## Sunday, December 22, 2013 ... /////

### Elixir of youth: nicotinamide adenine dinucleotide

Alchemists were hired and transferred to Prague by our leader, Austrian Emperor Rudolph II (reign in Bohemia 1576—1611), and one of their tasks was to develop the elixir of youth for the monarch who was aging, despite his blue blood. He was aging so quickly that at night, "they" were clearly hearing how "their" arteries are hardening with calcium and other waste products (arteriosclerosis).

Days ago, the research project funded by Rudolph II was finally completed. Well, maybe, if we believe the optimistic reports.

Anti-ageing compound set for human trials after turning clock back for mice (The Guardian)

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (technical article)
The article by Ana Gomes and sixteen co-authors from Harvard and New South Wales just appeared in Cell, an expert journal.

The short story says that aging "is" nothing else than the loss of the communication between the cells' nuclei and the mitochondria, the cellular power plants. And the main reason behind this loss of communication is the decrease of the concentration of NAD+, the nicotinamide adenine dinucleotide.

The recipe to get younger is therefore simple: you just inject nicotinamide adenine dinucleotide, or the elixir of youth for short, into your body and you will become young again.

So far, the researchers have demonstrated the elixir of youth using mice. In 2014, they will start the experiments with the people. Sounds great and straightforward. But I smell a rat or at least a mouse.

Could some biologists offer their informed opinions? Are similar stories in disciplines in which I am not trained as misleading as stories about the debunking of the uncertainty principle and tons of other "cool things" we routinely read in the media? And if they are, are there at least some folks who can see through it?

If thousands of most celebrated philosophers were thinking for thousands of years, they would probably not propose that a crazy molecule like that is the elixir of youth.

I am not saying that the claims are impossible. In fact, I do believe that they may be possible and I hope that they are. But if aging could be reversed in this simple way, why wouldn't Nature do such things naturally? It seems that organisms can synthesize the molecule rather easily – so why aren't they doing it? Maybe the change of the DNA from the parents to the offspring is so beneficial for the survival of a species that longevity is discouraged in the process of natural selection?

#### snail feedback (46) :

We're great at treating mice.

I suggest that in biology, it's healthy that mere radical hypotheses are both readily accepted for serious consideration but also personally discounted as indeed being mere new ideas. Experiments are easily enough over time to hash it all out and there isn't a lot of political corruption, so seemingly revolutionary claims only turn a few health nuts into small time quacks, far outside of mainstream science or mainstream culture. Yet both climatology and physics create spiritual and exinstential outlets for popular religious inclinations mostly in the subconscious, creating fanaticism.

Here subsidies do not reach with the fluency that they should (actually doesn't come with any fluency). So with the idea of ​​switch sides, I did the course on "Global Warming: The Science of Climate Change" at the University of Chicago / Coursera. I am ashamed to admit that I have finished the course with a "statement of accomplishment with distinction", however, I do not have enough stomach to abandon skepticism, and this Catechesis has strengthened me in my positions: scenarios of climate alarmism are pure pseudoscientific garbage, entire dogma of faith rests on ad hoc numerical models, and that they based much of their evangelical activities on skipping the scientific method, and in a repertoire of logical fallacies that would lead Aristotle to commit an instant suicide. Absolutely insane. And the question is, who subsidizes this academic crap? The big Green? (Do not answer me, it's a rhetorical question).

The paper discussed does not claim that NAD is the elixir of youth; merely that it can reverse some of the effects of aging.
Of course, their paper - while withstanding peer-review - was not independently confirmed; nor is it known whether the life span of mice was prolonged, whether it will have any effect with humans, etc.

I can answer 'why Nature didn't do such things naturally': there was no evolutionary pressure to do so. Until very recently, the life expectancy of humans was around 30 years due to predation, hunger, etc; as such, genes that confer longevity beyond this age were not selected for.

There is no grand theory at stake in such intensely empirical sciences, where not even the antioxidant hypothesis about aging could catch on in mainstream medicine. By now the falsified single bullet theory of dietary fat/cholesterol control over heart disease has already made medicine weary of big theories, whereas physics is dominated by very big theories indeed.

"You are counter-culture, counter-industry, counter-science, and counter-climate-change, comrades." ---> to summarize it: "You are enemies of civilization and mankind."

Yes... too mice to be true ;-)

This is hardly new, and IMO is being really hyped--wait and see. Calorie restriction, sirtuins like reservatrol, and NAD are all metabolically linked.
e.g. here is a paper from 2007:
http://www.ncbi.nlm.nih.gov/pubmed/18419308

Aging is multifactorial. The mitochondrial link is interesting. So is the whole apoptosis process, as are telomeres. For awhile the progressively shortening of telomeres (end repeats on chromosomes) were seen as the biological clock for organisms...didn't completely pan out. Also, what works for mice is not dual for humans---calorie restriction works in mice--only to a limited degree in humans.
Billions of dollars have been spent on looking into sirtuins by biotech firms of all sizes.
This NAD study is interesting and should be replicated and expanded, but so far, I am skeptical that there is a single magic bullet.
Mitochondria are interesting organisms that are symbionts which invaded cells early in evolution (Lynn Margulis---one of Carl Sagan's wives) which facilitate the ATP cycle (source of cellular energy).
In plants, their analogue is chloroplasts, which also are symbionts which use photosynthesis to generate energy. Interestingly, chlorophyll in the chloroplasts strongly resembles the hemoglobin in our red blood cells, with copper substituted for iron in the hemoglobin core---hence the green/blue hue of chlorophyll. (end of likely redundant mini-lecture.)

see http://hitchhikers.wikia.com/wiki/Mice

"Mice are merely the protrusion into our dimension of hyper-intelligent
pan-dimensional beings who, unbeknownst to the human race, are the most
intelligent species on the planet Earth. They spent a lot of their time in laboratories running complex experiments on humans."

Thanks, Gordon. I expected you to offer insight i to this issue and you did!

Sert sikişmek çok hoşma gidiyor sizinde hoşunuza giderse Sert sikiş izleyin derim.

--> Lubos:
"Are similar stories in disciplines in which I am not trained as
and tons of other "cool things" we routinely read in the media? "

In short, yes they are. A problem is that experiments involving organisms have so many complicating factors and variables that isolating what you are trying to quantify from sources of interference and error is like keeping a qubit in a superposition state.

Marcia Angell, first woman editor of the New England Journal of Medicine (and critic of both big pharma and "alternative" medicine) wrote:
"It is simply no longer possible to
believe much of the clinical research that is published, or to rely on
the judgment of trusted physicians or authoritative medical guidelines.
I take no pleasure in this conclusion, which I reached slowly and
reluctantly over my two decades as an editor of The New England Journal
of Medicine ."

(I am not a biologist, just a frustrated physicist, mathematician polymath whose thesis supervisor called him a biological obsessionist. I spend a ludicrous amount of time dealing with humans (http://hitchhikers.wikia.com/wiki/Human_beings), and an equal amount of time avoiding them.)

"It seems that organisms can synthesize the molecule rather easily – so why aren't they doing it?" Not quite true. To synthesize it, you need to start form nicotinamide or niacin (nicotinic acid; or go one step back to tryptophan, but that is really it) which is usually around in sufficient quantities (thus no need for efficient own synthesis), but if you do nto get enough of it, you are in trouble (pellagra is the niacin deficiency).

Well it does look interesting, Gene---
here is another paper---
http://www.ncbi.nlm.nih.gov/pubmed/18020963
You can buy NADH at health food stores. I am not sure if the reduced form is what they used and would have to look at the metabolic pathway.

My simplistic thoughts on this:

The differences in life expectancy between different species of mammals did always seem very strange to me. Why should ageing affect species that are very similar biologically so differently?

The answer is most likely that there are benefits to an "artificially" regulated life expectancy when it comes to the survival of a species or rather its genes. There could be something like local optima for the longevity of an individual that are found by the genetic algorithm, and these can differ from species to species, depending on the interaction with the environment.

We should still keep in mind that ageing is most likely multifactorial and that there are probably way more fundamental problems than an "off-switch" built in by the evolutionary process.

When the proper history of the " journalism" associated with "climate change" is finally written....Ms Goldenberg will be remembered with particular opprobrium.

I really should ask my most favorite medical bloggers, the Skeptical Scalpel, about this, but I'm sure he would agree that reversing the aging process can't be done any more than unscrambling an egg can be done. Perhaps this can be done in a parallel universe somewhere beyond the event horizon, but it most certainly can't be done in our universe, where we are hopelessly imprisoned by the Second Law. The most we can hope for is to slow the aging process. Here are some simple ways to do this: 1) eat right, 2) don't smoke or sunbath, 3) exercise regularly, 4) limit alcohol intake to no more than a couple of drinks per week, and 5) avoid stressful situations and substances that are likely to cause cancer.

Actually, it's a common misconception that the Second Law of Thermodynamics is responsible for ageing. It would be so if ageing was mainly "wear and tear" but it is not: it is mainly genetic. The evidence for this is the phenomenon known as "
negligible senescence": http://en.wikipedia.org/wiki/Negligible_senescence

Nice, 31072 people that should be immediately fired for having low iq's. Also the institutions that trained them should be reviewed for handing out degrees to idiots.

Completely OT but I remember you running a story on Neanderthal inter-breeding. New (improved) DNA evidence supports the physical anthropology and archaeology (e.g., your Generalka site in the Sarecky potok valley NW Prague). http://www.haaretz.com/archaeology/.premium-1.564781

What remains frightening is the 400+ posters who reflect these mind boggling stupidities in their apparently adiabatic echo chamber . I'm amazed they can retain the ability to read and write with such holes in their ability to reason .

I assume this : https://www.coursera.org/course/globalwarming is the course you took .
I see the "Recommended Background" is "assumes no scientific knowledge" .

This for a phenomenon which , if it is measurable , is on the order of the third decimal place .

I've seen too many such claim to believe it ...
There seems to be some fundamental law behind the scenes when it comes to aging. It says that by the age of 120 you will be dead (if you are a man).
I wished more physicists would think about that and try to understand it. The biologists tend to think that it is a matter of the genes, but I don't think so. Actually
But is biological aging mereley the manifestation of the second law ?

Clear, evolution does not always select for maximum longevity. So there may exist fairly simple hacks to extend lifespan.

But I doubt it will make a huge impact on our lifespan though. We are already at the limit of what has been observed naturally in animals as a whole. At some point you run into some fundamental issues, like cancers for instance. Also, we as a species are blazing new trail with this whole overt reliance on our central neural system, which has all kinds of entropic processes going on, and it isn't exactly known for its ability to regenerate.

And yes, if you think physics reporting is bad; welcome to the world of biology ;).

Hmmm, my friend in New York just sent a set of interesting abstracts regarding SIRT 1 in the brain ...

Horm Metab Res. 2013 Dec;45(13):960-6. doi: 10.1055/s-0033-1351322. Epub 2013 Aug 15.

The Brain: A New Organ for the Metabolic Actions of SIRT1.Al Massadi O, Quiñones M, Lear P, Dieguez C, Nogueiras R.

Author information: Department of Physiology, School of Medicine-CIMUS, Instituto de Investigacion Sanitaria (IDIS), CIBER Fisiopatologia de la Obesidad y Nutricion (CIBERobn), San Francisco s/n, Santiago de Compostela (A Coruña), Spain.

Abstract

The sirtuins are a family of highly conserved nicotine adenine dinucleotide (NAD+)-dependent deacetylases that act as cellular sensors to detect energy availability and regulate metabolic processes. Sirtuin 1 (SIRT1) is one of the family members that is activated in response to caloric restriction, acting on multiple targets in a wide range of tissues. Recent studies have shown that SIRT1 controls glucose and lipid metabolism in both liver and muscle, promotes fat mobilization, stimulates remodeling of white to brown fat, controls insulin secretion in the pancreas, and senses nutrient availability in the hypothalamus. SIRT1 is located in several areas of the brain and its central metabolic actions have attracted much attention in the last decade. In this short review, we summarize the main actions and molecular pathways triggered by SIRT1 that control feeding behavior, energy expenditure, glucose metabolism, and insulin sensitivity, with an emphasis on the emerging role of SIRT1 in the brain.

© Georg Thieme Verlag KG Stuttgart · New York.PMID: 23950036 [PubMed - in process]

When I pushed myself (really hard) to think about it, what came to mind was only the following not completely hopeful [but, to save my skin, hopefully more science-aligned than purely philosophical ;-)] outlook or overview:

We have many different ways undergo genetically determined endogenous biochemical dying.

We do - or do alt least according to evolutionary psycho[physio]logy type reasoning - because, as a matter of principle, whenever a family group or food-resource/habitat-restricted population of organisms start, basically by Quantum Mutational chance, to consistently produce offspring that lived 'too long' the result will be a more likely discontinuation of the lengthening of the group's or population's lineage.

In other words and more precisely: This lowering of the odds for a "too long"-living population to be able to avoid impending oblivion happens because of the negatively naturally selective (or naturally pruning) pressure [represented by the 'absolutely hidden variable value' of the complex-numbered 4-D coefficient to the 'semantic spinor' "too long" ;-)] would rise 'exponentially' in approximate proportion to a consequently increasingly overly stressful environment - i.e. an environment that has become overly stressful through overcrowding and a locally overheated intraspecies competition for procreation promoting environmental opportunities of all relevant kinds.
%-}

Note the pyridinium moiety on the acetal. it is incredibly ripe for Sn1 reaction via oxygen lone pair displacement and Sn2 reaction via external nucleophilic attack. It is also hot for reduction to an N-alkyl dihydropyridine reminiscent of the toxic mechanisms of MTPT and very human-nasty herbicides paraquat, diquat, and 1-methyl-4-phenylpyridinium chloride

http://en.wikipedia.org/wiki/MPTP
http://dmd.aspetjournals.org/content/28/5/538/F6.medium.gif
http://www.guidechem.com/reference/dic-819913.html
http://en.wikipedia.org/wiki/Paraquat

NAD+ must be immediately banned. All NAD+ must be confiscated by Homeland Severity to Save Our Children!

Ms. who?
If skeptics are getting a billion a year, where's mine?

I've read this paper. It extends work that suggest that dysregulation of NAD+/NADH. However, as you guessed this work is severely hyped.

First, this only worked in mouse skeletal muscle (not in neurons, liver etc) Second, although the molecular markers in the mouse muscle returned to a youthful state, muscle strength was not restored by treatment with the chemical (NMN) that increased NAD+ (they only treated for a week). Third, these results obviously need to be checked in people.

Btw, Vitamin B3/nicotinamide are precursors to NAD+ so they might be expected to raise NAD+ levels to some extent. People do take these, and yet appear to still grow old, which already should cast some cold water. To be fair, the authors of the paper would argue that the key enzyme (nicotinamide phosphoribosyltransferase) that converts nicotinamide into NAD+ is reduced with age and that is why Vitamin B3 isn't a miracle substance.

Overall, this particular aging phenotype is an example of aging-associated biochemical dysregulation. Humans, as well as other mammals (and most animals) for that matter, are unable to completely regenerate/rejuvenate their cells (and other biostructures) as part of homeostasis. Eventually, that leads to aging and death. This lack of "rejuvenation" eventually leads to biochemical changes such as the reduced NAD+ levels. Some of these dysregulated biochemical pathways may be corrected with possible benefit, which flies in the face of overly simplistic damage accumulation models of aging. But with time increased biochemical dysregulation requires repair/correction of an ever increasing number of problems.

A recent book that reviews these kind of results from the point of view of human aging is "Medical Implications of Basic Research On Aging."

Goldenberg got the figure all wrong.
It should be a few tens of trillions, not a billion, anti AGW money a year.

Much more than half the world population doesn't believe in AGW (counting in India and China)

So in the spirit of the article, their income should all be counted as anti-AGW money.

I have experienced health benefits from alternate day calorie restriction; my chronic allergies to mold and pollen have been greatly relieved and someone I know with mild arthritis has seen their finger joints return to normal size after adhering to same diet. The explanation is that a sirtuin is reducing the inflammation.Not sure this counts as anti-aging elixir, but the benefits actually have surprised me. It is not easy to adhere to this diet, however, the restricted days are 500-800 calories and one can feel deprived at times. I have been doing this diet for about 2 years, and my sinuses are clear most of the time, e.g., I use a box of Kleenex in about 2 months now, instead of a box a week. I use no sinus or allergy medications. It took about three weeks of the diet before I realized there was a noticeable difference.

You can live longer if you don't mind being miserable. Like in the old ditty:

With black-strap molasses
You'll live so long

Lucretius - I was just about to write the same thing. Great minds think alike. :-)

I don't think we'd have to be more careful about marriage vows. I think marriages that end in divorce would end about as soon as they do now, while marriages that don't would be even more stable.

An objective outside observer would look at the body of work we have conducted in biology and conclude that our only goal is to create a master race of genetically enhanced, immortal mice to rule over us.

BTW, all of this uncertainty is yet another reason to be leery of the claims of the CAGW people. That too is a field where we study very complex systems. But we have studied biology much, much more deeply, and can actually create experiments to test our theories... yet we seem to still know more or less bugger all about many key components of the subject, and can't even go a decade or so without reversing recommendations on everything from salt to cholesterol intake.

I recommend having a look at the work of the SENS Foundation. Briefly, the premise of SENS is that the best approach to anti-aging is to repair damage rather than prevent it, since damage is an unavoidable consequence of metabolism. http://www.sens.org/research/introduction-to-sens-research

Metabolic rate and body mass obey a strict inverse scaling law. Mice only live 2 years because they 'burn up' faster. What is 'burned up' is probably telomeres at the end of each chromatid, which are consumed during cell division and protect the genome. Eventually we are overwhelmed by cell death and non-replacement - a 'feature' of our programming.

That's very interesting. And with your model of aging, is it reversible or irreversible? Can we revert aging by forcing our organs to shrink, so to say?

Telomere destruction is the commonly accepted theory of aging. However some cancers cells become immortal by thwarting telomere destruction. Evolution may have therefore found an optimal balance between lifespan and cancer, so reverting aging may be quite a trick.

As I mentioned in other post, the basal metabolic rate of animals follows a strict power law (Kleiber's Law) with respect to body mass. The relevance of metabolic rate to lifespan, etc. is conjectural:

http://en.wikipedia.org/wiki/Metabolic_theory_of_ecology

but undoubtedly metabolic rate influences the rate of cell division and ultimately the time at which an organism 'burns up' its capacity for further cell replacement.

You are counter-culture, counter-industry, counter-science, and counter-climate-change, comrades.

And you sheeple are counter-common sense, counter critical thinking, and also counter-progressive thought (as well as being counter-humanity.) But what else is new form the likes of you?

Aside from supporting nuclear power as a green option, I think that most of you are full of shit.
AndAnd you are counter-sense, counterYou are counter-culture, counter-industry, counter-science, and counter-climate-change, comrades.ou are counter-culture, counter-industry, counter-science, and counter-climate-change, comrades.

It sometimes seems that nearly anything that is done to mice, fruit flys, or yeast cells rather dramatically increases their average lifespan, while appearing to have nearly no effect on humans. Does this have meaning beyond the notion that we are all just screwed?

Explanation is very easy. Either mice or flies used for experiments are highly inbred (= genetically almost identical) and are kept all in the same conditions. Thus, it is easy to see the effect of the experiment. You can never do with anything like this with people. Thus your starting point it too fuzzy and you will not see the small effects.