Reason for a New Age

Archive for July, 2016

Gettin’ Old – Part 2

Posted by publius2point0 on 2016/07/03


The basic idea that I introduced in the previous article is the Cellular Theory of Aging. In that theory, we age because our cells age. If we can keep our cells healthy, then we can extend our lives.

That theory is clearly insufficient. It may be true – and the evidence on smaller, similar species would seem to back the idea that gains can be made to lifespan by taking better care of our cells – but not complete.

In all of the cases that I gave, in the previous article, the question was “How to keep things going longer, when everything is shutting down?” And that leads naturally to the question of, “Why is everything shutting down?”

So, counter to the Cellular Theory of Aging, there’s also the Programmed Theory of Aging. In this theory, it’s part of our basic design, to age and die.

This theory isn’t as well-supported as the Cellular, and there are some arguments against it. Specifically, the theory seems to give the idea that death is hard coded. That would mean that there should be a gene that we could turn on or off to cause death, or a set of genes that we could find that would indicate a specific age at which we will, by programming, die.

That idea, I think, is overstating the programming case. The critics are right that there isn’t a “die” button built into our DNA. But that doesn’t mean that there isn’t a button which puts us into a “stop maintenance and let the body slowly decay and break down” mode. That, I believe, does exist. And I think we can prove it fairly easily.

Simply put, the body has growth phases. We have growth spurts, we have puberty, some of us have menopause, and we have old age. As we transition from and to these different stages, our bodies develop in different ways, based on differing levels of hormones and genetic instructions. Levers are pulled and pushed, and they do so in a fairly consistent, timed manner. The Cellular Theory of Aging does not explain this sort of progression. The Cellular theory, as the name indicates, is concerned solely with our cells. The human body is bigger than that and, even if you think that the individuals cells could be supported indefinitely, they still are at the mercy of the whole system and the changes being made to it.

The Biologic Clock

There is, somewhere in the body, a clock. It dictates when the body transitions from one stage of life to the next, and when the clock rings, the body changes to match the next set of instructions. If you can stop the clock from progressing…maybe you could live forever?

Well, maybe. Maybe not. There might be more than one clock. And there may be no set of instructions which supports “stasis”.

Let me go into that in a bit more depth.

For the first one, how many clocks there are, let’s consider telomeres. The telomeres are a bit of extra data at the end of our DNA. When a cell splits, the DNA is cut lengthwise and each half receives a copy of the part that was lost, to create two new DNA strands that are copies of the original. The exact mechanics of this process involve some loss at the ends, so the telomeres provide some material that is safe to lose. Every time the DNA is copied, the length of the telomeres shortens with it, and eventually the cell could no longer be safely copied without loss. There is a cap on how many times we can create new cells. This is a hard limit on how long we can live – since eventually we will need to replace all of our cells. But it’s also a good clock, to tell how old we are. The shorter your telomeres, the older you are.

This feature could be a very clear-cut timer on which the body could make its decisions on when it is time to change gears. But, the evidence is mixed. Growing the length of telomeres (via the activation of telomerase) has both been shown to extend life and to do diddly-squat for extending life:

http://www.ncbi.nlm.nih.gov/pubmed/19145831

http://owndoc.com/anti-aging/ta65-revgenetics-cancer-fda-complaint/

And, from everything that I have read, I have not really found anything which seems to show a mechanism by which telomere length would actually affect the body. I haven’t seen any chemical reactions that seem to vary by length. (Though, obviously, I have not read everything that is out there and, even if I had, that doesn’t mean that we know everything there is to know about the human body.)

Within the body there are several things that change naturally over time, like this. It’s possible that it is the interaction of these different “clocks” that causes the body to change, rather than there being a single source that governs everything. The human body, after all, was not engineered to be simple and straight forward – it just evolved to be as it is through billions of years of trial and error.

And, to go a little bit off topic, if there is one thing that I have learned from all of this research it’s how complex the human body is. Generally we learn about our major organs. And yeah, we might have a few dozen of those. But within each cell, there’s hundreds of proteins, interacting with each other, DNA, and other cellular structures in thousands of processes. And these interactions are generally just small steps towards the eventual product. The human body is less like “a car” or some other simple machine, and more like the whole process of mining raw minerals to selling thousands of different products in hundreds of industries, in the global economy. At the cellular/protein/hormone level, the scope of things to track and follow is genuinely huge and it’s impressive that we have as much information as we do.

That aside done with, let’s get back to my other statement that there might not be such a thing as “stasis” in the human body. From everything we know of the human body, after all, we are either growing or we are declining. If we could stop “the clock” when we were 18, well we might end up growing and growing and growing, until we are 10 feet tall and our brains are causing our skulls to swell. At 18 we’re not growing very much. You’re basically the height that you always will be. But you are still growing just a little bit and, given eternity, that will eventually start to add up and cause problems. Halting the clock even earlier would be even worse – like if you’re in a growth spurt.

Our bodies cap out at around 25. After that, are our bodies maintaining themselves in a stable manner for a few years? I don’t know. Maybe and maybe not. Possibly, at 25, the off switch has been pushed and everything is in free fall after that point. Maybe there’s a transition sometime between 30 and 40 where we go from maintenance to free fall. I couldn’t say. But it’s likely that we’re basically in “off mode” after 25. Stopping the clock anywhere after that won’t do much, because there is nothing to be stopped. The levers have been pulled to their final position.

Menopause could be evidence against that view. Or it could be that menopause is just a side effect of the downwards spiral, and was triggered decades earlier. Again, there just isn’t enough information at the moment.

Overall, we don’t know what the biologic clock or clocks are, we don’t know how to stop them, and we don’t know that “stopping” them would actually produce a good result.

On the other hand, as I said earlier, the indication would be that once we go into decline it doesn’t mean that we are programmed to die. The evidence goes against that. It just means that the body isn’t going to naturally produce what it needs to maintain itself. That doesn’t mean that we can’t try to maintain it, despite our body’s wishes.

Some Possible Clocks

Besides the telomeres, I have identified three other “clocks”. Actually, only one is a clock and the other two would be better called “feedback mechanisms”. Together, these are telomeres, chromatin, inflammation/hypothalamus, and cortisol/adrenal gland.

Telomeres

I have already discussed this to some extent. As said before, it is a part of the body which the body could use as an internal clock. When cancer cells want to become immortal, they do almost always mutate so that they keep their telomeres growing. (Testing for heightened telomerase – the protein that reconstructs telomers – is one of the ways that doctors can test for cancer, and it is also one of the ways they target medications at cancerous cells.)

I have found two telomerase activators. One is TA-65, a purified extract (cycloastragenol) from the herb Astragalus. Based on the research that the company has published, it seems to be able to grow back telomeres at a faster rate than they shrink. On the other hand, based on their research, this does nothing to extend the lives of rats.

The man who discovered cycloastragenol recommends against trying the product unless you are pretty near the end of your life as there is a cancer risk, both in it possibly spurring on cancerous cells. Or, simply, by getting in the way of anti-cancer medications and tests. Of course, there’s some reason to believe that cells with short telomeres are more likely to become cancerous, so lengthening short telomeres (which telomerase does – it targets the shorter ones first) may help to protect against cancer…. It’s a big question mark.

If you do want to try it, it is quite expensive. The off-label brands that are supposedly 98% pure should be about half as effective (this page says that you need 50X the off-label stuff to match the effectiveness of TA-65, but whatever math they used is wrong. The area under the lines in the graphs shown indicate half-potency.)

Of course, you could just take regular astragalus supplements. These will not be anywhere near as potent, but it seems to be fairly good for the body and it lets you dabble in telomerase activation without the same fear of cancer. Plain astragalus is also quite cheap to supplement.

The other telomerase activator are tocotrienols, featured in the last article as a good anti-oxidant. Tocotrienols would seem to be a two-fer.

Chromatin

If there is a single, core biologic clock, my bet would be on chromatin.

DNA is a long string of data. Very long. A single strand, stretched out, would be taller than your average person. And yet, we have a copy in every cell in our body.

It’s thin and, more importantly, it’s in curlers. Chromatin is a structure of macromolecules that DNA winds itself around so that it can compact down in an ordered fashion, and also to help “armor” the DNA from damage.

But, importantly, it would seem that DNA is still used to produce new proteins and who knows what else on a constant basis. It’s used as instructions and as a building platform for some of the many chemicals floating around in our cells. And that can only be done if the chromatin unwinds to provide access to the correct locations.

As we age, though, we lose our chromatin. More locations for synthesis become open on the DNA, but the DNA is also more exposed to potentially harmful reactive oxygen species or other sources of damage.

But it seems like a rather simple way to set up an aging clock. If the body would build stuff, if it had access to the DNA, and the DNA slowly exposes itself, then the body will undergo changes through the simple process of DNA becoming disorganized and damaged. It would simply be a matter of making sure that the DNA becomes exposed in the right order at the right times, but that could come down entirely on evolution. Based on how the chromatin folds the DNA, certain spots will be more likely to decay first. DNA which has building points useful for growing properly in those places or useful for exposing the next correct places in the DNA, will produce creatures that are more likely to breed and propagate that set of DNA.

That may or may not be correct, but it does seem to be that it is through helping to protect our chromatin structure that the first and most studied form of life extension seems to function, that is to say, caloric restriction.

The evolution behind caloric restriction and life extension – a question I had pondered in the last article – would seem to be that the body is smart enough to understand that the natural life cycle of growth and death needs to take a break during times of food shortage. It seems to do exactly what we are suggesting here and puts a halt on the biologic clock, so that we maintain our health through the time of hunger, and then resumes once we are through it. We begin aging again.

When resources are plentiful, we want to make babies and die off, to give them room. If times are hard, we need to stay alive until things are good enough to make babies again. Our bodies help us do this.

And the way the body does this is by releasing sirtuins, which fall into the category of HDAC inhibitors. These modulate the histones (helper buddies) who move things in and out of the DNA for construction and hence which bits of DNA are exposed and for how long. Some of this may be helpful, and some harmful. There are different types of inhibitors and we are still trying to figure out how they affect things. Valproic acid, for example, is known to cause autism in the children of mothers who were taking it. They are not interchangeable, and they are not all necessarily good. In the case of sirtuins, they seem to do something that allows the chromatin to stay as it is longer.

The ones which may be good are the class III inhibitors. Amongst these, the ones which seem to be the most well-supported by science are resveratol, curcumin, and sulforaphane. Both curcumin and sulforaphane seem to have more evidence behind them, for effectiveness, than resveratol. Unfortunately, I have lost the cite which allowed me to make that determination, but you are encouraged to do further research. There are a number of potential/known inhibitors, and many of them have barely been studied:

https://clinicalepigeneticsjournal.biomedcentral.com/articles/10.1186/1868-7083-3-4

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4210916/

Inflammation, NF-κB, and the Hypothalamus

NF-κB (nuclear factor kappa B) is a protein that cells use to inform the rest of the body of damage – e.g., from ROS’s or from other forms of damage. This signals to the body that it should send things in to help fix the problem.

Theoretically, this should be a good thing.

But, as we age, the amount of NF-κB is constantly raised, and the hypothalamus seems to use the level of inflammation in the body as a clock to module GnRH, a hormone that tells the body how much of other hormones to make. As time goes on, the balance of our hormones gets thrown off, causing the body to perform worse, raising the level of damage to our cells, raising the level of NF-κB. It is a positive feedback loop that seems to shorten our lives, compared to if we inhibit NF-κB as we start to age.

(Technically, NF-κB causes IKKβ production, which causes GnRH production, which causes the hormone modulation, and all of the inhibitors are for IKKβ. But NF-κB is the start of the chain.)

There are a number of known IKKβ inhibitors, but the best source that I found of inhibitors used a programmatic model to identify possible inhibitors for future study. But the top rated ones by the progam model do seem to be positively correlated to life extension. And, I would note, they also all seem to be linked to cancer prevention.

I discovered this while researching ways to protect against cancer, due to the concerns with telomerase activators. It seemed like one might safely try astragalus, so long as he was also taking something which helped to protect against cancer.

The best protection against cancer is p53, a protein that is able to find and repair mutated DNA. Besides the worry with telomerase, anti-oxidants also tend to lower p53 activation, as they prevent DNA damage from occurring. But, it seems like it is better to have p53 around checking our DNA at a higher rate than is spurred by ROS hits, as p53 activators do seem to reduce cancer rates. Genistein – a known p53 activator – is a soy product. The Japanese, who eat a lot of soy, have 2/3rds the rate of cancer as Western societies (like the USA), despite probably having a higher rate of smoking. Not necessarily great evidence, as Argentina also has lower cancer rates. But in my research, I noticed that there was a significant overlap between IKKβ inhibitors and p53 activators. The top rated IKKβ inhibitor that the the program identified, boswellic acid, seems to do amazingly well to fight cancer. Others that I have found and checked are hesperidin and ursolic acid. They all score well against cancer, for inhibiting (or believed to inhibit) IKKβ, and are positively correlated with increased lifespan.

How much the lifespan change is due to a reduction to cancer versus achieving stasis in hormones, I couldn’t say. But the indication seems positive in either case.

Cortisol, Stress, and the Adrenal Gland

This one, I have not researched greatly. But it seems to form a similar feedback loop as NF-κB and the hypothalamus.

When we are stressed, the adrenal gland produces cortisol. Cortisol is the “stress” hormone and it puts our bodies into a fight-or-flight mode, which readies the body for physical action, turning everything up to 11, even though the system is only rated to run in the 5-6 range. Being outside of the right range adds wear and tear on the body (yes, that’s a bit vague, but that seems to be the high level description), and you live for less long.

Theoretically, stress should be a short, situation specific state, like facing off against a lion. But it’s believed that in modern day, with tight deadlines and a busy schedule, we end up with a constantly raised level of cortisol in comparison with our human ancestors.

But even outside of that, it seems to be that our cortisol rate generally rises with age and that would, probably form a feedback loop. It causes our bodies to wear out faster, which will stress us out, which will raise our cortisol level even more.

Strangely, there doesn’t seem to be a large number of cortisol blockers. But the one which seems to work is rhodiola rosea. And yes, taking it regularly does seem to extend lifespan.

A Second Menu

In the previous article, I suggested resveratol. In light of new information, I would suggest swapping this with curcumin or sulforaphane.

Atragalus root extract, and tocotrienols can be used to grow your telomeres. Tocotrienols are good anti-oxidants. Be careful using TA-65 or cycloastragenol.

Boswellic acid seems to be the best IKKβ inhibitor / p53 promoter, but hesperidin and genistein are good alternatives.

Rhodiola rosea seems to be the only cortisol blocker.

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