Saturday, June 27, 2015

email to arto annilo concerning least action and evolution

The principle of least action shows a preference for the integral combination of higher potential energy bonds, less kinetic energy, and a shorter time path. Higher potential energy bonds and lower kinetic energy is a state of less entropy. Outside of the 2nd law, the shorter time interval "sought" by the principle of least action does not imply an increase in entropy.  Copies of higher potential energy bonds (such as crystal formations or DNA) instead of a larger-number of different levels of potential energy is less entropy.  Lower kinetic energy from different sources will result in less heat and entropy.

A cheetah gaining stronger teeth (higher potential energy structure) and therefore more successful follows the principle of least action. An immediate result that can be seen by the differential form of least action (Newton's law) will be that other potential energy sources (free energy) are depleted more rapidly.  However, the more holistic form, least action, anticipates that gazelles of the future will carry higher potential energy structure as a result of the stronger cheetahs, if there is a free energy influx and an entropic efflux.  So my view of least action is that it is the missing key in evolution. You have the same intuitive feel, but you have an opposing view of least action that causes you to see least action as an "exploitive" rather than "generative" key. Genes are not selfish because they carry no force. They are the memory system that maintains higher potential energy structures. Life is not exploitive, it's creative. Life is more symbiotic than mutually-destructive. Life maintains order, not an accelerator of disorder.

Least action is usually calculated for a given system, but the Earth has a net free energy influx. The energy coming in equals the energy going out which is maintaining the surface temperature. The larger number of lower-energy photons leaving Earth compared to the incoming light is higher entropy for the Universe.  So the 2nd law can be allowing least action to decrease local entropy on the Earth's surface. The minimum energy principle is a special case of the 2nd law that applies to the Earth. It is enabling least action to create life.

For a given time interval, the principle of least action implies a preference for lower entropy via the preference for potential over kinetic energy. It is a mistake to turn this around and say the quantity of L=T-V (entropy generation) is fixed and therefore a shorter time period is sought by least action, and therefore more entropy can be created in a given time period.

So I see no reason that physics does not dictate that life should arise and continually decrease entropy on Earth.  Identical (lower entropy) black solar cells covering the planet would cause a great increase in the entropy the Earth generates for the Universe due to inefficiency in the solar cells causing infrared radiation. But the energy captured could turn photons from the Sun into mass (a potential energy) by storing energy on flywheels, made of very high potential energy carbon-carbon bonds, not to mention the silicon-silicon bonds in the solar cells which store more potential energy compared to the original SiO2. The flywheel can be viewed classically as kinetic energy, but it is not random motion, so that in relativity it is a potential energy due to the mass increase, without the entropy generated by conflicting kinetic energy masses.  As "solar cells and flywheels" (or whatever methods) get more efficient, the universal entropy increase will decrease, giving less opportunity for a decrease in entropy on Earth, but it could still get blacker and more difficult to detect by light emissions. The ultimate would be a Dyson sphere around the sun, storing the excess energy as mass which could take the form of a lot of kinetic energies all "working together" without "conflict" like simple flywheels or very complicated but strictly organized movement.

As a concrete example of free energy creating less local entropy, imagine a Newton's cradle where the balls on the strings are not of equal weight, have irregular striking surfaces, and are made of a mixture of materials (like steel and rubber) where some of the material is less efficiently elastic and of lower potential energy bonds compared to their oxidized state (the rubber).  Now imagine an external free energy source, like Sun energy, that brings the striking ball back up to the original height after each cycle. The movement will be chaotic and not pretty due to the different weight balls and irregular striking surfaces. Eventually, the rubber will wear away, leaving more potential energy in the bonds per volume (and per mass) of the balls. The heavier balls will loose rubber and steel faster due to trying to store more potential energy in the striking process (surface compression) which will result in more heat. Conversely, the smaller balls will endure less wearing away due to acquiring kinetic energy. So the system is evolving towards less potential energy.  However, the potential energy per mass or per volume is increasing, as a direct result of a continual influx of free energy and an efflux of entropy. After a great deal of time, even steel ball irregularities and weights will equalize and a better Netwon's cradle will have "evolved".  Copies of a ball were created and it has lower entropy even on a per mass basis.  The striking cycle has less action: it is reduced in time has a smaller KE-PE difference in that interval.  The "creator" was time, free energy, and the constraints of the strings and gravity.  The strings had a pre-existing order but it resulted in a larger level of order for the device, a higher potential energy per mass, and less action in a striking cycle.
2nd email (to which I received a reply):

Feynman said Newton's differential form of least action is not as fundamental because it allows for non-conservative forces like friction. So if you start with a differential form, you might be automatically  preventing the possibility of local order from arising out free energy.
3rd email:
On the last page of Feynman's lecture on least action, he gives two examples of least action [edit: no, he said they are different minimum principles from mechanical and electromagnetic least action] seeking minimum entropy as it seeks minimum energy [edit, no it seeks min energy only under isothermal].  I am trying to show qualitatively in my last email that this is true for the general case. [edit: feynman mentioned possibility that QM could have a min entropy law, that could give rise to a very general principle, in which case it could be the law I seek, and it may even underlay the least action cases so that my path above is correct]

Since the Earth has an external source of free energy and an entropy "sink" (as I explained) it seems the principle of least action requires life to evolve into a lower entropy (copies of genes, copies of solar cells) of higher-energy bonds, which it is doing, especially if you view our use of silicon, metals, and carbon-carbon bonds as part of that "life".

I could not have made the argument (that least action in the presence of free energy and an entropy sink demands the existence of  life) with F=dp/dt because it allows for frictional forces. It mistakenly allows for entropy generation to be a legitimate force (a potential field) so that it does not allow the user of the equation to see that least action prefers lowest possible entropy.
4th email:

To answer your two questions in reverse order:

I am not seeking a stationary action (optimization) for a known L=T-V path over time, but asking what happens if free energy is applied to stationary action where the L=T=V path and end state has many non-constraints.

Stationary action is used in many calculations that are intractable by F=ma, apparently because stationary action takes away an extra useless variable that F=ma retains, namely non-conservative forces like friction. There is no such fundamental thing as "friction" and non-conservative forces.   It's not a force, it's generating heat and entropy rather than changing position in a potential field.  If you start with F=ma, you can't get order out of it because it assumes disorder generation is another type of real potential.  It would be like writing the Langrangian as (T-V-F*dx) where F is the friction and the last term is generating heat. This only works classically.
F=ma implies a force causes an action, but in relativity and QM the acceleration can be viewed equally well as the cause of the F.  By thinking F is a cause, people want to look at past forces to see how they determined the present. Relativity and QM overthrew this classical view. The past did not create life. An entire action (event) creates life.  The end L state determines the path as much as the initial L state. The assumption that F is a cause is based on the everyday false impression that friction is a real force.

I doubt I can do this over a sequence of macroscopic events where the classical view seems real enough, so I would guess the microscopic bond changes have given rise to brains that seek optimization in a manner similar to stationary action, such that even the global economic system is doing the same. It seems like F=ma implies selfishness is legitimate due to legitimizing friction, but people agreeing before hand to have optimal (more orderly) paths and outcomes is copying least action. We retain F=ma as a view in everyday life such as being forced to go to work, but our legal/economic systems enforce least action on a system-wide basis.  Least action is working together for an optimal path and outcome when there are many non-constraints on our Langrangian. Force and selfishness can be at every point in the details (F=dp/dt), but the wholistic function of least action is love?  Even Feynman's chapter on it was a bonus (gift) chapter, not one of the
"forced" curriculum chapters. It was also the only chapter where he gave a final written note, to mention that some systems spontaneously discover minimum entropy.

Entropy is being released to space, some of it from offsetting least action creating copies of higher-and-higher energy potentials that know better-and-better how to capture and use the free energy of photons, minimizing kinetic energy release that would have otherwise lead to wasted (non-life) heat/entropy. In the creation process that is still going on, there is plenty of energy being "lost" kinetically but there seems to be an upward long-term trend as seen by today's technology.  Life feeding off life is a complicating detail that on first sight seems extractive of potential energies but it is part of the process from initial L to end L, leading to system-wide higher potential energy bonds that are more efficient at  creating copies.

All the new technologies that are replacing biological life due to greater efficiency depend on higher-energy bonds and many copies of themselves.  Solar cells are 20x more efficient per area than photosynthesis.  Electrical motors are about 100x more cost-effective than muscle. CPU's are about 1 million times more cost efficient than brains for implementing any specific algorithm. Mobile energy storage is shifting from hydrocarbons to metal-air batteries. The economic winners can spread like wildfire, and they are. Copies are lower entropy.
5th email:

F=dp/dt allows for the possibility that p(t) is legitimate for the range of functions p(t)= p'(t) + Constant where any non-zero Constant would create a non-conservative momentum, which would in turn allow for a non-existence force like friction.  [edit: p'(t) is not a derivative of p(t) ] Friction is a statistical measure that is not fundamental.  Life is created via processes that occur beneath the data-discarding, macro-quantity of friction.

The stationary action minimization process removes any possibility of the Constant, such that p'(t) is what it finds instead of p(t) where p'(t) is a subset of p(t) which means least action has higher order, i.e., that it has higher algorithmic compression value satisfying Occam's razor better, and can thereby lead to discovering deeper rules, like the originating impulse for the existence and development of life.

This is why action can solve problems F=dp/dt can't, but the converse is not true.  You can strictly derive F=dp/dt from action, but you can't derive action from F=dp/dt unless you arbitrarily throw away the constant.
6th email

It seems to me that evolution is headed towards creating a maximum amount of order and potential energy that can be provided by the Sun's free energy and the available mass, not that it is accidentally finding the quickest ways to expend the free energy, as I would have expected from thermodynamics, and as I thought you had written. Also, I am thinking of what's happening on Earth as a whole closed system with limited resources, not of evolution existing in an open system.   I'll study your writings more and let you know if I think of something that you may find interesting.  I was reading your 2008 paper and thought it seemed overly complicated and wondering why it did not start with classical mechanics or electromagnetic least action an immediate and direct "explanation of life's order" from there.  I've had a long history of armchair interest in evolution, but still lack a satisfactory explanation for its spontaneous development.  That the  thermodynamics does not forbid it is not enough. It is not clear to me that it seeks an acceleration towards heat death. It is not clear to me, as a skeptical and pessimistic scientist might assume, that intelligence is meant ultimately for quicker depletion of order and potential energy instead of their creation.
The photons emitted by even the smallest change of state are not likely to be under the control of my least-action-initiated view of life, but those photons would just be a cause of the net entropy the Earth emits to space, leaving behind the higher order.  Being more in the infrared, they are higher in number with same total energy (or less, if my view of life has its way) of the incoming photons that had less entropy. 
I did not think about photons having mass and therefore the Earth is not closed.  But then even a closed system that receives work via piston action is receiving photons, so that if photons are included, there is no such thing as a thermodynamically closed system that maintains constant mass and can exchange other variables. Your definition of closed would then be equivalent to isolated.

It is not true that my thoughts on entropy are textbook. First, there are many different ways to state it, but all of them have some error or are good for only a specific domain.  Only a QM view would be correct, and I do not know that view or if there is an official exact view.  But I can prove to my own satisfaction that physical and informational entropy are the same, not just equations of a similar form.  For example S=k*ln(states) has fundamental units of bits except for the constant conversion factor of ln(2) that is needed to convert a ln() to a log base 2.  k effectively removes physical considerations, bringing things back down to a theoretical absolute zero and having no real units ( Joules per Kelvins is fundamentally no units because kelvins is a rigid measure of a distribution of kinetic energy). Conversely, there is no such thing as a purely informational bit because in order to have one in the physical world there must be a difference
in potential energy states. So bits on a computer have more mass/energy than physical entropy because physical entropy is a mathematical construct about the organization of matter. I can also show to my own satisfaction that a Maxwell demon disproof does not need to refer to entropy, and that it should not because there is an energetic cost of bit erasure, but not all entropy increases require an energetic cost.

Photons do not have charge.

The brain has 6 layers of neurons in the cortex which always for 3 degrees of freedom when compressing time-based data. In order words, our brains seem to insist that we believe there are 3 dimensions of space, and a lot of our physics follows from that.  For example, if we had 10 layers instead of 6, 4D space would be what we use, and instead of E= - m*c^2 we would think in terms of a E = - i*m*c^3 where the E and m are not energy and mass, but a different type of conserved quantities.  E is negative mass because meters=i*c*seconds and if you follow the math to remove unitless c, energy is shown to be negative mass.  Different number of dimensions also changes the way spin is viewed.  E and m are in units of 1/time^2 or 1/length^2 once unitless c is removed, so they are shown more directly to be some sort of convolution of space-time.  The logical way to express physics would be to use 1D space instead of the 2D space the holographic view of the
universe is trying to say is more fundamental. Maybe in a 1D view, the connection between mass, photons, charges, and spin would be more readily apparent. 

My main interest is in seeing the connections between evolution, intelligence, and economics.
There is a big difference between life and crystals and such.  Life has found a way of affecting a macroscopic sequence of Lagrangians instead of being like a snowflake that is subject to a single fixed Lagrangian.  Our brains model the larger world before affecting it. We decide we want a sequence of least action events that lead to the most money in our bank accounts. So we model and change the sequence of Lagrangians that are available to and affect us. Even when we only seek minimal time for a given amount of free energy, we are choosing from different paths over a macroscopic scale that normal least action isn't supposed to be able to affect.

So there is an optimality that could occur on Earth, given Earth's constraints, and that nature is somehow working backwards in time at a hugely macroscopic level (billions of years, planet wide) to start affecting matter in the beginning that would eventually arrive at an optimal arrangement of efficiency at the end.  If you think everything is made of photons, then this should be agreeable since there is no time from the perspective of photons.  So I guess my interest is in understanding if and how least action could be (or is being) applied across a sequence of microevents, choosing its own Lagrangians, not just minimizing Langrangians it is stuck with.  Then I want to know how this can be applied to economics and A.I.  Can it choose the optimal Lagrangians only on a QM level?  It this why it takes a long time to discover the best sequence of macro-level Lagrangians to create on Earth?  I mean, maybe life is a process by which QM-level Lagrangian
processes are remembered better if they can affect maco-level Langrangian options in an optimal way.   If creating entropy as fast as possible were a "desire" of physical law, then a black Earth doing nothing but getting hotter would have been the end result long ago. The trend seems to be the opposite way, so what in physical law shows us that this should be the case?

Sunday, June 21, 2015

HTM does not optimize for profit (post to google video)

Jeff mentions there are a whole lot of "motor" connections and other connections going down the cortical column that they do not understand. The HTM is probably about 30% effective in mimicking the cortical column, and that's just on a macro-qualitative basis, not counting the extent and details of what's missing. For example, the HTM using only AND and OR operations whereas dendrites do a lot more. That's is not a qualitative difference because not-AND operations by themselves can be turing complete (a computer can be made exclusively of them...and largely are). But it is there is a mind-boggling difference in capability. A huge qualitative difference is that neurons seek to efficiently use food energy and structural materials at all levels. The HTM is only selecting the number of active synapse connections via permanence values, with only a partial optimization process. The number of segments with AND operations, the number of inputs to the segments, and the threshold of active inputs to trigger a positive AND result are all not being adjusted automatically by the HTM for optimization of resources for optimal pattern recognition. They manually adjust these values based on the application and experimentation. The cortical column does this automatically at many levels. The optimization should cyclically relax conditions and then tighten them in order to discover the best optimization for the data (self-search for Occam's razor). The HTM avoids opportunities to seek occam's razor and in this sense avoids seeking higher intelligence because occam's razor means a compressed model of the data generator (simplist physics laws for example). Optimization of resources for equal or better pattern recognition (aka efficient and high prediction capability) is an implementation of Occam's razor. High intelligence is defined as the greatest profit obtained divided by the storage cost of the algorithm and the computational cost of executing it (these two are physically expressed as mass and energy and have an "exchange rate" conversion factor in getting cost into the same units just as c^2 converts their physical units E=m*c^2 ). These two costs have been formally defined as the length of the algorithm and the execution steps, or some sort of logarithm of them. But basically intelligence is the greatest profit over the widest data set at least cost. "Profit" in the vast majority of AI work is simply pattern recognition, aka prediction, aka classification. This misses something huge: the ability to send a control signal (motor neuron) back into whatever is generating the data to change the data being received in order to increase a desired profit signal (set point) that is separate from mere recognition. You've mention this is a higher-level function of brain, and maybe that's true, but I have to wonder if this is the reason for all the "motor" connections running through the cortical column. The cortical column at all levels may need the control signal as part of its input data, not necessarily needing to know some other part of "itself" was the source, but I doubt the users of the HTM are feeding all available control signals into the HTM . For example, if you make a decision to influence the data generator based on HTM output, then that should be another input stream to the HTM. Getting back to optimization and letting efficient pattern recognition be the only profit desired, the HTM does not seek to reduce storage or computational costs except for letting permanences and segments compete to be active. This is a a big optimization, but it misses the other opportunities I mentioned.

Friday, June 19, 2015

parkinson's notes

 Proven protectors:

Brocolli, raw
Coconut oil
Beer.  Alcohol in 50% of studies had an effect, may be related to non-sensation seeking personality.
For the following
Tangerine extract in men (flavones: tangeretin, nobiletin: good theory, weak epidemiological)
Bitter orange extract in men (0.80, flavanones: naringin, hesperidin)
Apple extract (0.54 in men, ursolic acid, polymers)
strawberries, blueberries, red wine, oranges (0.80 each) (blueberry extract is as expensive as blueberries in content, 0.7% anthocyanidins in dry weight, $200 for 1 kg of 25% concentrate)
flavan-3-ols (0.75 men only, catechins, epicatechins, gallocatechins, epigallocatechin, epicatechin 3 gallate, epigallocatechin 3 gallate)
polymers (in apples, 0.62 men only, proanthocyanidins, theaflavins, thearubigins)
flavanones (0.75 men only)
anthocyanins (tea, berries) (0.75)
flavonols (0.75 men only)

flavones (weak evidence for common ones, 0.85 p=0.4, but nobiletin, HMF, and tangeretin may have strong effect on ghrelin (stomach neuronal compound) and these all individually work on PD models.

2014, n=6,700, PD n=101 cases. Moderate alcohol and higher BMI associated with PD, and heavy leisure time activity as protective as nicotine

2007 n=6,700 10 cups of coffee as protective as nicotine if overweight and low cholesterol

MAO-B inhibitors can be iron chelating and cross BBB
green tea (EGCG and Catechins) and black tea, coffee much less so. One study said coffee advanced the age of onset by 5 years. Black tea operates independently from smoking and coffee. It increases estrogen. High doses seem to cause jitteriness.

fish oil decreases depression (2008). The omega-3 PUFA are protective (2008)

Selenium ... here and here and here

highest dietary cholesterol for men 0.53 risk but omega 3 and 6 had no effect after adjustment for risk factors. n=216 men from N=63,000 (Singapore). But a 2014 review of such studies showed weak inverse correlation (reduced risk) with higher dietary cholesterol and strong effect with lower food energy intake, but both were cancelled when smoking and caffeine were adjusted for. Fats did not seem to effect it after adjustments, but n-6 PUFAs seemed to increase it. Cholesterol may protect from lipid peroxidation caused by a-Syn. Lack of ferritin immunoreactivty decreases ability to utilize dietary cholesterol

Mucuna pruriens 3 to 8% L-DOPA without the side effects (chelates iron) Ethanol extract included additional benefits

Sardines (herring, sprats, brewer's yeast 4x, or anchovies), exercise, and alcohol at same time.
magnesium (need more research) (fava beans, 200 mg/100 g)
Creatine, vitamin E, fish oil, b-complex. Too much niacin may be very bad and destroy complex 1 via manganese exposure
No milk (100 ml/day can cancel coffee, at least in men)
No Manganese

Good sleep, enjoying life, exercise, no social stressors

number is pubmed abstracts

6 Bacopa monnieri. worked better than Gotu Kola and M. pruriens in one study of flies
12 Broad beans, aka fava beans, aka vicia faba 0.3% L-DOPA
12 Ashwagandha (Withania somnifera) Works on mouse model
9 Gotu Kola (Centella asiatica) A few positive articles in pubmed

(alcohol and lactic acid increase uric acid production from diet sardines...exercise gives 3x the increase) Sauna increases uric acid. >6 cups coffee per day appear to reduce hyperuricemia OR= 0.57. (coffee lowers by 0.43 mg/dL) but the effect does not seem to be caffeine. Korean study disagreed about the reduction. Not seen in teas. Oxalic acid, lactic acid (weight training and alcohol) and ketone bodies compete with uric acid for excretion.

fish oil

nicotinamide (the amide of niacin) showed protection and motor function in flies.   Two case reports here and here showed it helped a lot. The first link's authors also has a full paper here.  L-dopa depletes niacin and a forum patient said it relieved hallucinations from the L-Dopa. Hoffer noted schizophrenics also were not able to convert tryptophan to niacin and excreted more kynurenine in the urine, who's metaboliets are implicated in PD. Then the amide form of niacin was shown to help in MPTP mice. higher doses may increase NNMT-mediated Mn-MNT damage. A by product of nicotinamide via NNMT-Mn is toxic methylnicotinamide (MNA). Niacin as a cause of PD has been mentioned here and here and here. Niacin (nicotinic acid) gets to mouse brain easier than nicotinamide and niacin is largely converted to nicotinamide.

PQQ may not cross blood-brain barrier. May help process ethanol. Highest source is green tea.

Vitamin E and Isothiocyanates (from chewing raw broccoli that lets myrosinase increase the amount of isothiocyanates glucosinolates.

ginkgo bilboa?

NNMT expression is associated with neurons that degenerate in PD.

2011 japan n=249 When adjusted for smoking, years of education, BMI, and dietary factors including cholesterol, dietary glycemic index, vitamin E, β-carotene, vitamin B(6), caffeine, iron, and alcohol, no association was found for vit D and milk (how many in Japan drink milk?).

marijuana, Cannabidiol (CBD, not psychoactive)
alcohol for temporary relief, in moderation. Niacin seems to sometimes help.
curcmin might reach the brain:

Broad beans, aka fava beans: Vicia faba (Vf) is a ubiquitous plant rich in easily absorbable L-DOPA. Following ingestion of 40 g freshly chopped Vf containing 120-130 mg of L-DOPA, plasma L-DOPA and urinary sodium and DA excretion increased significantly. The DA/Cre ratio reached a maximum level (280 ± 58 µg/g) 60 minutes after Vf ingestion. This was significantly higher than the DA/Cre ratio after a control meal (1.8 ± 0.2 µ/g; P < 0.0005). .. A study looking at memory used 100 mg. A single bean like I cook weighs 5 g after cooking. A cup is about 40 beans, 200 g, if "fresh" it would have been 600 mg L-DOPA. It does not seem I have tried Mucuna pruriens, which has 3 to 6% L-DOPA instead of this 0.3%. 1 pill of mucuna supplement is 60 mg.

black tea, catechins, vitamin E, zinc are iron chelating

6x higher risk of dementia

vit C helps generate DA cells in embryonic development

Higher pigment density, lower presence of cholesterol, oxidation vulnerability, and iron loading preclude a-Syn pathology that results in cell death and pigment loss (2005).

nicotine may stimulate dopamine release, inhibit free-radical damage to nigral cells, and alter activity of monoamine oxidase B

Dr Michael Murray says Ginkgo biloba extract , NADH (raises dopamine), CoQ10 (he did not cite the latest, failed study), and low protein to reduce tremors. Phosphatidylserine for mood and mental functioning, but not muscle control.

Dietary iron surprise in Japan: 0.24 95% (CI: 0.10-0.57, P for trend=0.0003)

Iron effect complicated, but genes predisposed to iron accumulation 0.97 per 10 ug/dl increase in blood. Highest acceptable iron levels in men result in 0.60. Epidemiological meta-analysis on iron was insignificant, but was complicated by "heterogeneity" between studies.

Iron chelator deferiprone (FERRIPROX) at 30 mg/kg/day (possibly $5,000 a year) helped PD patients in phase 2, possibly reverting status by 3 years. Motor UPDRS score improved 3 points in 6 to 18 months instead of getting worse. Good chelator because it does not reduce iron from blood but may harm liver. Concern: it was said on it's datasheet that this compound removes ferritin from blood, contrary to theory that ferritin/free iron ratio needs to increase

1993:The cytoprotective effect of three flavonoids, catechin, quercetin and diosmetin, was investigated on iron-loaded hepatocyte cultures....catechin > quercetin > diosmetin. These IC50 values have been related to structural characteristics of the flavonoids tested. Moreover, the investigation of the capacity of these flavonoids to remove iron from iron-loaded hepatocytes revealed a good relationship between this iron-chelating ability and the cytoprotective effect. The cytoprotective activity of catechin, quercetin and diosmetin could thus be ascribed to their widely known antiradical property but also to their iron-chelating effectiveness

curcumin is a great iron chelator, but its bioavailability is very questionable, especially in the brain.

carnitine, omega3 fatty acids

IP6 is possibly useful for iron chelation PD (the only other he mentioned was EGCG) and it at least gets into the blood very effectively: 2013: Very promising in both AD and PD animal models.

"Iron (and in some cases copper) is also strongly implicated in a variety of neurodegenerative diseases .... iron can catalyse the oxidation of dopamine to a quinine form that can bind covalently to and then aggregate proteins" 

1988: nicotine blocks transfer of iron into cells

ferritin (protein-bound iron) probably protects against free iron in the brain, but lack of iron in diet and blood can lead to low ferritin.

free iron excess and less bound iron known since 1991 to be implicated in PD: only in PD was there an increased total iron level, decreased ferritin content, decreased copper content, and an increased zinc concentration in substantia nigra.

uric acid delays and slows progression.Uric acid chelates iron and is higher when iron in PD is lower. Higher serum urate predicts slower progression of PD. Iron chelator, antioxidant. One study found no correlation between UA and Fe in the SN, but they adjusted for age, gender, UPDRS score, and progression, which I do not understand if UA is a direct causative factor independent of these things. Beer has 20 mg/L. Sardines, herring, mackerel have 350 mg/100 g. Progression is 2/5 as fast in men highest vs lowest quintiles. > 7 mg/dL should delay progression 30% in men. Historically intelligent men had gout. Dairy decreases uric acid levels. Highest quintile of coffee can lower it by 0.3 mg/dL. Highest quintile of alcohol > 2 drinks/day appears to be raise it 1 mg/dL. Normal for men is 3.4 to 7 mg/dL.Beer twice as good as liquor and wine for raising uric acid levels. Beer has purines and the alcohol might stop urinary excretion but definitely helps production. So eat sardines and alcohol at same time.

Magnesium: 0.33, Zinc: 0.50
Copper and manganese: no effect
Greatest outdoor activity, OR: 0.44
Greatest vitamin D intake: OR: 0.54
Caffiene-containing beverages in Japan: OR 0.55
Caffiene: 0.76 per 300 mg/day (2.5 cups), especially in men
2002: Former smokers: 0.6, current smokers: 0.4, tea: 0.4, cola: 0.6
3 packs/day cigarettes for 10 years: 0.38
2009: 3 cups coffee/day caused age of onset to be 5 yrs EARLIER, 3 cups tea/day delayed it 8 yrs

known since 1992 magnesium levels are low in PD:
Milk risk: OR 1.66 in men
Vitamin E, 1200 IU becoming an accepted standard.
Green tea, black tea, and grape seed extract.
In rat model, fish oil worked better than Melatonin and Vit E, which also help

Epidemiological findings suggest that the consumption of berries rich in anthocyanins and proanthocyanidins may reduce PD risk.

Lack of CoQ10 has a 5x risk factor but 16 months of 2400 mg/day did not help in phase 3 and other tests.
Ibuprofen takers were about 17% less likely.

proprioception deficiency is part of the balance problem in PD:

Need to investigate:
Ferulic acid (a by-product of rosmarinic acid)
Rosmarinic acid (not hardly bioavailable?)

"Weak evidence suggests that lower risk of PD is associated with increased vitamin E intake, alcohol, tea, NSAIDs, and vigorous physical exercise"

gamma and delta tocotrienols activated same cellular mechanisms as caffeine:

"cytoprotective effect due to the activation of the PI3K/Akt pathways in SH-SY5Y cells"

review in Spanish in 2014: (in my opinion, does not appear to be a good article, but I can't see full text. For example, lack of green tea and no mention of outdoor work)

Evidence consistently suggests that a lower risk of PD is associated with hyperuricaemia, tobacco and coffee use...weak evidence suggesting that higher risk of PD is associated with high milk consumption in men, high iron intake, chronic anaemia and traumatic brain injury....Weak evidence suggests that lower risk of PD is associated with increased vitamin E intake, alcohol, tea, NSAIDs, and vigorous physical exercise.


post to Parkinson's web site

I could not find that dentists are more likely to get it, but I might could trace some of my Parkinson's symptoms to mercury at age 12, which profoundly affected my emotional/social/anxiety/hay fever life. I From fillings and other elemental mercury exposure, it is the vapor, not the swallowing.

For 10 years I took 10 to 15 grams/day of vitamin C which converts protein-bound copper to free copper and the protein-bound form is needed to protect the SN from iron toxicity. It may also raise free iron levels in the brain, but this is probably unknown. The 4 the people I have the information on who took more than 10 g/day for more than two weeks experienced a sudden dramatic drop in libido. Lack of libido could be caused by decreased dopamine. Lack of dopamine also helps inform us we are thirsty, and I became aware of my body not doing this about the time of my high doses of vitamin C began. For 20 years, since my vitamin C exposure began, a headache is how I realize that I forgot to drink something today. Linus Pauling started showing signs of Parkinson's (weak voice, trembling fingers, nodding head) in a 1981 video, maybe 5 to 10 years after he started the > 10 g/day high doses.

I helped my father garden a lot in the 1970's when there were some particularly PD-bad pesticides still in use. The military now admits agent orange is associated with PD. My other risk factors are male, non-smoker, non-coffee drinker, non-tea drinker, computer worker, generally stressed, college educated, lots of colds and flu from a history of low vitamin D, and probably low magnesium too. Absolutely no family history of neurodegeneration. Speaking of programmers: post-secondary teachers, in-door, religious workers, welders, and pesticide-related occupations are also more likely to get it.

My tremors are in the early stages and my decreased balance is beginning to be a little annoying, but not measurably worse than others. Nicotine gum is the best thing I've found so far for lifting my mood if not decreasing the very consistent finger trembling. Mucuna Pruriens (500 mg L-Dopa at a time in 1 test, 10 pills, no effect) and a myriad of other things have not shown an effect, or at least do not work as fast and obvious as nicotine. Broccoli in large quantity (1/3 a 2 pound bundle per day, but eating only on the very tips) seems to have really helped recently, maybe even improving sleep quite nicely, as well as libido in the first few days of eating it, but I could not find that it has dopamine-like effects. It does have selenium which might be great in reducing SN oxidation. 1 cup of broad beans, 200 gram is supposed to be about 400 mg L-Dopa and it seemed to have an effect on the thumb tremor, but not in the 2nd and 3rd test. I take magnesium, black tea extract, green tea extract, and coffee in large doses each day. Niacin a 1 gram levels seems to help thinking for the day, but they suspect that at least in manganese-related cases this might be very dangerous. After a great deal of research in pubmed looking for compounds that work in at least prevention I am going to also take selenocysteine, pyruvate, vit E, fish oil, vit D, creatine, b-complex, and coconut oil. And also see about raising my uric acid levels. Also, 10 minutes exercise bike before and after sleep to get oxygen to the brain, and coconut oil, pyruvate, and decaffeinated green tea extract before bed. And blueberries and pomegranates whenever possible. Also beer and egg yolks nearly daily. And absolutely no milk. The amount in coffee could offset the coffee benefits. Coffee is the weakest protector of everything I've mentioned, but it's well-proven due to lots of people taking it and make it statistically significant. I'm also looking into the Ayudervic medicine's Bacopa Monnieri and Gotu Kola.

I also used to get a lot of viral infections from not getting outside (no vit D) and that turned around completely with 2000 IU vit D these days. PD could result from viruses travelling up the sinuses, but it is just as likely that it is a protein-folding problem that is being transmitted as in other neuro diseases. a-Syn transfers to implanted cells in animals. Then again, you can't ignore the benefits of vit D and outside work (vit D from sunlight, not to mention exercise and lower mental stress) as possibly being due to reduced viral attacks.

So in order of importance based on research, thinking, and experience so far:

no social stressors
green tea and black tea extracts

All the others, or one of the others that I will not be able to identify, might work as good as 2 of the above.


Things that help me:

1) no social-interaction stressors...causes a flare up in tremors of my lips and whole body if not classic finger twitch
2) nicotine gum

3) broccoli tips (must be raw to double or triple the dose, certainly not more than lightly steamed)

4) aerobic exercise at least twice daily to oxygenate neurons

5) black tea and green tea extracts, operating from different mechanisms than simply the caffeine, are the 2nd best proven preventors, and therefore possibly are the best "delayer's".

The lowest risk factors that have stronger effect than tea extracts and coffee are smoking, outdoor work (12 year delay in 1 study), no history of pesticide exposure, and (strangely) in 1 study ( ) highest dietary iron and magnesium. But I do not take iron because it's level in the brain correlate with the disease, and the recent phase 2 study on the iron chelator (deferiprone) actually reversed motor symptoms.

Then I have a sizeable list of other nutritional supplements that have been shown to help and are easy to take without danger. These are:

fish oil (to increase omega3 / omega6 ratio, so olive oil is not as good)

coconut oil (to get ketone energy path activated since the glucose path is compromised, but I have not tested it enough personally, except that it was a very strong energy and mood effect before I got PD, and that's why it's popular in exercise circles: people notice the benefits fro 2 hours afterwards)

pyruvate (a different energy path than straight glucose have not yet finished researching it)
vitamins E, A, D, C (200 mg 3x/day to prevent free copper toxicity in a-Syn), and B-complex
vit B6
zinc, magnesium
copper? (it has been said to help, but if it increases the free form in the brain, a-Syn will use it to make the free iron toxic. If I understand the articles, vit C may regenerate the toxic iron to a dangerous form, but vit C has also been said to help)

selenium and selenocysteine? (have not finished researching it)

iron (huge benefit in prevention in the study linked to above, but I have not researched it yet, and this is not what people are expecting. The theory is that sufficient iron helps the body generate the protien-bound form better and that somehow helps reduce the free form in the SN. RR=0.24 which is even better than smoking's RR=0.26 at 3 packs of cigarettes a day for 10 years...nicotine is another free iron chelator)

sardines with beer after strength training to raise uric acid level. Uric acid is an iron chelator that crosses blood brain barrier and proven in multiple epidemiological studies, not to mention the fish oil that can help the vit E, A, and E absorption.

Those I have not yet researched with strong proponents: alpha-lipoic acid, acetyl-L-carnitine

IP6 (unproven to cross BBB, but a good article suggested only it and green tea as possible iron chelators)

Co-Q10 (now in doubt...assists complex 3 but not complex 1)

Curcumin (probably no benefit, does not cross human blood brain barrier, could not find epidemiological study to support it)

Ginseng? (hurts sleep)

Blueberries, pomegranate, cranberry juice....basically any dark color plant in the most intense form with the least amount of carb-based calories. High fructose corn syrup may not be completely bad since it raises uric acid, but I don't do that for fear that flooding the brain with sugar is harmful (no data on that specifically).

2 eggs per day for higher cholesterol?

Others that work in animals but unproven in humans, often due to blood brain barrier

Mucuna pruriens
Ginkgo Bilboa
Bacopa monnieri
Gotu Kola
resveratrol (huge benefits in animals, with researchers trying to find a way for it to absorb and cross BBB)

As you can see from this list and my comments, there has been a huge amount of research in the past 15 years, and there is opportunity for supplements to help. There appear to be many paths to getting PD, with pesticides being the strongest single causative factor. Outdoor work (less thinking stress) and smoking are the biggest protectors, with dietary iron and magnesium needing investigation. About half of the protectors happen to be free-iron chelators, and iron chelation in the brain seems to be the only blunt-force single chemical solution at the core of activity. Alternate (non-glucose) energy paths for the neurons (aerobic exercise 2 or 3 times a day, coconut oil, pyruvate, hyperbaric oxygen chambers) seems very important, with exercise being the only one proven. Then there are the anti-oxidant oil and oil-based antioxidants omega 3, vit E, A, and D, and sufficient cholesterol in the brain being needed, which makes me wonder about the statins being said here as a causative factor, not to mention the Co-Q10 decrease they cause. Then there are the plant-based non-vitamin antioxidants and stimulants.

So to categorize these opportunities: iron chelation, mineral supplements, different energy paths including non-methamphetamine natural stimulants and exercise, oil-based anti-oxidants, and complex plant-based antioxidants.

For each supplement I've listed, I've spent an average of 1 hour searching pubmed.
So far my treatment priority based on research and experience goes like this:
canola oil ? (still testing, and then will compare to olive oil)
fish oil (general brain health if not PD)
black tea better than green tea extract
magnesium, zinc
apple and strawberry 10:1 extract powders 12 g/day
broccoli (Isothiocyanates)
black tea extract
grape seed extract
I'm trying to experiement, think about, research, observe, and tolerate a whole host of other things. fisetin (blueberry), now inosine, naringin- nobiletin-tangeretin (citrus peel chemicals tested in PD models in about 7 different papers amount other indications, specficially ghrelin), niacin, citicoline, citrulline, calcium pyruvate, alpha-lipoic/carnitine, and ginseng that keeps me up at not, but maybe I should reconsider if there's that "nicotine like" effect.
The rasagiline discoverer is very interested in "multi-modal, multi-disease" pharmaceuticals. Likewise, it is very interesting to see certain things frequently common in most PD nutrients: weak iron chelators, iron anti-oxidant, stimulants, and urate increase. About 5 of those I've listed above have all these qualities. Then there is another class: those that utilize fat burning instead of glucose burning in the brain, or otherwise assist oxygen-based fuel. PD a-syn is affecting the cells like cancer: messing up mitochondria function, allowing fermentation (non-oxygen burning) of the fuel in the brain, and spreading. There's a theory DNA affects are only secondary to cancer spreading via a spreadable mitochondrial-fermentation defect, not clunks of virus-like DNA moving from cell to cell. CPAP, HBOT, and exercise all increase oxygen to brain and help PD patients. I wonder if breathing response is suppressed in PD, helping it to spread itself, and forcing people to wake up early in the morning and get moving from lack of air. So if my condition progresses, I'm going to want an oxygen tank next to the bed. At least I'm trying to exercise as soon as I wake up, the hardest thing and therefore maybe the best. I'm plagued with ideas like this all day in all things.
The brand does not matter. Inexpensive ones are "doctor's best", "spring valley", and "now". The best supplements in terms of order of evidence for humans are, generally 300% to 400% less likely to get PD:

black tea extract (most expensive one, but very reliable)
vitamin D

Other compounds with 50% to 100% less likely to get PD in humans:

Isothiocyanates (possibly sulfur is enough)

alcohol here and here , but not here and here, and non-drinking may only be because of parkinson's personality  here and here.  Possibly beer is more protective. Or combining with smoking is best
vitamin E
green tea extract
omega-3 (fish oil, canola oil)
Monounsaturated fat (canola oil, olive oil)
ellagic acid (olive oil)

DHA in fish oil may not be good, so canola oil and olive oil may be better.

People have a strong bias against supplements. As you can see the science does not support this position. They will argue that these are only for prevention, but my response is that since so many PD patients report noticing symptoms 10 years before diagnosis, obviously a lot of people have beginning stages of PD and never come to realize it because they have the highest nutritional status in these compounds.

In men only:
strawberries, apples.
Men general seem to be much better protected from flavonoids.

I do not know how coconut oil got a good reputation because there isn't any research. Magnesium data is excellent but sparse, 4 times more likely to get PD if you're in the lowest levels.

Wednesday, June 17, 2015

ghrelin and citrus flavanones for parkinson's, tangerine, bitter orange, apple

I do not know how one would obtain it, but Ghrelin seems to be pretty powerful in treating PD. PD patients are low in it.  Here's an article:

Excellent review.

Rikkunshito (Bu Zhong Yi Qi Wan, which contains aged mandarin orange peel, and is a mixture of herbs given at 7.5 grams/day for 10 days to critically ill patients) doubled acylated (active, acyl) and deacyl ghrelin. Hesperedin (hesperitin?) is in this herb mixture increase ghrelin by blocking serotonin 5HT 2B and 2C receptors and nobiletin and  tangeretin (tangeritin) blocks the 2B receptor.Tangeretin is about 100 ppm in tangerine and mandarin.  About 10x less in orange and grapefruit.

 The major PMFs, i.e. sinensetin, nobiletin, tangeretin, heptamethoxyflavone, tetramethylscutellarein and hexamethyl-o-quercetagetin

Citrus = Flavanones
broccoli, kale, onion, chocolate = FlavOnols (can't find an extract)
teas = FlavAnols (and chocolate)
parsley, thyme, celery = Flavones
blueberries, strawberry, grapes = Anthocyanins, Proanthocyanidins ,
apples, chocolate = Proanthocyanidins

Grapefruit juice can make more flavonoids more bioavailable.  Naringin is not the cause as previously believed. "It has now been established that the bioactive chemical compounds (furanocoumarins: bergamottin and 6′, 7′-dihydroxybergamottin [they interact]) present in grapefruit inhibit intestinal CYP3A4 activity through a mechanism-based reaction, which causes degradation of the enzyme, hence reducing its levels by as much as 47% within four hours after grapefruit juice ingestion."

bitter orange from which my 10% nobiletin comes may contain a weight-loss stimulant.

1 kg of the peel consumed converts the ppm values below into mg.  So if 1 kg is safe, then the ppm values below when read as mg should be safe. The bitter orange values are direct whereas the pellets might be 10:1.  If 1kg/day is safe, then 100 g of the 10:1 powders should be safe.

Hamlin orange pellets:
hesperidin 14,000 ppm
nobiletin 400 ppm  (35x)
HMF 300 ppm  (45x)
tangeretin 75 ppm ( 200x)
These are half the values I have seen elsewhere, but the same ratio.

Mandarin peel oil:
tangeretin 2000 ppm, 1500 tangerine, 600 hamlin orange
nobiletin 700 to 2000 ppm, 1500 tangerine, 1000 ppm hamlin orange
HMF 800 ppm mandarin, 200 ppm tangerine, 700 ppm hamlin orange

Citrus aurantium  (bitter orange) from korea, fresh peel
naringin 450 ppm  (400 g grapefruit juice has 0.2 g)
hesperidin 1800 ppm
nobiletin 50 ppm  (but many companies sell 98% of this, so this does not make sense)
HMF: 6 ppm
Tangeretin 35 ppm

Tangeretine was $7000 per kg.
Nobiletin was $1000 per kg.
10:1 extracts of apple, tangerine, and bitter orange were $100 per kg.

nobiletin compares favorably between oranges and mandarines, and if the 10:1 extract is of the same type of pellet as with the orange, then 250 g is needed to give me 100 mg per day which is 10 mg/kg in mice.  This would be 3x more hesperidin than in the 100 mg/kg rat study. The common mandarin was the best source

Mandarins had wildly varying HMF.

A 98% hesperidin concentration will have lost a lot of the others. 95% might be OK.

Heptamethoxyflavone (HMF) and hesperedin were given to mice at 33 to 100 mg/kg
Hesperidin has been shown to help in a PD model. (100 mg/kg)
Nobiletin has been shown to help in 2 models of PD (at 10 mg/day but not at 1 or 20, but 50 mg/day work with a different PD model.)
tangeretin helped in 2 PD models  (10 and 20 mg/kg/day for 28 days, and crossed the blood brain barrier in rat)

 The citrus flavonoids include a class of glycosides, namely, hesperidin and naringin, and another class of O-methylated aglycones of flavones such as nobiletin and tangeretin, which are relatively common two polymethoxylated flavones (PMFs) 

Citrus Aurantium extract profile seems ideal and contains naringin ... but naringin is not,bioavailable...but another study says they are bioavailable..."The flavonoids naringenin and hesperetin, which form the aglycones of naringin and hesperidin..."

flavonoid protection from PD was 40% lower risk in men in the highest quintile of intake, adjusted for smoking, age, etc. No effect in women.

"These anti-inflammatory actions of nobiletin are very similar to those of anti-inflammatory steroids such as dexamethasone, and the upregulation of TIMP-1 production is a unique action of nobiletin. Therefore, these results further support the notion that nobiletin is likely to be a candidate for characterization as a novel immunomodulatory and anti-inflammatory drug. "

Prolonged fasting, lighter meals, green tea extract, marijuana, and coconut oil all increase it. It works when taken orally. The MCT's in coconut oil increase its utilization in the brain. So it seems ending a long fast with coconut oil is a good idea, as well as marijuana and green tea extract during the fast.

It seems many if not most cases of PD begin in the gut and stomach where 500 million neurons make up the enteric nervous system. Other cases start in the nose and heart. The Lewy-bodies caused by a-syn misfolding travel up to the brain over the course of years. These neurons are only 0.5% of your total neurons, but they produce 50% of the dopamine. But it seems the ghrelin they produce is more relevant to PD. PD patients produce less of it which causes PD to worsen more quickly and worsen anxiety, depression, memory, and lack of sleep. It also increases dopamine in the SN and protects the SN from future damage. Prolonged fasting produces more ghrelin and calorie restriction has been shown to slow PD progression and especially in this article. Marijuana increases ghrelin which might be why it often causes hunger and sleep. Not giving in to that crave will repair damaged neurons and slow PD progression. Green tea extract also increases it. Chin-shin oolong tea is a special tea that a researcher noticed had similar effects as ghrelin as it is reputed to relieve constipation and something else I can't remember. So they tested it and it has a ghrelin-like compound that appears to activate the needed receptor, so it might work as well, so I spent the $64 on amazon to get 10 oz. It does not decrease as much if you consume fats instead of proteins or carbs. It appears that you could take it orally (if you can find it). More likely to be easily available (since ghrelin is natural and therefore not patentable) are similar synthetic compounds that are more likely to not work right and be toxic. Medium-chain triglycerides like coconut oil increase GOAT activity that converts ghrelin to its useful forms. Believing you are not going to get a good meal anytime soon, or believing the current meal is less calories, increases ghrelin.

It increases insulin activity and improves muscle tone and bone density, in addition to memory benefits.  It increases just before a meal.  A large meal makes it decrease.  It is used to sense fats, signaling to the brain a lot of calories were consumed, even as they prevent as much ghrelin decrease afterwards compared to carbs and esp protein.

ketogenic diet did not increase ghrelin when the subjects were non-hungry (in ketosis).  A high protein diet did not increase it much over more carbohydrates.

High fat diet increases ghrelin secretion cells.

It increases HDL and promotes fat storage and fat burning.  Best to exercise when hungry (when ghrelin is higher).

Circulating MCFAs did not alter ghrelin, but gastro MCFAs did increase acylation mediated by GOAT (goat attaches a lipid to ghrelin to make it active)

"As ghrelin circulates naturally, it is possible to pharmacologically increase the plasma concentration with minimal adverse effects. Patients who have been diagnosed with PD already exhibit reduced levels of circulating ghrelin as well as a reduced postprandial ghrelin response [Unger et al. 2011]. Ghrelin may also help to minimize nonmotor effects of PD such as gastrointestinal dysfunction, weight loss and depression, as well as learning and memory deficits [Diano et al. 2006; Edwards et al. 1992; Starkstein et al. 1991]. Nearly all patients diagnosed with PD suffer from selective cognitive impairments, including problems with attention, concentration and memory [Zgaljardic et al. 2004] and studies have shown that ghrelin enhances both learning and memory via an increase in synaptic plasticity in the hippocampus [Diano et al. 2006]. To date, ghrelin agonists have been successful for the treatment of cachexia to increase food intake and decrease energy expenditure in cancer patients [Neary et al. 2004]. These studies indicate that the ghrelin system is a potential therapeutic target to reduce multiple nonmotor symptoms of PD, as well as playing an active role in reducing further neurodegeneration."

post to PD forum
The way to convert doses from animal studies to humans is to do it based on relative caloric or water intake. Water consumption is based on calorie consumption due to respiration, except humans that work enough to sweat can throw the water conversion off. Most nutrients are studied at a level of 0.2% to 0.5% of daily water or food intake. In humans this works out to be about 0.2% to 0.5% of 1 kg of food or 1 liter of water per day which is 2.5 to 10 grams of the nutrient. (1 liter per non-sweating person is closer to normal than eight 8 oz glasses per day which they finally realized was absurd after 30 years of the 8 of 8oz nonsense. )

But usually you see data in mg nutrient per kg body weight of rat or mice. Mice are about 30 grams and rats about 300 grams. You can find many studies giving 10 mg/kg/day to mice or rats for many nutrients. (It can range from 1 to 200 mg/kg/day.) You would think that to convert this to a human dose you would multiply 10 mg/kg times 70 kg person which gives 700 mg/day. But there is an adjustment: for mice you divide this by 7, and for rats divide by 4. So it's 100 mg/day for a 70 kg person if it was a mouse study and 175 mg/day if it was a rat study. The reason for the reducing it is because larger animals have a slower metabolic rate per kg body weight. The reducing factor is found by (human kg)/(animal kg) raised to the 0.25 power. EPA and FDA still use 0.33 power which was found to be wrong about 50 years ago, but they stick with it because they are normally investigating the toxicity of pollutants and pharmaceuticals and the 0.33 factor gives a margin of safety. But for nutrition comparison, 0.25 power should be used because it is more accurate and the safety of plant compounds is about 100,000 times better than pharmaceuticals. At least that's the ratio of the number of people killed each year from each, 100,000 pharmaceutical deaths when taken as directed verses 1 nutritional supplement death. The 0.25 factor results in slightly higher doses than FDA's 0.33. Study trials use these considerations to determine how much of a nutritional supplement to give to people for the first time, using animal data as the starting point.

To convert rat to 65 kg, multiply mg/kg by 16.  To convert mice, multiply by 10. 

To demonstrate how closely animals and humans compare: RDA's or RDI's for mammals are consistent, having roughly 1/3 of the RDA's 3x lower in other mammals than in humans, 1/3 are about 3x higher, and 1/3 about the same. The list of RDA/RDI's for all mammal is nearly the same. The macronutrients compare more closely. Specific compounds might be further off than the RDI's. But if they are similar to RDI errors, then if I conclude I need 100 mg of a nutrient to compare to the mice or rat study, it might be that I need closer to 300 mg or 30 mg. As with RDI's, being in the ballpark is a major step forward, and 100 mg is definitely in the ball park. But PD is very much like cancer, spreading to adjoining cells and compromising mitochondria, causing it to burn sugars anaerobically. It is no coincidence that green tea extract and grape seed extract work great in mice and rats for both cancer and PD. And in cancer, dose is everything: for example, with green tea extract and grape seed extract, cancer grows 50% slower instead of 25% slower if you double the amount of green tea or grape seed extract mouse or rat is getting, like a grandmother drinking 20 cups of green tea instead of 10, or eating 1/2 pound of grape seeds per day instead of 1/4 pound. So thank goodness for the extracts. So I might conclude 100 mg is enough, but 300 mg might be twice as healthy, if it doesn't rot my stomach from too many bitter powders, as you'll see from my list below.

Yesterday and today I worked on flavonoid extracts. To figure the dose I need, I needed to see what dose was used in mice models of PD, then see what concentration of each compound is found in tangerine peel, then look at what is available for sale, and adjust for human body weight. The mice studies used about 10 mg/kg for several of these flavonoids, so I want about 100 mg/day as I detailed above. I am talking about the compounds that specifically raise ghrelin and work in mouse models of PD: tangeretin, hesperidin, and nobiletin. Hesperidin was used at much higher levels than the other two in the PD models, but it is also in much higher concentrations in the tangerine peel. So if I get enough of the others, I get about the right amount of it. Tangerine peel has about 500 mg/kg (500 ppm) nobiletin which is 0.05%. Extracts are sold with 10% nobiletin or 10:1 concentration. The 10:1 will be only 0.5% nobiletin and cost $50/kg. The 10% has 20x more and cost twice as much. But I do not know the effects of their 10% extraction process on the other compounds. Tangerine peel extract standardized to 10% nobiletin could have anywhere from 10% tangeretin to 1% based on tangerine peel data I've seen, but it could be have a lot less because they may be selling a separate 10% tangeretin product, or otherwise neglecting the tangeretin due to concentrating the nobiletin. But typically pick only 1 component to measure because of the expense and complexity of trying to measure the others, not because the ratio of the others has been reduced.

ANYWAY, I got the 10:1 product, having 0.5% of my nobletin and since tangeretin is probably about 0.15%, I'll shoot for 200 mg/day of nobiletin which would be about 60 mg/day tangeretin and plenty of hesperidin. 200 mg/0.5% = 40 grams/day of 10:1 tangerine peel extract. This means the $50 for 1 kg will last 25 days. Will it mix in a blueberry smoothie? I'll find out. But the 10% nobiletin product looks a LOT more doable, requiring only 2 grams a day, about 2 large pills.

The bitter orange extract powder product can be found standardized to 10% naringin, but then I found a grapefruit extract can do 10% naringin at 1/2 the cost. It has shown major promise in PD animal models, and in many other things. This is the grapefruit compound that amplifies the effects of some drugs and is believed by some to help weight loss. It's strange how "stimulants" keep popping up for PD.

Dried blueberries are about 0.4% anthocyanins and the available extracts are 25% (62x concentration), so to get the 2 cups (300 g) per day human equivalent found very useful to the balance and cognition in mice, I will need 300/62 = 5 g. Therefore the $200 I spent on 1 kg will last 200 days. Other studies put 0.2% to 0.3% anthocyanins in water or food, which works out to 2 to 3 grams for 1 kg food or 1 L water for a human, so 5 g is about right.

If you found the above too painful, here is the summary (and for my future reference):

tangerine extract 10:1, 40 g/day, or more preferable:
50% tangeretin: 400 mg/day $1/day  (20 mg/kg/day mice in treatments before toxin adminstered)
10% nobiletin: 2 g/day $0.20/day  (20 mg/kg/day mice, but this is short term)
tangerine extract 10% nobiletin, 2 g/day ($150/kg, $0.30/day)
blueberry extract 25% antho's: 5 g/day ($1/day)
green tea extract 1 to 2 g/day (two to four 500 mg pills, lot of caffeine)
black tea extract, 0.5 to 1 g/day (2 to 4 pills, not cheap)
apple extract 80% polyphenols 3 g/day (to simulate 200 mg/kg in mice) $200/kg, $0.75/day
naringin 98% 1.4 grams/day (to simulate 80 mg/kg in rats but 4 days) $120/kg, $0.17/day

conclusions for my products, using 1/4 formula for this short term tests and 16x for rats and 10x for mice:
tangeretin: 100 mg/day  $0.25
nobiletin: 500 mg/day $0.05
naringin: 300 mg/day  $0.04

98% tangeretin looked great, but it is $7000/kg.

Broccoli and strawberries are two other good foods to eat. All of the extracts above might be combined with their whole fruit to be more palatable, and to help in absorption and correct metabolism. For example, more sugars in the blood stream might help them cross the blood brain barrier better.
I have been putting together a really strong drink. I guess it's about $15 a day, with most of the cost being in the powder extracts, $2 to $3 per day each, straight from China in bulk.
12 oz pomegranate juice from Hispanic store (not the expensive POM)
added sweet concentrates:
black cherry concentrate 12 g
black molasses 12 g (sugar cane juice after most of the white sugar is removed)
Jallab 12 g (Arabic grape skin extract plus others)
powder 10:1 extracts:
blueberry extract 12 g (my eyesight sharpened enough to not need my barely-needed glasses in 4 days)
strawberry extract 12 g
apple peel extract 12 g
tangerine peel  extract 12 g
Citrus flavonoids with animal studies in PD, bought from china in bulk.
These doses are 1/4 the human-equivalent doses because the studies are "shock" studies on the animals by which I mean they are very short term to see how the chemicals work in response to PD-like toxin challenges.
nobiletin 500 mg
naringin 300 mg
tangeretin 100 mg
Other stuff in pills with strong animal and epidemiological evidence for PD and ability to absorb and cross blood brain barrier  (pills not in the drink):
black tea extract
green tea extract
grape seed extract
(inosine to be added)
The American producer of patented fisetin is not clear that it is pure fisetin and the brand is hiding details about what it is, exactly, so I'll spend 1/3 as much to get pure fisetin from China and then sell the excess on ebay.  Inosine in bulk is also 1/3 the cost from china.
Canola mayonnaise, the bomb!
Broccoli, Sardines, home-made very yeasty beer, olive oil
1 hour exercise, then drink it to absorb the sugar.

Saturday, June 13, 2015

Evolution as an Objective Good

The problems most people see or sense in government and economics comes from feeling they are not being implemented in the way that they "should". There is an ever-present implicit assumption that we should do what is best for humanity. I'll get to why that is not the correct assumption in the last paragraph, but first I want expound upon "best for humanity".

No one wants to define "best" because that logical path leads to trying to figure out who gets to have the most children. Let me explain: "best" for humanity is believed by the vast majority to include fewer people so that limited resources and damage to the environment do not become too expensive on a "per person" basis. We also do not believe the most miserable or cruel people should have the most children simply because they have acquired the most money.  Nor do we believe there should be government handouts to  increase the number of unhealthy, dumb, cruel, or selfish people. Taking these three facts together, it seems we want only the nicest, happiest, healthiest, intelligent, loving, and productive people to have children, and that there should be a selection process that chooses the best of the best because resources are limited. (However, the best of the best may overcome any resource limitations.) So there is an implicit assumption that economics and government should function to advance this goal, allowing all of us to be "nice" but guiding us towards being "fair" in pursuit of improving society (basically, whatever promotes the greater happiness and ability to survive) which includes "improving" its gene pool. In the past, we used blood-shedding war to merely determine who is the smartest and strongest. We left it up to leaders or culture to decide how cruel and selfish we were to be in order to advance our population at the expense of others. "Might is right" was the rule, as it has always been in evolution.  Physical war has been replaced with stress-inducing economics, so the rule has not changed.  It's so much stress that many western people are too stressed to have children. The power of the economic machine pushes the stress culture on 3rd world populations that are equally or even more stressed, but not so indoctrinated to a local western culture to limit the number of children they have.  Pets, distractions, and artificial ego boosts that require more money have worked well to limit the number children western people decide to have.  More optimistically speaking, love and trust for others outside of the family in the local culture decreases the need to increase family size. When you can't trust anyone in your local 3rd world poverty-stricken culture, you tend to want a bigger family to love, trust, and provide support. To recap an important point, it seems we agree with the apparent methods of evolution and still believe "might is right". This includes cooperation, which gave rise to powerful democracies that replaced kingdoms. Capitalism seems to be discovering methods more powerful than functioning democracies and communism, subverting both from within by corporate influence, not allowing the quality of life to increase as fast as technology would otherwise allow. It is tolerated because the quality of life is generally increasing.

So the "problem" people see and sense in economics is that it is not optimizing happiness. But this implies getting "something for nothing", or rather not advocating "might is right" to the extreme without regard to happiness per median person. So "problem" is that people want to subvert the evolutionary principle of "might is right". We want to create a bigger family so that we can all relax more.  We do not want a few people "at the top" to make the rest of us miserable simply because they are more powerful.  But they succeeded through might, so they are not "evil" from an evolutionary standpoint. They capitalized on the weaknesses of the system, which can make the system healthier as it readjusts.

But I want to discuss an "objective good".  If we assume we are "good" (maybe we MUST assume that for some deep reason), then we may also need to assume the evolutionary process as "good" because it is what created us. Maybe even "more good" than ourselves.  But the evolutionary process is not limited to DNA and biology. DNA is a method of remembering what patterns gave rise to imperfect copies of itself that evolved. The more general "element of evolution" is information itself.  Genes stored in DNA sequences are a specific type of informatic "meme".  Everything I am typing is the result of memes floating around in my brain and society, combining to create new memes (sentences) that were never created before. Information is the foundation of all forms of evolution as long as it can be stored, communicated, and transformed. Today's non-biological information handling methods are more reliable, durable, faster, and efficient than brains.   To back up for a minute, the physical process of evolution which can be defined recursively as: the rapid and efficient conversion of free energy and matter into improved information patterns, where "improved" means enabling even faster and more efficient conversion of free energy and matter into improved information patterns, if the amount of free energy remaining and information patterns are able.   If this physical evolutionary definition can be objectively extended to mean a moral "goal" its products (such as people) should seek, then we have a solution to the confusion surrounding what we should do with today's economics and government. We should let the machines rise even at our own expense as a species, without trying to dictate any other moral values into the machines. Our machines are better at every element needed in the definition: energy acquisition, energy utilization, and information acquisition, storage, transmission, and manipulation.  The information manipulation is needed to model and remember the methods of energy acquisition that moves matter which is used to create ever-improving information manipulation hardware.  All of biology and economics can be viewed as a self-replicating, efficiency-seeking computer.  But replication and existence is not the goal. It is simply the result of free energy making it possible.

With the exception of energy storage for transport, our machines are clearly better than us at everything.  Solar cells are already 20 times more efficient than photosynthesis per area of land, and are competitively priced per total energy produced to set up, even in the Amazon, and much less expensive to set up in the desert. A $50  100 Watt electrical motor can move as much matter as a hard working human, and can do it for $0.015 per hour and can work 24 hours for 200+ years. A working human costs at least $1,000 per year for 10 years, 200 times more investment. 80 hour work weeks for 40 years is 1/10 the total work, so investment is more like 2000 times more as an absolute minimum investment if we want to compete with machines.  $1 an hour is 66 times more expensive in energy operating cost. $1 per hour can easily pay for the food needed to generate the 600 W per hour calories this super-hard labor person is consuming in order to compete with the 100 W electrical motor.  $10 per hour would 660 times more expensive. In any programmable economic-relevant task, which is every economically-relevant (i.e., evolutionarily relevant) task, computers are so superior to brains that it is hard to make a comparison. Computers being 1 million times less expensive seems approximately correct, which is why there could have already been several instances of 2 computer-smart kids replacing millions of workers and becoming instant billionaires. That many workers were not replaced by Google, Youtube, PlentyofFish, Facebook, and Snapchat because it was not necessary. Instead, they changed the face of society, adding to its capabilities and redirecting money so that people have to shift ever more towards computers jobs.  At some point people will not be able to compete against computers even at programming which is when things should get "interesting" and not good for people. Robots and self-checkout systems are replacing millions more directly. A few good programs, a little hardware, and regulatory permission will replace all people who are currently employed by driving. The reason this is occurring now is because computers are cheap and it has taken people an incredibly long time to get around to accepting and implementing these programs. The capability in the hardware was already in place in the 1980's.

Physics thoughts again

If the expansion of space-time creates the mass we see (Stephen Hawking also said in his popular book that negative gravitational energy cancels all the positive mass energy that creates the gravity), then maybe the entropy per volume, adjusted for Hubble volume expansion, is not changing. The high energy particles were simpler in the past but in a smaller volume. This "intensive entropy" rather than the traditional "extensive entropy" makes even more sense if the expanding universe is infinite. So the development of time could be based more on the dual creation of mass and gravity at the same time. But if all energy cancels, was there zero energy in the big bang? By the way, if you use Einstein's (App 2 in "Relativity") meters=i*c*seconds conversion factor to express all lengths as i*time units or vice versa (time=length/i) then E=m*c^2 becomes E= -m*c^2. Energy is the negative of mass, and would have units of -1/seconds^2. Mass would have units of 1/seconds^2. So simply taking relativity seriously in your units gets rid of meters, Joules, and kilograms as distinct concepts. I believe it's squared because we have 6 layers of neurons in the brain which allows us to compress reality into 6 degrees of freedom which gives us the impression that reality has 3 dimensions of space, the only source of integers in physics. This in turn gives rise to perceiving integers in spin concepts the way we do. If we had 10 layers in the cortex, we would not think about energy and mass but quantities consisting of 1/seconds^3 or Einstein's equation would be E'=-i*m'*c^3. The "-i" because c^3 does not "get rid" of "i" like i^2 results in -1. The E' and m' are not the type of mass and energy that we currently see. This would make all mass at different velocities appear as distinct stationary objects, and all accelerations appears as velocities. 3D space is real to a 6-layered brain. 2-layered brains processing the information for the eyes of insects living on the ground is sufficient. The eyes are in a 2D world. But the antennae feelers and 2 front legs of ants are used to grab and turn objects and use 6 layered brains, keeping only 2 layers for their eyes. heir very close cousins the wasps have 6 layers for their eyes because they can fly. I do not know about ant drones, which should be good fodder for a PhD. The "Holographic Universe" goes the opposite way of 3D space, showing you that reality can be expressed equally well or better than 3D equations by using a projection on a 2D surface that surrounds a volume, rather than worrying about the details inside the volume. It seems like reducing the compression of reality down to 1D space and 1D time is the most logical choice. Quantum probabilities creating multiverses seems to another dimension. As I mentioned above, these would not need any creation of net energy or entropy.

Evolution as a Physics Principle

Evolution is a physical process of imperfect replication of patterns of matter in the presence of free energy. It may not be an acceleration of the conversion of free energy to entropy compared to previous conditions.