TCA peels and the Hayflick limit

[vozarov]

Are TCA peels with the concentration of say 15% to 25% that considered to be mild are safe or are they pushing skin cells closer to the Hayflick limit? How do you really know?
Also, can you reverse such skin condition?

[Guest]

Infrequent peels are probably relatively safe. Exfoliating too much can, in theory, push you closer to the Hayflick limit. But nobody knows for sure how much closer since this phenomenon has been studied in the tissue culture, not in living humans. Once the Hayflick limit has been reaced, it cannot be fully reversed without genetic manipulations. However, some signs of senescent phenotype can be reduced (at least in tissue culture) by carnosine and possibly other chemicals.

[Guest]

After reading up on the dangers of hitting the hayflick limit, I did some seaching on the internet to see what I could come up with. I'm a big fan of AHA's and retin A and exfoliation products and I'm very concerned about this. I'm finding article after article on L-carnosine and how it can have enormous affects on skin aging and on the aging body in general. This one particular article http://www.jonbarron.org/documents/brcarnosine.htm
even says that it has the potential to prevent one from hitting the hayflick limit!

Upon further searching, I found a web site promoting a skincare cream containing L-carnosine claiming that carnosine can actually extend the hayflick limit by 10 times!!! http://www.biovita.fi/english/tuotteet/carnosine_cream.html

Could it be true that in order to prevent hitting the hayflick limit, simply taking L-carnosine supplements or applying it in a cream base to our skin will be effective?

[drtodorov]

Carnosine may mitigate senescent phenotype in a tissue culture, but it does not prevent telomere shortening and therefore does not help you escape the Hayfllick limit.

[cjdavis]

[cjdavis]

[drtodorov]

[cjdavis]

[johnny]

The so-called "Hayflick limit" is a finding by Dr. Hayflick, many years ago, that fibroblast cells, in culture, will only have a finite number of doublings, after which they stop dividing and become senescent. However, a fibroblast is a somatic terminally differentiated cell which produces collagen. In contrast, all tissues which make extensive use of fibroblasts, including skin, bone, etc., are also well well supplied with fibrocytes.

Fibrocytes are undifferentiated stem cell versions of fibroblasts. They are not yet functioning to produce anything. When you were young, they continually produced replacement skin cells for no other reason other than the fact that they could. But, with increasing age, fibrocytes, and other stem cells become more and more likely to just sit there, waiting, in your skin, and elsewhere. Sometimes they may wait for many years, until some kind of serious damage is perceived by the body. This might include peeling by acids, lasers or otherwise. In the face of massive injury, the fully differentiated fibroblasts generate large numbers of signalling molecules, chemicals such as cytokines, which tell the fibrocytes

"It is time to come out of slumber. You need to make new fibroblasts."

Generally, the fibrocyte will then divide, producing one fibroblast destined copy, and one fibrocyte to replace itself. Depending on how bad the damage is, and how persistently the existing fibroblasts call for help, this same process may repeat itself, over and over again, until many eventual fibroblasts may be produced by one fibrocyte. But, always, one replacement fibrocyte will remain.

Like all stem cells, fibrocytes produce a certain amount of telomerase, and we are able to measure this in skin, after injury. Telomerase is an enzyme that acts to elongate the chromosomal "caps" called telomeres/ In mitosis, other enzymes, which stimulate division and duplication of the chromosomes, bind to each chromosome by holding it at the telomere. As a result, the particular nucleotides are blocked, and they cannot be copied. This results in a progressive shortening of the telomere caps.

Thankfully, there is a lot of telomere, at least to begin with. And, furthermore, the telomeres don't code for any needed proteins. So, losing a bit of nucleotide sequence is not devastating to the cell. However, the telomeres are essential for chromosomal stability. A measurable length of telomeric nucleotides are sacrificed with each population doubling. The telomere eventually becomes so short there is barely anything left for the mitosis enzymes to latch onto, and the cell stops dividing. That is called senescence, and the maximum number of times that a fibroblast can divide is called the "Hayflick Limit.

Fibrocytes, however, unlike fibroblasts, produce a sub-optimal amount of telomerase. This enzyme functions to add back sections to the telomere after mitosis, restoring the chromosomes to the pristine state it once enjoyed, prior to the time that the cell divided itself. I say sub-optimal because adult stem cells do not produce enough telomerase to quite equal the rate of telomere shortening. Unlike embryonic stem cells, therefore, adult stem cells do, eventually, become senescent. The time it takes for that to happen, however, is so far beyond the so-called "Hayflick Limit", that an adult stem cell is essentially "immortal," when we are talking about people who currently live to a maximum life span of about 120 years. We have enough skin stem cells, producing enough telomerase, to last a lifetime of well over 1,000 years.

How can this be? Well, as stated, your existing stock of stem cell fibrocytes are sufficient to regenerate your skin for 1,000 years. Indeed, if you believe the quasi-historical accounts in the Bible, people, like Methuselah, once did live that long. We could, potentially, even lengthen stem cell productivity far beyond that. All you would need to do is, somehow, figure out how to upregulate the production of telomerase in adult stem cells. If you did that, successfully, you would have the potential of eternal life, and eternally renewing skin. You could do as much peeling as you wanted, and never ruin your skin.

We actually have some idea on how to upregulate the transcription of telomerase, in individual cells. It has been done in the laboratory, most recently by the Geron Corporation. The most important hurdle to achieving eternal life is not in upregulating telomerase. What we don't understand is how, why, and what signaling mechanisms are involved in causing the normally quesient stem cells to activate to the point where they replace worn out somatic cells, as they do when we are young.

It has been shown that blood, from a young animal, transfused into an older animal, stimulates stem cell activity, and replacement of somatic cells, especially in areas of the body that have been injured. Scientists have shown that the healing response, of old animals, can be restored to the level of youth, simply by transfusing young blood into them. Conversely, by transfusing old blood into younger animals, healing can be retarded.

All of this takes us back to the Bible, once again. In Genesis, God says that "the life is in the blood." Well, now, we know that this is true. The problem, as always, is that we don't know why or how.

It is abundantly obvious that there is an unknown substance, in the blood of younger animals which is in much shorter supply, in older blood. This unknown chemical(s) stimulates mobilization of stem cells. Mobilization of stem cells, in turn, acts to maintain the organism in a youthful state. Stem cells are stimulated, to regularly replace worn out somatic cells (such as fibroblasts, in the skin). Such microscopic activity can be seen, macroscopically, by the increased turnover of skin cells and healthier looking skin of the young, compared to the aged. In a very primitive way, by utilizing techniques that burn off the outer layer of skin with acid, lasers, etc., we are trying to stimulate some of the chemicals of youth.

Beyond all this, we just learned, about 2 years ago, in addition to normal stem cells, our skin, and that of all other animals, also has abundant reserves of an unusual type of stem cell, dubbed "spore-like" stem cells. We call them spore-like because, like the spores from fungus or bacteria, these mammalian spores are very basic packages of DNA, and lack most of the baggage of full developed stem cells and somatic cells.

From their structure, spore-like stem cells probably should function like a sort of emergency "backup" DVD. If the computer fails, you put this backup in, to restore the system. Similarly, if the stem cells fail, the spore like stem cells can take their place. These cells have all the same basic DNA codes of normal cells, but the DNA is tightly wound, the tiny amount of cytoplasm surrounding the DNA has a very limited number of mitochrondria, and they are coated with tough membranes, designed to withstand great stress. If called into action (and we don't know how to do that yet) spore-like stem cells can quickly absorb nutrients from the surrounding serum, multiply mitochondria to full numbers, activate their nuclei, and convert themselves from "compressed archives" into full fledged stem cells. These can then further differentiate, like any other stem cell, into terminal somatic cells, repairing damaged tissues.

Spore-like stem cells are highly resistent to heat. acids, radiation, etc. If we knew more about stimulating them, we could, potentially, use one single spore-like stem cell to reconstitute the entire organism.

For unknown reasons, at the present time, not only are spore-like stem cells "disabled", but normal stem cells stop replacing worn out parts, for unknown reasons, simply because we reach a certain age. And, humans are not the only animals that suffer from aging. All mammals, and almost all (but not quite all) other species, do, also.

Theoretically, aging is an aberration that the living organisms should not be subject to. We can see, in experiment after experiment, that the human body can and should be fully capable of maintaining itself for a 1,000 years, or more, even without direct genetic tampering. Yet, this does not happen. It seems as if some very knowlegeable person (God?) has deliberately turned off the backup systems, forcing aging and death.
All the talk about anti-oxidants only addresses the issue of prolonging the life of somatic cells. Stem cells, with limited exceptions, are not susceptible to being worn out by oxidation.

Perhaps, "God" has ceased to exist, or is preoccupied with other things. Or, maybe, a genetic error randomly occured billions of years ago, in an early organism, which, over time, transformed itself in most of the current forms of life we see on earth. Whatever the reason, our job, as scientists, is to learn how to switch these backup systems back "on" again. If and when we do, it will no longer be necessary to worry about anti-oxidants and similar treatments to keep worn-out somatic cells running as long as possible.

[drtodorov]

The problem with fibroblast senescence may be not that the skin runs out of stem cells and ability to produce new cells but that the percentage of senescent fibroblasts in the dermis goes up, and those senescent cells just sit there and disrupt normal skin functions, not letting enough new cells in to replace them. The approach to address that may be either to not let fibroblasts get senescent by [reversibly] inducing telomerase, or by inducing apoptosis [programmed cell death] of senescent cells. At this point, there is a long way to go before practical implementation of either.

[johnny]

Turning on telomerase in somatic cells would be problematic. The existing group of somatic fibroblasts have been subject to oxidative damage for many years. If we suddenly turned on telomerase production, we risk runaway cancerous growths, due to damaged mitochondrial and nuclear DNA. The key, I think, is mobilization of stem cells to react and regularly replace worn out somatic cells, as they once did, when we were young. Studies have shown that the fibrocytes of elderly persons, when appropriately stimulated, are just as capable of producing healthy fibroblasts which are, in turn, just as capable of producing healthy collagen and elastin, as those derived from much younger people. The key is getting them to do something more than simply sitting there, without having to indiscriminately destroy the outer surface of the skin, like in lasering, peeling, etc.

I suspect that inducing apoptosis, might work very well, if we knew how to do it in a controlled manner. In a sense, we induce apoptosis when we use lasers, glycolic peels, etc. Okay, it isn't apoptosis, but it is cell destruction. The problem is that these methods are crude, and destroy many healthy cells, both somatic and stem.

The biggest problem with selectively inducing apoptosis is 1) figuring out how to do it selectively, and 2) making sure that the "apopped" cells send out the appropriate cytokines, to mobilize the stem cells to replace them. In the absence of the massive tissue destruction that arises out of lasering or peeling, there is no indication that this occurs in aged skin. For example, much of the reason that elderly skin is so seemingly lax, and nonresilient, is that many of the somatic cells have, in fact, apopped. That is the basis for the business of companies, like Isolagen, who promise to reinject newly created cells, into the skin, to rejuvenate it, in the face of massive apoptosis of the worn out cells of middle aged and elderly adults.

If we don't learn how to stimulate stem cell utilization, first, we'd have a situation where the skin function might end up severely impaired, with large sections becoming semi-necrotic, as is the case with the very old.

We need to figure out what series of biochemicals, exists in young blood, that are deficient in old blood - and it isn't melatonin, DHEA or any other known substances. Once we figure that out, it should be possible not only to improve the skin, but to rejuvenate every part of the aging human body, generally.

Identifying the responsible proteins, lipids, lipoprotein, cytokines, etc., is a significant undertaking, and might take years of research, but it is not impossible. The way to do it is to fractionate a sample of young blood, down to a macro-molecular level, and try each component, one by one, and in combination, to see which stimulates mobilization of stem cells. This may have to be done many times before an answer is obtained.

If we figure out what biochemicals are stimulated by ingestion of large quantities of curcumin, we'll have a head start. There is experimental evidence that curcumin stimulates mobilization of muscle stem cells (satellite cells) in aging rats. Although there is no evidence that this substance lengthens lifespan in any significant way, curcumin treated old rats are able to repair injured muscles as if they were young rats. Unfortunately, curcumin has little known effect on mobilization of skin stem cells. That being said, assuming that slightly different biochemicals are required for different types of stem cells, if one of the mobilization signalling molecules is identified, it will be much easier to identify the rest.

[johnny]

Oh, and, also, since we already know that the biochemicals, at issue, reside in the sera, and not in the blood cells (acellular young plasma works very well to mobilize stem cells), we can concentrate our efforts on the chemical constituents of plasma and/or lymphatic sera, without worrying about the serious problem of how to fractionate red and white blood cells.

[drtodorov]

Thanks for a very good input. Sounds like you have some background in cell biology. I agree that the approach of stimulating dermal stem cells to divide may have potential (although even dermal stem cells may have accumulated significant oxidative damage, considering high level of LPO in the skin, and may not be that easy to stimulate in an orderly fashion). Even if that works, there is still an issue of accumulated senescent fibroblasts in the dermis. As opposed to keratinocytes, fibroblasts do not just migrate out of the dermis and slough off as they age. Still, there may be ways to deal with it, e.g. via controlled deep peels perhaps. Or somehow triggering apoptosis depending on a certain senescence marker (the latter would be cleaner, but may be very hard to do in practice.)

[neveragain]

what is the hayflick limit?

[drtodorov]

Search this forum for 'Hayflick limit", it has been discussed many times.

Also, see http://en.wikipedia.org/wiki/Hayflick_limit