 3 treatments a day, maybe 7 minutes each, each treatment followed by 1 large vitamin C pill. Based on the theory of how it works, I would not be surprised if 10 minutes every two hours is an ideal treatment plan. I would guess maximum results (including improvement of the condition) to be seen in 2 or 3 months, and then holding steady after that. I am also using due to simply enjoying it, subjectively thinking it makes me more active or "awake".

I think that the answer is yes, however I think that works better for prevention than restoration.

[BieraK]

 

Start at 0.5mg/kg. For 165lb person this is ~38mg of Methylene Blue.

Not sure about the time for the chamber

 

I've been messing around with it at much lower doses, 10mg max but I upped it today.

 

Going to try an experiment:

 

Fasting for 14 hours

600-700mg vit. C early morning

30mg MB just now with 1000mg niacinamide

1 hour of HBOT (about to jump in)

 

If I don't respond back, I'm dead.

 

Wow, perhaps is better to start with a lower dose of MB, like 10 mg and with a bit low time in the chamber... just for stay safe, this is highly experimental, there are studies about MB+Oxygen Therapy (perhaps in the near future we will see things like that). If oxygen produces ROS and MB enhances antioxidant genes, then I think that there is a good sinergy working here. 

In my case I'm in love with oxygen, definitely I want to get a concentrator. For now I've only breathed a small amount of 98% oxygen+MB. Today I will increase the dose, my MB dosage for now is 80mg.

[BieraK]

correction: There are NO studies about hyperbaric chamber combined with supplements that enhances oxygen consumption by cells like MB.