Work on Metformin

 Metformin has been in use for 60 years to treat diabetes. It has a good safety record and is the first-line treatment for type II diabetes. It works by reducing glucose production in the liver and increasing the body’s sensitivity to insulin. Studies show that metformin extends lifespan and lowers the risk of age-related diseases in experimental mice, worms, and flies. And preliminary results from human observational studies suggest people with diabetes who take metformin may see similar benefits.

Metform is interesting for anti-aging and anti-cancer but anecdotal, situation better after 2016 CDC double randomized study. Interesting questions are

1. How much metformin per day. How many doses. 2550 mg limit, 2000 mg preferred, 1000 mg for non-diabetics. Metformin should be given in divided doses with meals and should be started at a low dose, with gradual dose escalation, both to reduce gastrointestinal side effects and to permit identification of the minimum dose required for adequate glycemic control of the patient.
2. Contraindicated for whom, answers before clinical data from mechanism of digestion and excretion.
   To determine dose, 500 and 1500 mg doses are being tried. Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (i.e. shit). Means kidney better be good. Likely in age 80+ or patients before. Ensure adequate urine clearance. Other contraindication on clinical use data. Best wait pioneering use, ie to 2025. I must for use it for diabetes! Fasting means elimination of Teneligliptin.

Special Populations i.e. Patients with Type 2 Diabetes In the presence of normal renal function, there are no differences between single or multiple dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table I), nor is there any accumulation of metformin in either group at usual clinical doses, or race/gender differences in type-2 diabetic effects. Can safely await clinical data.

So major testable contraindication is renal insufficiency. Other common sense no go are congestive heart failures, known allergies to metformin, and metabolic acidosis with insulin emergency fix.

Can people with type 2 diabetes live longer than those without? 

Clinical and observational studies have shown an increased risk of cardiovascular events and death associated with sulphonylureas versus metformin. However, it has never been determined whether this was due to the beneficial effects of metformin or detrimental effects of sulphonylureas. The objective of this study was therefore to compare all-cause mortality in diabetic patients treated first-line with either sulphonylurea or metformin monotherapy with that in matched individuals without diabetes.

METHODS:

retrospective observational data from the UK Clinical Practice Research Datalink (CPRD) from 2000. Subjects with type 2 diabetes who progressed to first-line treatment with metformin or sulphonylurea monotherapy were selected and matched to people without diabetes. Progression to all-cause mortality was compared using parametric survival models that included a range of relevant co-variables.

RESULTS:

We identified 78,241 subjects treated with metformin, 12,222 treated with sulphonylurea, and 90,463 matched subjects without diabetes. This resulted in a total, censored follow-up period of 503,384 years. There were 7498 deaths in total, representing unadjusted mortality rates of 14.4 and 15.2, and 50.9 and 28.7 deaths per 1000 person-years for metformin monotherapy and their matched controls, and sulphonylurea monotherapy and their matched controls, respectively. With reference to observed survival in diabetic patients initiated with metformin monotherapy, adjusted median survival time was 15% lower in matched individuals without diabetes and 38% lower in diabetic patients treated with sulphonylurea monotherapy.

CONCLUSIONS:

Patients with type 2 diabetes initiated with metformin monotherapy had longer survival than did matched, non-diabetic controls. Those treated with sulphonylurea had markedly reduced survival compared with both matched controls and those receiving metformin monotherapy. This supports the position of metformin as first-line therapy and implies that metformin may confer benefit in non-diabetes. Sulphonylurea remains a concern.

Anti-aging literature review by Dr Arya

Revolutionary anti-ageing drug makes you look younger and live longer: If you believe, I am not your type, get lost.

These are notes to self to summarize my study on aging only being made available for possible help in vast difficult-to-navigate literature on aging; selected by a transparent method of filters. One filter is knowable belief of the author, my belief is not that stupids cannot have valuable ideas; but that if valuable, then okay-people will copy the idea any way and hence purging of nuts does not diminish valuable ideas. A numerical majority of existing doctors may be opposed but a at least a minority of established doctors must allow; I am a very bad argumentative fresh convert. For example, ayurveda and yoga has some great idea, all filter by so called allopathic (mm or modern) medicine and ignored till selection. I talk of fasting, neem, haldi, shavasan etc. That they are considered good STILL means NO credit to the methods, simply being useful from 1000 bad or ineffective! Also fasting for a diabetic.

Basics

It is not possible for a human to do an unclouded literature review by the very nature of aaqgs-memory which converts the transcript of events to do a network selection and a nodal sort, thus losing global event sequence relation, but still local nodal sequence is kept. It means that the review is selective, and the only way to make it more valuable ion future is to incorporate consistent criticism. Unlike the normal prescription of incorporating all criticisms, I have NO tolerance for inconsistent, religious, or magical criticisms; I will incorporate other consistent weltanschauung.
Chemically, consistency means a theory of aging. Such a theory must explain how it happens, utility of food limitation (experimentally calorie restriction increases lifespan in all species) and also different rates in different species and differing rates of infection. Calorie restriction has been tried for nine months directly as losing strength in exercise, looking awful, feeling bad etc. If thats what lifespan increase means, I prefer to die fast! Question is – can you get lifespan increase without calorie restriction?

Allopathic theories on aging

There is chemical narration foreign to me, I convert it to simple engineering story as if a course was running in the first 3 years of IITK at our time. That roughly is the level of knowledge that I shoot for! Mitochrondia can be thought as operating on chargeable batteries – food-in energy-out. Insulin is a hormone that among other things makes you feel hungry thus encouraging for energy-recharge. There are no feelings in my narrative, simply chemicals that cause them. Brain has the job of balancing multiple urges,

Chemically, the primary function of mitochondria is respiration, which promotes energy production. Mitochondria break down organic compounds into water and carbon dioxide to release energy in the form of adenosine triphosphate (ATP). Each mitochondrion is contained in a double membrane. The outer membrane is relatively permeable to small molecules via transport proteins known as porins. The inner membrane forms folds (cristae) that increase the membrane area. Mitochondrial respiration generates a proton gradient across the inner membrane and a transmembrane potential through respiratory chain complexes (I–IV), enabling electron flow from the reduction equivalents NADH and FADH2 to oxygen. Simultaneously, the energy released in the oxidation of NADH and FADH2 is used to pump H+ ions out of the matrix into the space between the outer and inner membranes. Thus, the intermembrane space of mitochondria is charged positively; and the matrix, negatively. Stored energy is used for ATP synthesis by the other membrane-bound protein complex – ATP synthase./

Accumulated Damage versus programmed death

Nearly all current theories of aging have in common the fact that the fundamental cause of aging is the accumulation of molecular damage brought about mainly by ROS, but the role of amyloid protein, glycation end-products, and lipofuscin is acknowledged as well. The current theories differ in the extent to which the buildup of waste is encoded in the genome and whether it is programmed death or this accumulation that is deemed to bear the costs of evolutionary benefits. In addition to damage itself, the rate of accumulation is also of concern, which results from overall metabolic activity. The most significant changes in the longevity of model organisms prove to be mutations in metabolic pathways. Alongside the analysis of model organisms, it is possible to extend to a genome-wide analysis of longlived animals and short-lived counterpart species.Nearly all current theories of aging have in common the fact that the fundamental cause of aging is the accumulation of molecular damage brought about mainly by ROS, but the role of amyloid protein, glycation end-products, and lipofuscin is acknowledged as well. The current theories differ in the extent to which the buildup of waste is encoded in the genome and whether it is programmed death or this accumulation that is deemed to bear the costs of evolutionary benefits. In addition to damage itself, the rate of accumulation is also of concern, which results from overall metabolic activity. The most significant changes in the longevity of model organisms prove to be mutations in metabolic pathways. Alongside the analysis of model organisms, it is possible to extend to a genome-wide analysis of longlived animals and short-lived counterpart species.

The Sci Fi Alternative

Sensleader Dr deGrey, is abnormal biologist, CS like me. He criticizes both Gerontology and Geriatrics as focused on amelioration of damages from aging related diseases, not on repairs of the damage of aging that makes the diseases so bad in the first place! I have great philosophical respect for this. 

Consider politics and mindless criticism of nation building, say in Afghanistan. If you don't want a drug source, you have to bleed, indulge in nation-building. Can't cut and run!

Consider diabetes, insulin-resistance. High-sugars is a consequence not the disease. Fixing that and only that deteriorates the situation to death. Can both be done? Fasting and regular treatment (oppose insulin inducing Teneligliptin in ziten, pure metformin if allowed).

Teneligliptin increases the amount of insulin, perhaps bad on fasting, released by the pancreas, which in turn lowers the blood glucose levels. Common side effects include Headache, Hypoglycaemia (Low blood sugar level) in combination with insulin or sulphonylurea, Upper respiratory tract infection, Nasopharyngitis

1. Metformin has anti-cancer and anti-aging effects too. There are anecdotes like Group of 8 diabetic patients expected to live 5 less years less living more than the compared non-diabetic group lived MORE! CDC started a study in 2016!
2. Mistaken excess can not cause hypoglycemia which IS deadly.

How long can cells live?

Assuming that transfer to electric memory transfer is impossible. Cells of trees have lived for 4000 years. Division of cells produces errors. Point is the availability of stem cells at all sites to replace the errors. It need not be natural. Technology now has 2 remarkable things

1 If nearby, stem cells automatically ensure proper cell division happens. If not, they become the cell! Link explains tree life of 4000 years. Human can not get stem cells every where from roots but an injection needle can deliver iPSC to needing sites.

2 cells can get converted to stem cells called iPS cells for Induced pluripotent cells. There is a magical thing in all cells of all life – the DNA contains the complete genetic history. Conversion to pluripotent cells adds some factors which were removed in specialization.

Stem cells can be converted to pluripotent cells

Consider my plan for indefinite life. 95 by normal means. T0 120 by methods like metmorfin. To 200-4000 by hibernation or stem cell therapy. Some where in next few millinum, transfer to electronics. As usual in Tech Fi, sci fi makes it only faster, you have to give generous research time!

Retro-casualty, confused me

Retro-causality is effects preceding cause, travel to past etc.

Einstein had pleaded to Feynman, “the moon exist even when I don't look at it”?! I was convinced my self that BB interpretation of QM made sense. I was part of tiny minority, that opposed standard QM (no reality exists till you look at it) to many-world interpretations. Weak measurements were starting to prove me right. Till I read about this Australian ANU experiment of 2015 that shook me. QM is best displayed as behavior in double slits. 

Eraser experiment brings out the strangeness. If it is single slit,. Electrons pass as particle. But if both open,. They interfere as waves! Which slit does an electron go through? It is undecidable, standard QM says through both! As if it were a wave! But then closing one slit won't make it a particle! So eraser is paradoxical, hard but explainable in BB. 

The ANU experiment is awful to explain. Using two lasers to make a channel, and another to make a double slit, its is possible to tie the second laser to a random number, Particle is shot between the two starting lasers and registers as a particle. Whenever the spilling laser if on, it forms a double slit and interference happens. Problem is the random numberconsistently makes a double slit BEFORE the effects seen!

Some how, the two-slitnessinformation goes to past! Else Copenhagen QM is right, electron goes though both channels, Or super determinism is right and everything that happens is predetermined even causes for all events in future so that future results can happen right for past. It devastates all definite science theories, only magic theories with collapse on measurement remains and objects don't exist till looked at, the bother of Einstein!


Perhaps there is non-retro casual BB explain for it! I am neither ready to collapse magic, retro-casualty or super determinism explains. but have no choice perhaps.

Amazing Answers

It is my firm belief that the last seven decades of the twentieth century will be characterized in history as the dark ages of theoretical physics. Carver Mead – from his book Collective Electrodynamics

Tes, BB can! Actually  extension  the produces  a join of GR and QM with these amazing properties -

1, retro-casualty only happens at quantum level particles. It is a loop-free retro-casualty, grandfather-paradoxes cannot happen.

2. entanglement is a manifestation of retro-casualty!

3. The GR produced is lorentz-invariant.

4. It is based on dilaton model, distinct from strings and loop quantum gravity.
For once, I do not feel sad about being confused!

More on Metformin and 120 years

Metformin is known by type-2 diabetics. Investigation into its mechanism of action not only explained its primary use, but also other things for good and bad, good being anticancer and antiage properties, principal bad being overweightness.

The most well-known mechanism of metformin action, one of the most commonly prescribed antidiabetic drugs, is AMPK adenosine monophosphate-activated protein kinase activation; however, recent investigations have shown that adenosine monophosphate-activated protein kinase-independent pathways can explain some of metformin's beneficial metabolic effects as well as undesirable side-effects. Such novel pathways include induction of mitochondrial stress, inhibition of mitochondrial shuttles, alteration of intestinal microbiota, 
suppression of glucagon signaling, activation of autophagy, attenuation of inflammasome activation, induction of incretin receptors and reduction of terminal endoplasmic reticulum stress. Together, these studies have broadened our understanding of the mechanisms of antidiabetic agents as well as the pathogenic mechanism of diabetes itself. The results of such investigations might help to identify new target molecules and pathways for treatment of diabetes and metabolic syndrome, and could also have broad implications in diseases other than diabetes.


Thepaper presents applications in antiage and anticancer applications. CDC is evaluating the drug since 2016 and there are lot of anecdotal stories of being beneficial. Given the minor effects of mild overdosing, a doctor-mediated self-experiment is foolhardy but not fully arguable against. Certainly diabetics like me get full benefits at no additional cost, just need to be more aggressive on insulin.

Ancestors to the gods

Can a science-compatible religion find a purpose to life? Yes, my aaqgs can, the only science-compatible agonistic religion in the world. Agnostic means there can be no God to please, or gods to serve. What can then provide a life-purpose to aaqgs-flock, bother with religion, to live well and be happy, certainly not as religious morons or epicurean aimless, but faithful agnostic (not an oxymoron in aaqgs)?
This discourse will talk on all the darkened phrases.

One must have some faith, else doors are shut on any new research. Yet faith implies trust in some tome or persons and is the 99.999..9% way to abuse any one! How does one locate 0.000..1 % people worth trusting? That is the first deepest aaqgs question! Deepest but simple science-compatible answer is by extrapolation of results!

How does one select a professional, doctor, mechanic,...? Examine the work so far! 99% religious guru and 100% thugs will fail this filter! What about me? Examine my answers, forget about me unless extrapolation makes sense! Never trust any one unless they prove themselves. Privacy (relevant) is not allowed for people requesting faith!

purpose to life – aaqgs posits a particular universe scenario that is science compatible, although one of many, all science-compatible and different from ANY extant religion, i.e. agnostic. It states that we might be ancestors to gods. Till godhood or cyborg stage is developed, usual biological inheritance will be used. Enough is known about genetics to know that acquired characteristics are genetically transmitted, partly through genes, partly epi-genetics and partly instruction. It is known that epi-genetics is largely responsible for next genetics as much as blind survival of the fittest and that to live well and be happy is essential for best epi-genetics. If I am the ancestor of gods and if my being happy and live well is essential to them, then I have a selfish purpose to my life, learning, assisting next generation and being content.


bother with religion - people who are free of doubts should not bother with religion! If you are like me, and have otherwise unanswerable questions like purpose of life, feelings as dead, why be good, happy, content, resistant to manipulation etc, learning how is not enough and deeper questions of why begin to rear up. One can find absurd answers,. call them unanswerable or unify to meaningful (falsifiable) implications of answers. In the last case, you need aaqgs. Even when not directly falsifiable, implications and derivations are and methods exist to compare two narratives (of both producing identical falsifiability)/

Being faithful without context is very stupid and can/should be exploited. Only faith allowed by aaqgs is extrapolation with periodic testing of the trusted!

ONE MONTH TOO EARLY!

To 120 year life

My requirement of 200 life to strong probability that reliable singularity is reached through perhaps usual help of ordinary doctors received a major boost when I found that FDA approved study was starting! For 200, first 120 years.

It is through the drug I take any way for diabetes, called Metformin  for which doses 1000-2500 mg make sense for diabetes and life-extension. The zten M has 1000 mg of Metformin. To be on safe side, I will ask my doctor to allow me 1 carbophage at night too – keep next morning fasting sugars low. Note that NEVER do I play with chemical drugs without Dr. agreement. That goes with changing Doctor who objects without explicit reason! Best way on self-trial. NEVER try more than 1 at a time – elementary error most friendly intelligents make. Let FDA verdict come whenever! My diabetes will be helped and I know 2 things about M

1. Impossible to low-suigar on metmorfin! It kicks your gland for more insulin, the gland will ignore fairly often unnecessary kicks.
   
2. Cheap like hell
   
3. Almost no side-effects but those ALL controlled (like overweightness) by vigorous exercise.
   

So I sleep better!

My epistemology allowed me to violate my golden commandment – thou will obey thy doctor. When is it OK? The question required a lot of thinking. I pen it to be criticized, more mercilessly the better, for empty evil words do not bother my thick skin and even bad words are either ignored or retaliated solely by fouler language. In other words, criticizing me, howsoever, is a safe occupation.

The class letter

Sir all, Fundamental to my epistemology is detailed review of what seems to make sense, largely I have learned to doubt self and friends using them and me as valid excellent sources of worth-investigation hypotheses but very poor sources of evidence. My life change seriously with an off-hand link by DM (gave me stoicism) as knowable example and another one by Ashok on diabetes that also made sense to me.

Turns out, the MD he talked about and intermittent fasting are symptoms of a paradigm shift in medicine, happening visible to us. Unlike many friends here, my disquiet with allopathy does not drive me to less effective OIE of medicine of gone days, instead to cutting edge, perhaps less statistical strong, allowed only for newbies and NEVER anecdotes, no matter how good. This guy is unlikely a flake or others rejectable as NOT having academic background. The point is wonder of logic – total ass may wrongly apply logic and still get right answer! Fasting is one, that my friends swear by it, deep religious thinkers say it, adds zero evidence. They also get zero credit! But Atkins diet works!

My wife, US MD had long discussions with me on why it works despite being opposed to usual (OIE) medicine! Now here is the fun – after my research, fasting (start 1 per week) has been started. Horrible idea for diabetics! BUT I took precautions -

1. heart med are not taken empty stomach. Tranches were quaffed after some oats curry morn and night.
   
2. Did not take diabetes med while fasting
   
3. FIRST Fasting is bad. I had 5 glasses of water, 5 cups of green tea and three glass of lemon.
   
4. For every non-diabetic, watermelon (EVEN LARGE BUT NOT SUPERLARGE) size OK.
   
5. His kind of advice marks me an idiot in else-motivated people, welcome to my case with ignored comments unless how else to deal with heart drugs and headaches! There is allopathic fasting, ha ha.
   6. Give myself 2 months. Goal is elimination of ziten M.
   0
   

Missing Points

why is the step dangerous?

Traditional medicine considers fasting diabetic as sinful.

Why?
Low sugars can hit very hard.

How avoided?

Some oatmeal by force. Stop diabetic medicine – even blue moon sugar spike OK. Test blood six times.

How should normal people do it, even intelligent s?

Doctor care essential.

What makes you different?

1 erudite discussion and reference lookup on Atkins's diet in with wife, then, a US MD. In other words, I encourage you to talk to a concerned doctor own or spouse.
2 Knowing current medicines, purpose, impact of missing, method of administration - heart med
3 Close-by emergency and being able to afford them.
4 etc

Point of paradigm shift is progressive idiotification of experienced senior people. Has neen seen by me and resolutely avoided – programmer 1955-1975 structured, pre-internet 1975-1995 UNIXERS, visual 1996-2015 java c++, encryption 2015+ interpreted phone-based IoT tor tails. A paradigm shift against ALL newbies is happening. So is it in medicine - 20 century versus 21.

How characterize?

The world consists of allopathic [modern medicine] and ALL others. Within allopathy is a aaqgs-clear distinction between acute and chronic. Current mm is VERY good at acute care, MUCH better than all others. Situation is very muddy for chronic. A chronic situation is one where no cure is known, best prescriptions are holding strategies, short term improvements are sometimes possible and abused by essentially criminals passing off as alternate doctors. Any technology giving temporary relief but not a cure is sometimes useful in end-stags but criminal before and allopaths who do it are as criminal unless having diagnosed end-stage before!

So what is the shift you see?

1 Unification of chronic diseases causes – not microbes but oxidation, insulin and telomeres.

2 Reduction of chronic cures to ant-oxidants, ant-diabetes and anti-telomere-shortening 

3 Increasing role of non-chemical cures like stomach-stapling, looks-surgery, exercise, ecp.

4 Enormous role of stem cells

5 bio-copying engineerng

Along with newer drugs 95-120 age is possible; hibernation to 200 or maybe by life-extension of cells like long-lived trees; electronic transference for ever. You MUST live to 95 with conventional medicine. That means aggressive sugar control, exercise, safe diet, anti-oxidants. I do them all and invite others to do it themselves or even borrow notes.

Immortal life as cyborg with unlikely but doable plan (which must benefit even if it fails)

Plans with that property deserve a name missing in english, henceforth bounce-plans, where you get a significant boost though unknown amount which depends. Allopathic fasting gives a boost in chronic medicine.