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!

Aging characteristics of NMN

Who knows in detail! What will convince me that my money is not being wasted on a supplement without FDA testing? It can be done!

Earlier research by Brown-u says 2 things

1 calorie-restriction works thru m-Tor molecular pathway

2 Anything that reduces Insulin, but also sugar, is good for you if done without insulin or making the pancreas make more by suphonyl-urea drugs! These include metformin acting on liver and acarbose type drugs interfering in sugar absorption in stomach. Both have claims to improving longevity. I happen to believe (unlike most existing doctors fully complacent of new research, dependent on studies on big samples).

There is one reason to explain lack of studies, NMN around for ages, the users at 500 mg per day paid $2000 per month!  Sinclair MD did, himself and father! Reportsenergy-level for both is 20 years lower age. He could, being a billionaire. Empirically proved it on mice. Fountain of youth for mice. Safe for humans.

Apart from being diabetic, I am also an exercise freak, excellent with NMN. What is more, even better than Dr. Sinclair, the sublingualroute is as good as injecting, possible for NMN. 500 mg is like 1000 mg dose!

90% of my fasting sugars are within 100-110. If they are 90% within 90-100, NMN has proven graceful aging properties for me after 3 months. Exercise route for this is estimated to 400 cal per day (1.5 hours of brutal exercise). I test every day and meter zero errors are irrelevant! Three months later, post experiences! NMN is advertised on eBay for Rs. 20,000 per month for 500 mg but only edible, as capsules!

 In a novel experment in mice, MitoQ was shown to protect against insulin resistance.  All these studies were reviewed in a 2011 paper by Smith and Murphy.  Historically, there is a strong correlation of life extension drugs and the ability to enhance stress resistance.  “Together these findings show that MitoQ is protective against pathological changes in a number of animal models of mitochondrial oxidative damage that are relevant to human diseases.”

Aging – Sinclair view over all others

https://www.youtube.com/watch?v=hgQM9l8RWCw

Sinclair is an MD, faculty in Harvard medicine, MD-PhD with MIT. His views are minority but being adopted explosively fast.

What is the basis of fame?

Yeast, made of very simple cells in a colony, suffers from aging! What is more, it can be studied fast. Using yeast, he found aq number of genes related to Sir genes. 7 are found in human, called Sirtuins, of which Sirt1 is the most prominent.

One entire line of medicine is focussed on anti-oxidants. Another attempts to understand two techniques, applicable to many species that have demonstrated benefits but are difficult to adopt – calorie restriction (hunger) and exercise (tiring). Both have molecular basis that may be amenable to much easier adoption, or even act as to increase the effectiveness of these two techniques.

Cutting through the chemistry thicket is the block diagram above. Of the three pathways, two are benefitted by metformin and nmn (nicotinamide mono nuclide). Upto last year, nmn was $2000 year per month of recommended dose. Two great things have happened since

1 Direct synthesis of nmn has been discovered

2 Sublingual administration of nmn is shown to be possible and effective so that stomach penetration losses can be avoided (sharply reducing required dosage) and 4 or more divided doses  per day is feasible.per day are feasible

THIS MEANS, STARTING JUNE 15, IN usa, A 500 MG/DAY DOSE PER DAY, DIVIDED INTO 4 OR MORE SUBLINGUAL SUBDOSES IS POSSIBLE FOR ANNUAL $500.

What does it mean to oxidant-guy like you?

Above indicates a tectonic shift in my thinking away from anti-oxidants to helper molecules. Why?

1 Beliveable partial empirical proof. The doctor takes his drugs as does his father. Doc claims feels like 30 when 60 (looks so too in video linked!) and wears no makeup! Father in 70’s claims feels 50’s.

2. Metformin (10,000,000) records and nmn (3 year human, countless mice) is safe.

3. Program is easy, super-easy for me who needs metformin for diabetes! 500 mg of nmn as four or 5 sublingual sub-doses, 4 times a week, supplement day 300 kcal exercise. Two dinners off per week. Age ninety, here I come, expecting to make 2050 decade, current tech, despite diabetes and heart triple bypass! Plenty of time to acquire boost and live past current expectation.

4 Plausible narrative, experiment worthy, low risk. Results can be visible within 3 months! So blow $200, limited risk.

Three ingredients of belief in my epistemology (absent credible attacks) are sho benefit, show safety and affordable! All met. Further requirement is short interval (3 month). If no visible benefits in 3 months then bye bye.

How come you trust him so much?

1 Experiments on himself and loved

2 Critical of own Reservetrol (sold for 750 million dollars. Empirical disaster from sales process losses and stomach barrier!

3 Avoids the glamourous but FDA-avoid route to FDA welcome to test

4 Hard won NASA commission to supervise health of Long-term astronauts to Mars

Why deaths – road, medical, crime etc – aaquantum scholarly research

There are commonalities deducible from hard statistics, not chosen. First rod then medicine Finally crime. Suggest from statistics is that causes can be divided into controllable and uncontrollable factors; different degrees of loss of liberty in remedial steps is involved; politicians, lawyers and law enforcement and philosophers who do not consider liberty-loss in suggestions upfront and fail to identify this consequence of trade-off up front are motherfucker criminals.

They must be severally punished in my ideology which only respects limited “no law, no crime” i.e. forbid of retroactive crime, not prohibited but subject to “prohibited, unless necessary” like “guilty, unless innocent” philosophy. This allows criminalization of slave-owners, tax-cheats, cigarette companies, nazi, apartheiders etc.

Deaths happen in road accidents for many reasons. Following is 2018 report on Yamuna expressway to agra (HT may 25, delhi). Sleep drivers = 45%. Drinking = 14%. Speeding = 19%. Traffic rules violations = 11% Mechanical 11%. Aaquantum style human = 90%, mechanical 10% (tyre burst, bad mechanics, damaged warning, highway layout,…). Sleepy drivers, speeding, violators and drunk are easy to fix and catch, difficult to enforce. Mechanical are difficult to catch, easy to fix but are only 10 % of total. They also are 90% of intellectual conversations. This is a simple example from many of why I consider intellectuals pointless! That is 90% of class-of-75 !!!!!!!!!!!!!!!!!!

In medicine, death happens for many reasons. Following is report. Why do people die normally? Diet? To say that it’s little known that key crops are getting less nutritious due to rising CO₂ is an understatement. It is simply not discussed in the agriculture, public health or nutrition communities. At all.

You can find true data of choice from here.

Everyone has unique risk factors and causes of demise. Risks do not add as they come with inner correlation. Risks are divide-able into fixed and fixable. Factors like age, sex, genetics etc. are fixed.

Fixable (me) are divisible into two – measurable and statistical. There are varying costs, pain and error rates of measures. The proper investigation method is Very subjective and experience+SKILL dependent with inverted-U (quality vs. experience). Perfect for AI robot or my current mehod od scepticism unless confirmed by sens or Cochrane collaboration (not even mm doctors say so) or journals sceptically, only if peer reviewed.

These methods work for diabetes treatment as death analysis as buying-decisions and indicate an underlying epistemology certainly shared as it evolves.