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

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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

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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.

AGING RESEARCH – ARUN’S VIEW 1

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These are notes to self, made available in hope they will attract tough comments, reveal my directions and their reason; are not intended to hurt any views – I am a stoic, perhaps buddhist, consider all not so to be noxious vermin, but see no reason to propagate my views. Some people who can discern scholastic approach to questions (hard stoic but not skeptic) requiring a rational conclusion for all questions rangfing over UNinteresting to besides the point to sophistry if unrational, Rational stoic (not a persistent skeptic!) to distance from pure scientist.

the fellows referenced have a common theme

approach is scientific path to amortality

consider empirical studies on humans to be gold standard

are in possesion of data on models

have narratives on why applicable to humans

experiment on self first

have reasons to believbe they are honest

are not commercially driven (OK after studies only)

hence can be emulated pre-proof

FORGET THE BLOOD OF TEENS. THIS PILL PROMISES TO EXTEND LIFE FOR A NICKEL POP.

 

Nir Barzilai,

Dr. Nir Barzilai is the director of the Institute for Aging Research at the Albert Einstein College of Medicine and the Director of the Paul F. Glenn Center for the Biology of Human Aging Research and of the National Institutes of Health’s (NIH) Nathan Shock Centers of Excellence in the Basic Biology of Aging. He is the Ingeborg and Ira Leon Rennert Chair of Aging Research, professor in the Departments of Medicine and Genetics, and member of the Diabetes Research Center and of the Divisions of Endocrinology & Diabetes and Geriatrics.

Dr. Barzilai’s research interests are in the biology and genetics of aging. One focuses on the genetic of exceptional longevity, where we hypothesize and demonstrated that centenarians have protective genes, which allows the delay of aging or for the protection against age-related diseases. In a Program he is leading we take full advantage of phenotypes, DNA, and cells from the Ashkenazi Jewish families with exceptional longevity and the appropriate controls and his group have established at Einstein (over 2600 samples of which ~670 are centenarians) and discovered underling genomic differences associated with longevity. Longevity Genes Project (LGP) is a cross-sectional, on-going collection of blood and phenotype from families with centenarian proband. LonGenity is a longitudinal study of 1400 subjects, half offspring of parents with exceptional longevity, validating and following their aging in relationship to their genome. The second direction, for which Dr. Barzilai is holding an NIH Merit award that focuses on the metabolic decline of aging, and his team hypothesize that the brain leads this decline. His lab has identified several central pathways that specifically alter body fat distribution and insulin action and secretion by intraventricular or hypothalamic administration of several peptides that are modulated by aging including: Leptin, IGF-1, IGFBP3 and resveratrol.

He has received numerous grants, among them ones from the National Institute on Aging (NIA), American Federation for Aging Research, the Ellison Medical Foundation and The Glenn Medical foundation. He has published over 230 peer-reviewed papers, reviews, and textbook chapters. He is an advisor to the NIH on several projects and serves on several editorial boards and is a reviewer for numerous other journals. Dr. Barzilai is in the board of the American Federation for Aging Research, is its co-scientific director, and has served on several NIA study section. He is also a founder of CohBar Inc., a biotech that develops mitochondrial derived peptides as therapy for aging and its diseases. He is co-PI on the R24 Geroscience (Apollo) grant that is an effort to move the field of aging to translation. Dr. Barzilai has been the recipient of numerous prestigious awards, including the Beeson Fellow for Aging Research, the Ellison Medical Foundation Senior Scholar in Aging Award, the Paul F. Glenn Foundation Award, the NIA Nathan Shock Award, and the 2010 Irving S. Wright Award of Distinction in Aging Research.

He is currently leading an international effort to approve drugs that can target aging. Targeting Aging with METformin (TAME) is a specific study designed to prove the concept that multi-morbidities of aging can be delayed by metformin, working with the FDA to approve this approach which will serve as a template for future efforts to delay aging and its diseases in humans.

Born in Israel, Dr. Barzilai served as chief medic and physician in the Israel Defense Forces. He graduated from The Ruth and Bruce Rappaport Faculty of Medicine at the Technion-Israel Institute of Technology in Haifa and completed his residency in internal medicine at Hadassah Medical Center in Jerusalem. He served in a refugee camp during the war in Cambodia (1979-1980) and built a nutritional village in the homeland of the Zulu (1983 – Kwazulu). He has completed 2 fellowships at Yale (metabolism) and Corenell (Endocrinoology and molecular Medicine). He was an invited speaker to the 4th Israeli President Conference (2012) and a Vatican conference on efforts to enhance cures (2013, 2016). He has also taken part in Global initiatives and spoke at The Milken Global Institute, Asian Megatrends and is an advisor for the Prime Minister of Singapore on Aging. Dr. Barzilai has been on the ‘Forward 50, top 50 influence Jews in the US (2011). His work has been profiled by major outlets, including the New York Times, the BBC and PBS' NOVA science now, TEDx talk Science and is the leading feature on the Ron Howard/Jonathan Silberberg/National Geographic film about the Age of Aging.

 Matt Kaeberlein,

Matt Kaeberlein (born 1971^[1]) is an American biologist and biogerontologist best known for his research on evolutionarily conserved mechanisms of aging. He is currently a Professor of Pathology at the University of Washington in Seattle.

 James Kirkland, and

The major research focus of James L. Kirkland, M.D., Ph.D., is the impact of cellular aging (senescence) on age-related dysfunction and chronic diseases, especially developing methods for removing these cells and alleviating their effects. Senescent cells accumulate with aging and in such diseases as dementias, atherosclerosis, cancers, diabetes and arthritis.

The goal of Dr. Kirkland's current work is to develop methods to remove these cells to delay, prevent, alleviate or partially reverse age-related chronic diseases as a group and extend health span, the period of life free of disability, pain, dependence and chronic disease.

Focus areas

·         Cellular senescence. Dr. Kirkland's team developed the idea that removing senescent cells may enhance health span, partly based on the observation that mice with mutations that increase life span have lower senescent cell burden than normal mice, and that short-lived mice have more of these cells. To test this idea, Dr. Kirkland and his team, in collaboration with others at Mayo Clinic, eliminated senescent cells from genetically modified mice, in which a drug-activated "suicide" gene was expressed only in senescent cells. They found that this process enhanced health span, at least in the context of an accelerated aging-like disease. This gave proof of principle for the notion that clearing senescent cells with a drug in non-genetically-modified individuals might be beneficial. They continue to work on developing interventions that selectively target senescent cells.

·         Diabetes, other chronic diseases and cellular senescence. Diabetes and obesity are associated with accumulation of senescent cells in fat and other tissues. Dr. Kirkland's group is working on ways to reduce severity and alleviate the complications of diabetes by clearing senescent cells or blocking them from producing factors that cause or exacerbate dysfunction. Effects of eliminating senescent cells or the factors they release are being investigated on frailty and a range of other chronic disorders in Dr. Kirkland's laboratory and with collaborators at Mayo and other institutions.

Significance to patient care

Dr. Kirkland's work is important in developing methods to enhance health span and delay onset of the chronic age-related diseases as a group, rather than one at a time. These conditions, including diabetes, dementias, atherosclerosis, cancers and arthritis, among others, account for the bulk of morbidity, mortality and health costs in most of the world.

 David Sinclair 

he Sinclair Lab studies the processes that drive aging and age-related diseases, and works toward discovering methods for slowing down or reversing these processes. Work ranges from dissecting novel pathways and identifying target genes, to assessing small molecules that may slow the pace of aging and increase healthspan. The overarching goal is to establish new biological approaches that can be translated into radically different medicines to promote longer, more productive lives. A focus is on how genetic and epigenetic changes drive aging, common diseases and disorders such as cancer, heart disease, inflammation, neurodegeneration, infertility and diabetes. To advance our studies we use a wide range of genetic, genomic and proteomic tools. In addition we employ several unique mouse models to assess the role of these factors and how well genetic and pharmacological agents may impact them. We are a team with a broad range of skill sets, who work together and complement each other to solve key scientific questions about mammalian biology and human health. Skills in the lab range from enzymology and biochemistry, to genetics, genomics, proteomics and systems biology.

Their recommendations compress to two – metformin and NMN. I add a third - MITOQ. Here is my reasoning – pointless to debate but med MD-PhD. ALL life is cellular, all animals age. So aging is cellular – mitochondria based. MITOQ feeds COQ10 to Mitochondria bypassing all, to be greatly bio-available. No wittig-like Carrier for NMN or metformin. Metformin good for actual diabetic and aging pseudo-diabetics. Insulin promotes aging as do high sugars! Sublingual administration of 500 mg of NMN per day is twice the dose taken by Sinclair! Metformin is dirt cheap. MITOQ is $1 per day, so is NMN. That plus NMN and exercise is to be given up, if no benefits in 3 month. The drugs should enable you to do exercise! If you attribute your health to exercise, don’t forget what enabled you!

Meet the phages

Virusesthat specialize in infecting bacteria are often called bacteriophages, orsimply phages. We've known of some of them from shortly after we startedstudying bacteria, since their spontaneous infections would leave open holes of what would otherwise be an even lawn of bacteria. We've studied a number of them in detail, and some of the proteins they encode have become key tools in our genetic-engineering efforts. And they're not simply oddities that strike when bacteria are forced to live in artificial lab conditions. Surveys of DNA obtained in environments from the deep ocean to the subways show that, wherever you find bacteria, you also find viruses that prey on them

https://arstechnica.com/science/2018/07/researchers-treat-lung-infections-in-mice-with-bacteria-killing-viruses/?utm_source=pocket&utm_medium=email&utm_campaign=pockethits

5G- 21st century revolution begins

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I have talked about NMN + metformin, the joint revolution to human ageing, NMN is already at prices affordable to upper middle class around the world and metformin is dirt cheap everywhere. 5G is new tech, available advanced countries by 2019, extensive by 2020 and world wide by 2021. If you guessed ‘successor to 4G’ in phones, faster than 4G, you are right. So what? Better phones for sure. But 5K is like internet, say I! At most 2 years from start of another internet! So far, to me, Internet defines 21^st – business, communication etc.

It is what else that happens, is why 21^st century revolution begins. Basically, 5G is communication at 10 gigabit range. What can happen at that speed?

All local information becomes pointless. Much worse for libraries, photo-albums, CD etc.! Large TB level USB solid state only will remain.

Essential for self-driving cars, virtual reality, smart cities and networked robots.

Enables remote weapons. Why build expensive local computation in each fire and forget weapon? Just do computation remotely and communicate with bomb encrypted!

A surgeon with virtual reality equipment and haptic gloves, which sense motion and pressure, could operate on a patient on the other side of the world via a robot.

Remote surgery has been possible for a while, but 5G speeds should eliminate all delays and lag. That means the surgeon could get instant feedback via the gloves.

"With 5G and the new networkingarchitecture we're building, we're hoping to get this delay down to just thespeed of light," said Mischa Dohler, a professor of wirelesscommunications at King's College.

Dohler, who moonlights as a composer and pianist, also plans to digitize his piano skills and teach people remotely to master the instrument. Why record the music when can record and reproduce the play? You can already modulate your voice as per another singer, so as to sound as good! (Expensive but doable, I intend to buy a unit and make it available as cloud connected franchise!) Within 3 years, one can make citizen-movie – substituting only one character in movie to the buyer! I can imagine vast sales with just the heroine replaced by the lady-buyer and my franchisee providing blue frame acting studio and post-acting integration on the cloud (otherwise very expensive)!

Like Netflicks and Amazon, one can consider self-production of replacement films (Shot with few blue-clad replaceable characters!)

I am ready with great ideas – use 0f 5G and low-cost start. A Bangalore techie started flipkart in 2012! 2020 here I come. Can even enjoy the wealth!

Start of Anti-aging revolution

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Everything that follows is based on hard biology, without any apology to those influenced at all by religion or spiritualism, even if my presentation attacks their belief. Don’t then read-on.

A human robot is managed by brain. All feelings are either converted to nerve signals, or generate hormones. Biology is by evolution by punctuated natural selection. The being is constructed by epigenetic envelope over DNA.

Aging is by cellular damage accumulation in all life – plant or human. Wrongly I believed that compensation of missing DNA products would lead to better age. Old belief leads to healthier life but has no age extension benefits. Dr. Sinclair changed my paradigm. To extend age, one starts from proven methods, determine their molecular pathways, identify the molecules one tries to help, find the genes helped by the helper and thus consider the effects. Metformin and NMN are anti-insulin perhaps, effecting the mTor molecular pathway!

This summary of why think so, explains to me why Ayurveda is unlikely to help! If there was ANY herb/combination, I view our continuous history of several thousand years and say to self – if there was any plant or combination that had +ve aging effects, it would safely be discovered by now! Our ancestors even discovered the good effects of Shilajit by unscientific blind empiricism since it has +ve strength properties and no –ve side effects! Clearly then NMN is not a plant or animal product as it was discovered in west with several thousand year old non-vegetarian history over all kinds of animals or in Africa with cannibalism in past!

Why does it work?

It increases NAD+, better than NR which suffers from NAMPT bottleneck.

Epistemology?

Here means who to believe! Bastard criminal sellers (i.e. most US Marketeers) means that there is NO way to discover truth – if there were, it would already be abused elsewhere! What then? My esteemed brother-in-law had the same question in 1998 when I sang re Java, writing me off as victim of Clever US Marketeers! So I was forced to examine my own epistemology. I claim general scientific view. Which means rational skepticism! In other ords, ALL the excellent reviews were bull shit, simply extensive ads. All the endorsers could be liars. Videos photo-shopped. So on. The devil was not ordinary but US sellers, who have to be respected for their bull-shit!

My belief is twofold – try it on self-first for 3 months, and try only because Dr. Sinclair has been followed by me since 1998, discovered Reservetrol, sold his company for billion dollars, hence has NO economic reason to lie, sells nothing and consults to NASA re HEALTH of astronaut going to mars, has PhD from MIT, tenured MD faculty at Harvard! He looks 30 and claims to feed his father, living proof of small trial, NMN behind $2000 per month cost till 6 months ago, tolerable only to motivated billionaire.

One thing all agree on – no ill-effects. Only thing I lose 3 months from now is NMN has NO benefit!

Aging properties of NMN?

Big question is – how do know after 3 months (no death needed) that NMN indeed helped aging. Interestingly, I can!

What if NMN works?

Living to 150 or more as a vegetable is not my goal! There are 3techniques to enable me to a worthwhile life – ECP, HOT, parabiosis! These are extra to NMN vitality. I can usefully chase women for next 100 years! By then transfection would develop for 1000 year boost!