PREPARING FOR PARKINSON

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Philosophically, I am not satisfied by the doctor saying, no Parkinson yet, pointless to worry about a disease with no medicine, only symptomatic medicine! I am not like 99.9% who take it lying down! At the same time, I chase only philosophically valid (have untested but possible rationale) wind mills and never mills that defy current medicine. In other words, attribute innovations filling completeness only. Parkinson is better than similar Alzheimer’s being more visible, even then an elderly disease.

Why believe US MRI and MRA?

Taking sections of my brain images, specially the substia-nigra part, normal people have dopamine cells appearing black. These are progressively reduced. That is what has happened to me, even though current symptoms are not debilitating. Why? Don’t care yet!

How do doctors handle it?

Symptomatic. There are 3 steps on any disease.

1.      Stop the damage.

2.      Restore the chemicals not being produced.

3.      Restore the damaged part.

The doctors are helpless in 1 and 3. L-dopa is given for 2. It works for 5 years. By then the body gets used and low effective even as disease progresses. Switch to others for another 5 years. By then the patient has progressed to dementia!

So how do you expect to be different?

Parkinson’s disease involves gradually worsening tremors and movement problems. It is thought to be caused by a protein called synuclein found in nerve cells folding into the wrong shape, which triggers a chain reaction of misfolding in nearby synuclein molecules. This leads to a build-up of long strands or “fibrils” of the protein, killing neurons.

By nature I consider homeopathy criminal, Ayurveda rarely applicable, allopathy dumb half the time. The applicable part is modern medicine, mm. Most doctors don’t educate themselves in modern practices and are routinely dumb, especially against diseases on elderly and aging. Not surprisingly, Parkinson and Alzheimers resemble Aging, may have common solutions outside the comprehension of mm doctors. I believe we have discovered anti-aging in nmn, anti-debilitation in Mitoq and metformin for pseudo-diabetes from aging. Time will tell. I do believe that my anti-aging program will make me first human to attack Parkinson and Alzheimer’s and make survival to age 150 worthwhile, awaiting transfaction based extension to tghousands of years!

What differences in your routine?

Parkinson is basically mitochondria based disease. For it to be helped, you must essentially do to brain-cells what is done for anti-aging outside, namely nmn. That crosses the blood-brain barrier. Neither ECP or HOT will help. How can one do ECP on brain fluids?One great opportunity is in quantum dots in brain, possible in 5 years! Note that elderly diseases of Alzheimer's (amyloids)and Parkinson's (synclein) are both caused by protein aggegates, attacked by the quantum dots.

Graphene quantum dots prevent α-synucleinopathy in Parki nson’s disease

Nature Nanotechnology (2018) | 

Abstract

Though emerging evidence indicates that the pathogenesis of Parkinson’s disease is strongly correlated to the accumulation^1,2 and transmission^3,4 of α-synuclein (α-syn) aggregates in the midbrain, no anti-aggregation agents have been successful at treating the disease in the clinic. Here, we show that graphene quantum dots (GQDs) inhibit fibrillization of α-syn and interact directly with mature fibrils, triggering their disaggregation. Moreover, GQDs can rescue neuronal death and synaptic loss, reduce Lewy body and Lewy neurite formation, ameliorate mitochondrial dysfunctions, and prevent neuron-to-neuron transmission of α-syn pathology provoked by α-syn preformed fibrils^5,6. We observe, in vivo, that GQDs penetrate the blood–brain barrier and protect against dopamine neuron loss induced by α-syn preformed fibrils, Lewy body/Lewy neurite pathology and behavioural deficits.

Roundtrip agaist Facabook

Encapsulated link for interesting friends

https://aaqg-arunarya.blogspot.com/2018/08/biology-of-aging-for-engineer-friends.html

Biology of Aging for Engineer friends

https://www.youtube.com/watch?v=AIzEjm7O11M&feature=youtu.be

The purpose of these series of notes is not to convert into new researchers, only to provide a basic set of ideas to understand some work. Entwined are descriptions of some kingdoms, for some botany, entomology etc. are also needed and thrown in. 99.99% human believe that aging is natural. I don't, and have reasons to believe in life extensions before expected death naturally and even widespread life extension in USA by end of 2020. Any life-extension would dwarf every political dispute ever.

Life is cellular. Less than a cell are viruses. They are perfect salts and reproduce only by invading a host. Routinely, they attack true unicellular beings called bacteria (or archea etc). This attack and destruction can be utilized for narrow spectrum antibiotics against resistant bacteria!

Most important to any life is a cell. A cell for us the main DNA and 0 to 2000 mitochondria. 0 in red blood cells to 2000 in liver cells.  Mitochondria have their own DNA and give rise to own diseases and aging However we ignore aging from it, focusing on main DNA in the nucleus.

The study of aging - gerontology - is a relatively new science that has made incredible progress over the last 30 years. In the past, scientists looked for a single theory that explained aging. There are two main groups of aging theories. The first group states that aging is natural and programmed into the body, while the second group of aging theories says that aging is a result of damage which is accumulated over time. In the end, aging is a complex interaction of genetics, chemistry, physiology, and behavior.

 Theories of Aging

By understanding and describing how we age, researchers have developed several different theories of aging. The two categories are programmed theories and error theories.

• Programmed Theories assert that the human body is designed to age and there is a certain biological timeline that our bodies follow.
• Programmed Longevity: Aging is caused by certain genes switching on and off over time.
• Endocrine Theory: Changes in hormones control aging.
• Immunological Theory: The immune system is programmed to decline over time, leaving people more susceptible to diseases.
• Error Theories assert that aging is caused by environmental damage to our body's systems, which accumulates over time.​
• Wear and Tear: Cells and tissues simply wear out.
• Rates of Living: The faster an organism uses oxygen, the shorter it lives.
• Cross-Linking: Cross-linked proteins accumulate and slow down body processes.
• Free Radicals: Free radicals cause damage to cells that eventually impairs function.
• Somatic DNA Damage: Genetic mutations cause cells to malfunction.

I have no toleration towards people who subscribe to programmed theories, even if they were to be mostly right because if there is any man-effort in challenging the gods, that belief weakens my morale!

Genetics and Aging

Studies have demonstrated that genetics can play a major role in aging. When researchers adjust the genes in certain mice, yeast cells, and other organisms, they can almost double the lifespan of these creatures. The meaning of these experiments for people is not known, but researchers think that genetics account for up to 35 percent of the variation in aging among people. Some key concepts in genetics and aging include:

• Longevity Genes: There are specific genes which help a person live longer.
• Cell Senescence: The process by which cells deteriorate over time.
• Telomeres: Structures on the end of DNA that eventually are depleted, resulting in cells ceasing to replicate.
• Stem Cells: These cells can become any type of cell in the body and hold promise to repair damage caused by aging.

Biochemistry

No matter what genes you have inherited, your body is continually undergoing complex biochemical reactions. Some of these reactions cause damage and, ultimately, aging in the body. Studying these complex reactions is helping researchers understand how the body changes as it ages. Important concepts in the biochemistry of aging include:

• Free Radicals: Unstable oxygen molecules which can damage cells.
• Protein Cross-Linking: Excess sugars in the bloodstream can cause protein molecules to literally stick together.
• DNA Repair: For unknown reasons, the systems in the body to repair DNA seem to become less effective in older people.
• Heat Shock Proteins: These proteins help cells survive stress and are present in fewer numbers in older people.
• Hormones: The body's hormones change as we age, causing many shifts in organ systems and other functions.

Body Systems

As we age, our body's organs and other systems make changes. These changes alter our susceptibility to various diseases. Researchers are just beginning to understand the processes that cause changes over time in our body systems. Understanding these processes is important because many of the effects of aging are first noticed in our body systems. Here is a brief overview of how body systems age:

• Heart Aging: The heart muscle thickens with age as a response to the thickening of the arteries. This thicker heart has a lower maximum pumping rate.
• Immune System Aging: T cells take longer to replenish in older people and their ability to function declines.
• Arteries and Aging: Arteries usually to stiffen with age, making it more difficult for the heart to pump blood through them.
• Lung Aging: The maximum capacity of the lungs may decrease as much as 40 percent between ages 20 and 70.
• Brain Aging: As the brain ages, some of the connections between neurons seem to be reduced or less efficient. This is not yet well understood.
• Kidney Aging: The kidneys become less efficient at cleaning waste from the body.
• Bladder Aging: The total capacity of the bladder declines and tissues may atrophy, causing incontinence.
• Body Fat and Aging: Body fat increases until middle age and then weight typically begins to decrease. The body fat also moves deeper in the body as we age.
• Muscle Aging: Muscle tone declines about 22 percent by age 70, though exercise can slow this decline.

• Bone Aging: Starting at age 35, our bones begin to lose density. Walking, running and resistance training can slow this process.
• Sight and Aging: Starting in the 40s, difficulty seeing close detail may begin.
• Hearing and Aging: As people age, the ability to hear high frequencies declines.

Behavioral Factors

The good news is that many of these causes of aging can be modified through your behaviors:

• By eating foods loaded with antioxidants, you can minimize damage caused by free radicals.
• By exercising, you can limit bone and muscle loss.
• By keeping your cholesterol low, you can slow the hardening of your arteries and protect your heart.
• By practicing mental fitness, you can keep your brain sharp.

Lifestyle factors have also been shown to extend life. Rats and mice on a calorie restricted diet (30 percent fewer daily calories) live up to 40 percent longer. Positive thinking has also been shown to extend life in people by up to 7.5 years.

Cell Biology

 https://upload.wikimedia.org/wikipedia/commons/thumb/1/11/Animal_Cell.svg/800px-Animal_Cell.svg.png

Components of a typical animal cell:

1.    Nucleolus

2.    Nucleus

3.    Ribosome (little dots)

4.    Vesicle

5.    Rough endoplasmic reticulum

6.    Golgi apparatus (or "Golgi body")

7.    Cytoskeleton

8.    Smooth endoplasmic reticulum

9.    Mitochondrion

10.  Vacuole

11.  Cytosol (fluid that contains organelles, comprising the cytoplasm)

12.  Lysosome

13.  Centrosome

14.  Cell membrane

Remember that a cell does ALL the things that a life does, all without any magic, spirituality etc, by simple chemistry in my thinking. It is simple if known, very hard if not. Energy is produced by Krebs cycle from food particles, which are carbohydrate, protein or fat through Krebs cycle. This very complicated cycle is idealized as three sub cycles with one tracer molecule. The three tracers are NAD+, ATP and rest of citric acid cycle. NAD which in turn can be synthesized or reused by salvage cycle from the waste products of the previous sub cycle. Synthesis from amino acids is rare. Salvage step is constructed from NMN.  NR makes NMN with the NAMPT filter. Best idealization in my mind is that NMN is one step away while NR is two steps away from NAD+ we need. Direct NAD+ is a bad idea. Every step in biology is about 10% from bio-availability. NAD+ is produced inside mitochondria.

Bioavailability is great engineering block on all bioscience!

Consider CoQ10 which is required by the ATP sub cycle. There are commercial losses before eating. Then there are stomach wall losses, while the molecule enters the blood stream. Then there are cell absorption losses. Finally there are losses to mitochondrial wall. There is always the limiting concentration of the safe carriage of the chemical in blood. So you can at most ingest 1000 mg of CoQ10 is the safe limit on ingesting. Lucky to get 10 mg on all mitochondria!

Science is about determining effects, doctors are really engineers that determine what is needed, then package the needs based on quantity, time and dosage considering the side effects.

Bioavailability is crucial.

It is. So low for glutathione anti-oxidant and melanin reducer (skin whitens). So much that useless in quaff form. Best injected into bloodstream by a drip. That means a medical establishment, common in Korea and opening in India slowly. In both cultures, fairness of skin enhances marriage value! Another is resveratrol. It is the latest failure – great bioscience but poor engineering with catastrophic unpassable bio-availability failures.

What is Coq10?

It is a vitamin like substance which acts as a usefulanti-oxidant in ATP production and thus helps the heart muscle with mitochondria-rich cells. I recommend it at 400 mg per day in divided doses to all above 60, independent of need, solely for Aging disease.

What is called (Arun neologism) a wittig form?

By witting reaction, a form of CoQ10 exists without losses in mitochondrial absorption. Not surpsingly, this form called Mitoq needs only 5mg to equal 500 mg of CoQ10! The general concept is conversion of any molecule to a form that delivers the base molecule without losses at mitochondria.

What more about wittig forms?

There are no wittig forms that came from literature searches except one, the skq1 molecule similar to Mitoq, is loved by Russians and being human tested for anti-aging properties. The wiitigified anti-oxidant is however plant based. Mitoq I suspect has Anti-aging properties not tested properly because it is very pricy ($1-2 per day) (link discounted as sales-pitch). SKQ1 has been approved for human use in Russia! Sold in drug stores!

 

In many ways 2018 is a water-shed year between classic think and new quantum-think. The old dreams will cease to realistic, new dreams will be radically different. I envy those being born. It is all about exponential speed up. An Arab fighter of 1000AD would not have much to learn in 1500 in launch of ships to America. The world changed radically between 1500 and 2000. That difference now happens in 20 years! About others I don’t know, but I still remember CS MTech (1975-1977) at IIT Kanpur and me trying to guess what humans would do with projected IBM mainframe on a chip! There was no internet, Microsoft, Google or Apple or Facebook or mobile phens then! Even more shocking is about encryption in 2000 and today! In 2000AD, I saved for a Gigabyte drive and 128K memory. My latest purchase is 8 GB RAM and 4 TB disks

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Past the watershed is my phone-sleeve (surrounds any phone for) universal panic button, reminder's to eat medicine - programmable sleeve not software, mobiles that can do lot more using local AI,  5G and killing of TV. Welcome to the 2nd industrial revolution, WHERE DEATH IS RARE AND 1ST GENETIC REVOLUTION WHERE DEBILITATION IS RARE..

Stem cells

A human is formed from union of male and female pluripotent cell repatedly splitting and specializing. Apoptosis message are generated to delete cells produced, The entire process is probabilistic. Biologists classify cells whicch are not in their final specialization into pluripotent 9all can form) to multipotent     Mesenchymal stem cells or MSC. Most early researchers used human PSC obtained from abortions. Nowadays iPS cells (induced) exist which are artificially created.

Mesenchymal stem cells are multipotent stromal cells that can differentiate into a variety of cell types, including osteoblasts (bone cells), chondrocytes(cartilage cells), myocytes (muscle cells) and adipocytes (fat cells which give rise to marrow adipose tissue).

So called iPS are created many ways - one is small chemical/biological modifications of extracted bone marrow from the patient. These can be coaxed into dopamin bearing cells for humans!

Why must go faster

The science of Parkinson

Idea of Arun Arya trial, better than FDA now

There are 4 phases to a trial accepted by FDA

·         Phase I determines if a treatment is safe in humans (this is conducted in an ‘open label’ manner)

·         Phase II ‘double blindly’ assesses in a small cohort of subjects if the treatment is effective

·         Phase III involves randomly and blindly testing the treatment in a very large cohort of patients

·         Phase IV (often called Post Marketing Surveillance Trials) are studies conducted after the treatment has been approved for clinical use

In open label, the researchers and patients are known to each other and investigator. It is Phase II/III which is actively sabotaged by true patients since many are unhappy at secretly be chosen as guinea-pigs fed the ineffective placebo.

The Arya trial keeps the other phases intact, only modifies Phase II/III . Squeamishness of real patients is considered genuine and undermining of Phase II/III considered rational. A MUCH better approach is not to compare against ineffective but another best treatment at this time. Point is then there is no rational strategy and what you get is how much better this treatment is, over the past.

Only in rare cases a placebo be used. Only in cases of new vaccines does one truly need a placebo. Even in this case, one can subject one half to placebo and other to placebo then, and assume that trial was twice as big, and of half the duration!

Aging research – Arun’s view

Happiness Grows with Age

Many but not me.

Biology of Aging for Engineer friends

Elementary Aging research

Why must go faster

The science of Parkinson

The Science of Parkinson – Arun’s view on Aging 3

self link

I study Parkinson because it will strike. Unlike most more, it is NOT the headache of the doctor for best care. Anyone who plans to live post 90 will be hit by Alzheimer, Parkinson or essential tremor, I am just grateful to USA for early diagnosis. Happens to dovetail into fight against Aging. I have no intention of living even 150 afflicted with these elderly diseases.

This is excellent reference for keeping track of new researches. It is a periodical, good enough to serve honest historical documentation of the field. Great source 0f quotations. Past quickly shows what excited the field, NAD is just 1 of many in the sequence of LRRK2, EEF2 inhibitors etc. So wat is new and Game changing about NAD other than I picked it!

One thing that even if I am totally wrong, the efforts will have positive effects in an even deadlier disease, namely aging! A second reason is the absence of some miraculous chemistry that underlies Parkinson. Science is very mysterious but only till it is understood! Broad-spectrum strategies exist to convert science into engineering. I have become quite proficient in dentistry by always asking my sir Dentist interesting questions. Fortunately, he is a professor of dentistry in local college too. That is why I am confident that I will be the first human to lick Parkinson. Way I look at it, it is not worse than TBI and I have a running start. Another is my devotion to contemporaneous (Bell labs, Murray hill) best example of beautiful mind, alas no more, defeating his likely TBI. If I can think of having licked TBI, what is Parkinson and likely Dementia that follows? Note that it is the major reason for state of mind before death of most elderly!

So the trick is to pursue NAD. NMN will help, as with NR, although FDA is out of NR v. NMN fight. Best yet is that Nicotinamide crosses that blood-brain barrier too!

Crossovers (like Aging and Parkinson) never cease to amaze me. Consider “Graphene quantum dots prevent α synucleinopathy in Parkinson’s disease”!  Next I expect “Quantum theory applications in management of Parkinson”       !

Theories of Aging - ARUN's VIEW 2

self link

The stupidest theory believed by 99% of humans is on Aging is “that is how God or Nature wills it”. Aging is a disease, FDA disagrees, their reason is that “no one has established provable (empirically visible) improvements of the purported disease”. It leaves the field open to likes of Dr. Gurante, enormously gifted faculty from MIT who was a faculty advisor to Dr. Sinclair and Dr.  Matt Kaeberlein at M IT, has assembled a team of Nobel Laureates at Elysium, and peddles an excellent but very mild improvement in aging, if at all, in my opinion. They CAN avoid FDA since supplements are not drugs and they are careful to avoid FTC! The war between NR and NMN has no federal referee!

Situation is Similar in India except that FSSAI seems to some control over mix of drugs like Vitamin and supplement claims.

My theory of aging is proven to me by the observation that all cell based life ages and that cells have have Hayflick limit of about 50 subdivisions before apoptosis. In fact I consider the HL essential to life because the only cells with unlimited life are cancer cells, avoided only by apoptosis! This is why I do not consider nmn to be a final fix, just enough to extend the age to 150, longer life happening by transfection, which allows some trees to live few thousand years even with the HL since every cell division has a stem cell dividing too, and the stronger cell survives. Telomere is a red herring!

Given my belief, have narrowed down to a regimen, expect to be able to do it within a few months, see no urgency in applying it. I expect world to be so by 2020. In fact, there is NO probability advantage in following any particular life style.  I expect (weak claims even now) of improvements in heart disease and Alzheimer’s from nmn. There is nothing urgent for self.

But wait. There are two reasons for speed. One I visited USA and underwent 3 MRI and one MRA, why irrelevant. What was discovered was the start of Parkinson. Confirmed on return to India. Poor doc here had no way to decode the CD I got. Never mind, I will make 4 color prints next time. Nothing better than excise and L-DOPA till the latter misses effectiveness due to progressive doping. But there is a blog that analyses NR  in Parkinson! To cut the long short, NAD boost helps PD! That is because NR can cross blood-brain barrier and salvage NAD+ helps with neuro-protective effects. NR has been tested to 1000 mg per kilo, so is human safe. It does show promise as it is effective against neurotoxins. This is common property of all forms of vitamin B3, including Niacin. Given the cost-differential I have started on Nicotinamide, non-flushing Niacin,- just overdose of water-soluble vitamin i.e. useless in worst case. Of course, NMN is planned, is better than NR, provided it can bypass brain barrier. It  can very well following a vigilant search!

Two, it is not so for Dad. He, rightly, will not listen to my theories. His doctor’s do not oppose but say only that they expect no benefit or find human trial empirical evidence on internet (there is anecdotal and mouse based). So I will begin soon on self, hopefully this self-test will either cure me of pretensions of  philosophical/chemistry aggregation of dependable researches, or push him into doing it. MY full regimen is significant exercise + metformin + nmn + Mitoq. I expect significant exercise + metformin + nmn + coQ10

within a month, anecdotal self-proof within 4 months  and business plan for metformin + nmn + Mitoq within 7 month (in 4 sublingual pill supplement per day). Only diversion is self-pursuit of ECP and HOT first, by then!

By then my doors will be ready for in-house 2 month plans for ECP (To date, more than 300 studies have been published showing the benefits of ECP therapy) and Hyperbaric-oxygen-therapy (HOT) (Popuaar with aged Movie stars but also bad wounds, sports, TBI etc) along with supplementation! I do no drugs, hence immune to IMA and only claim improvements to Aging, not a disease even in India! If positive effects are reached by willing friends and relatives first few years, that is good enough. If all works according to plan, I have captive facility of High-quality life-extension for family for repeats every 3-5 years for life for under a crore!

What is cell transplantation?

Parkinson’s is a progressive neurodegenerative condition.

This means that cells in the brain are slowly being lost over time.

What makes Parkinson’s particularly interesting is that certain types of brain cells are more affected than others. The classic example of this is the dopamine neurons in an area of the brain called the substantia nigra, which resides in the midbrain.

The number of dark pigmented dopamine cells in the substantia nigra are reduced in the Parkinson’s brain (right). Source: Adapted from Memorangapp

Approximately 50% of the dopamine neurons in the midbrain (not me with very early analysis) have been lost by the time a person is diagnosed with Parkinson’s (note the lack of dark colouration in the substantia nigra of the Parkinsonian brain in the image above), and as the condition progresses the motor features – associated with the loss of dopamine neurons – gradually get worse. This is why dopamine replacement treatments (like L-dopa) are used for controlling the motor symptoms of Parkinson’s.