speculations on keto diet and longevity

Discussion in 'Anything and Everything about dietary supplements' started by virtualcyber, Jun 14, 2002.

  1. rgallucci

    rgallucci New Member

    I think what you mean here is "glycosylation".  And yes, lots of things get glycosylated when there is a ton of glucose floating around unused in the body.  Actually, one of the worst effects of glycosylation is the thickening of basement membrane in the capillary beds of various organs such as the kidney.  This is one of the pathways by which diabetes causes kidney damage.  Many physicians have drawn the erroneous conclusion that ketones (which are high in diabetics) are the cause of kidney failure, when really its glucose.  I too have not seen any studies to indicate that a ketogenic diet has any deliterious effects on kidney function.  This doesn't mean that it doesn't have bad effects, but since this diet has been around since the 70's, you would have thought something would have shown up by now.  Right? And it's not like people haven't been trying to discredit Adkins. Heck, most dieticians would like his head on a platter. Thus, if there were any indication that this diet were at all a health risk, it would have been jumped on and researched to death years ago.

    Thus, I am not sure if Edziu's "cat" analogy is entirely correct.  Certainly they have to deal with lots of ketones, but you are literally comparing apples and celery.  One has to be very careful drawing correlations between animals and humans.  For instance, dogs are omnivores, yet have a very low tolerance for ibuprofen--far below that of humans.  So, can you say that ibuprofen is toxic to all omnivors? Certainly not.  Rats which are omnivorous, can also drink alcohol at 10-20% in their drinking water for 50% of their lifespan with no liver problems--whereas humans can't.  I have to admit, I am not a cat physiologist, but cats may have very large kidneys for many and quite different reasons than merely handling lots of ketones.

    Also, speaking of radicals, Edziu mentioned that most radicals are from lipid peroxidation.  This is not true.  Some sort of radical (oxygen, toxin, etc.) has to be formed first, which then abstracts a hydrogen from a polyunsaturated lipid molecule, resulting in lipid peroxidation.  If you believe Bruce Ames (a famous toxicologist) the ultimate source of >99.9% of the oxidative stress that our body is exposed to comes from the oxygen that we breathe.  His theories go that oxygen radicals are produced at enormous levels by mitochondria all the time, just merely as a consequence of producing energy.  As was stated before in this thread, we have antioxidant systems to take care of this, and it is only a problem when these radicals are produced in excess of what your system can handle.  Calorie restiction may, as stated earlier, reduce oxidative stress, but it has also been shown to increase the expression of antioxidant systems, and enzymes like manganese superoxide dismutase (MnSOD).

    What I find interesting about calorie restriction research, at least from Hansen et al's work, is that in non-human primates they find these longevity effects by maintaining bodyfat percentages (to between 10-20%) and not really by "classical" calorie restriction.  If this is true, then a BB lifestyle may very well increase lifespan.  But, then again these animals don't spend much time at a squat rack either.  Incidentally, these researchers also believe that most of the early deaths seen in the ad lib fed group in their primate studies are caused by type II diabetes, again pointing toward excess glucose as the culprit.
  2. virtualcyber

    virtualcyber New Member

    Hi, rgalucci

    I might be mistaken but I think glycation is the right term. Glycation = non-enzymatic glycosylation of proteins, nucleotides and lipids by saccharide.

    The following is one version of "aging" I heard -- perhaps it is totally wrong -- but let me present it here anyways. If I am mistaken, please correct me.

    We know that DNA strands are important in cell metabolism, during mitosis, cell-repair, etc. We also know that they determine what the cell is (its behavior). As long as its DNA structures are left intact, the cell can repair itself, go through mitosis (if conditions are right), etc. It is the control unit of the cell. It is worthwhile noting that if protein synthesis occurs, it is ultimately via cell DNA. Great damage to the cell itself can be repaired or properly taken care of, provided DNA's are functional. Of course, DNA damage is permanent.

    As we age, as it turns out, DNA strands become filled with non-usable molecules (glycation). Some have referred to them as "masks." The older an animal is, more its DNA strands are "covered" with non-usable molecules. In one sense, the DNA "covers" are like rings of trees; by looking at the amount of these non-usable molecules, one is supposed to be able to tell how old the cell host is.

    In other words, there is evidence that the "age" is not caused by random damage to the cell, but specifically related to how much of its DNA is "used up." You see, cell damages can be fixed; DNA damage cannot.

    As you might have guessed, the "rings" of these DNA is due to glycation. As long as we have glucose in our body (which is all the time), we will be covering our DNA with them (sooner or later).
  3. virtualcyber

    virtualcyber New Member

    Hi, rgallucci (sorry for misspelling your name in the previous post)/

    I forgot about telomere "problem". But I don't think that will be solved anytime soon.
  4. rgallucci

    rgallucci New Member

    I stand corrected.  Yes, glycation is non-enzymatic, glycosylation is.  I have been using the term glycosylation inappropriately all this time (I hate it when that happens).

    Anyway, about the DNA glycation theory.  I can't say that I have heard of that particular one, and a quick scan of Pubmed looking at "glycation" and "longevity" didn't turn up anything.  Mostly people seem to be concerned with advanced glycation endproducts (AGE's), which are glycated proteins, and not nucleic acids.  I can't say I have ever heard of glycated DNA.  If you could list a reference, I would be happy to peruse it.

    I am not sure if I buy the theory though, since (as you allude to) we have very good DNA excision/repair mechanisms to handle something like glycation, and as it turns out DNA repair mechanisms are also still quite active in old people (albeit it becomes a losing battle as you get older).  Certainly, DNA damage occurs in the form of nucleotide crosslinking (say from UV damage), or chemical adducts (from toxins like dioxins--or sugars perhaps) almost constantly.  Fortunately, we have these repair mechanisms or else we couldn't survive.  As it turns out, there are people who don't have completely functional DNA repair mechanisms, such as those with xeroderma pigmentosium.  You may have heard of these people as being "allergic to light".  This of course is not an immunological phenomena, but has to do with UV damage to skin cell DNA, and the lack of its repair. So you can see that damage to DNA leads almost immediately to a pathology.

    So, in a normal healthy person, DNA adducts are usually not a problem.  They are detected quickly and repaired.  Where you run into trouble though, is when you take into account the fidelity (accuracy) of these DNA repair enzymes.  The vast majority of the time, these enzymes make no mistakes--really they can't, the survival of the organism depends on them--but sometimes they do.  Fortunately, if a single base is inserted wrong and it doesn't pair correctly with the opposite base, it too will be replaced by the correct one, but if a wrong but stable base pair is put in, you then have a "fixed" (non-detectable) point mutation.  This mutation can now be passed to daughter cells when the cell divides.  Now, supposedly these point mutations can drive evolution, but most of the time they wind up changing the amino acid sequence of the protein that the DNA encodes.  This can have all kinds of bad effects, including loss of activity of the protein, or possibly even cancer.  You also have to keep in mind that these point mutations are ONLY a problem in dividing cells.  For instance, if the cell is not dividing, and its job is to be, lets say, be a muscle cell, a point mutation in its genome coding for an protein irrelevant for muscle function (like one for oh, say, spermatogenesis) and never expressed, is completely inconsequential.  That muscle cell can go on existing and doing its job perfectly well with that mutation.  

    I have heard it mentioned that the fidelity of DNA repair enzymes might decrease with age (possibly from mutations to the genes encoding the enzymes themselves), and this may indirectly fit with this "glycation" theory.  I think the hotter (those if interest most recently) theories of ageing concern telomere shortening, and immunological, and endocrine disregulation.  Certainly they are all just "theories", and no one really has any idea of what ageing really is.  I suspect it is a complex combination of things, and a magic bullet (a single treatment like inducing telomerase) may never be found.  That is just my opinion, and I have to admit I am an immunologist so ageing research is just a side interest of mine.
  5. virtualcyber

    virtualcyber New Member

    Hi, rgallucci

    Thank you for your posts -- they have been _really_ informative.

    You attributed aging to many factors -- you are probably right that there is no single magic bullet. In a way, it is a good reality check -- but depressing as hell at the same time.

    It is funny how I deal with my own morality as I age. :)


    BTW, there have been "successful experiments" for lengthening telomeres. Check out


    It seems that the author really believes we can live to 200.
  6. virtualcyber

    virtualcyber New Member

    On a final note here is an interesting blurb from

    </span><table border="0" align="center" width="95%" cellpadding="3" cellspacing="1"><tr><td>Quote </td></tr><tr><td id="QUOTE"> ... While studies have shown that glucose-rich diets decrease longevity in mice (19), no conclusive studies have documented the same thing in humans. ...
    [/QUOTE]<span id='postcolor'>
  7. virtualcyber

    virtualcyber New Member

    Hi, rgallucci

    Oh, ONE more thing (sorry about keep posting here)

    The DNA corrective mechanism you mentioned _doesn't_ work, because it cannot detect glucose molecules (that is what I heard). Also that is why the glycation is irreversible.
  8. rgallucci

    rgallucci New Member

    Hmm, it doesn't work for glycation? From what I understand about basic DNA repair, any adduct (foreign molecule) that can interrupt transcription (as a bulky sugar molecule would) would be detected, excisized and repaired. If it can't, the cell most likely would go through programmed cell death (apoptosis), since it is not functioning properly. Now, if a sugar was hooked onto a gene that is never transcribed, it might escape this mechanism, but then if it is never transcribed, of what consequence is the sugar adduct anyway?

    I will take a look at a few text books, and scan pubmed to check this out and get back to you though.
  9. rgallucci

    rgallucci New Member

    I did some digging and found a recent review article, which hypothesizes glycation may occur in DNA.  However, the author also acknowledges that there is no evidence that glycated DNA occurs in any animal, and that if it does, it is not cumulative and it is quickly repaired (i.e. &quot;silent&quot;).  He also goes on to say that it is not the glycation that is the problem, but the repair enzymes (fidelity) that determine any subsequent detrimental effects such as mutations (you'll note that this supports what I posted earlier).  

    I am not sure who has come up with the theory you are quoting, but perhaps this person has misinterpreted this author’s theory.

    Here is a link to the pubmed reference:

    Here is the citation:
    Baynes JW. The Maillard hypothesis on aging: time to focus on DNA.  Ann N Y Acad Sci. 2002 Apr;959:360-7. Review
  10. virtualcyber

    virtualcyber New Member

    &lt;scratching my head&gt; I was talking to my sister-in-law (she is in biochemistry) who said that the reason why glycation would not be fixable is because the correction mechanism does not &quot;see&quot; sugar molecules (???).


    From what I (mis-)understand, the abstract is neutral about what I have been saying (I maybe totally mistaken, so, please bear with me, and correct me!!&#33;).

    To quote one part of the abstract:

    </span><table border="0" align="center" width="95%" cellpadding="3" cellspacing="1"><tr><td>Quote </td></tr><tr><td id="QUOTE">
    Measurements of AGEs and ALEs in proteins are useful for assessing the rate and extent of Maillard reaction damage, but it is the damage to the genome that undoubtedly has the greatest effect on the viability of the organism.[/QUOTE]<span id='postcolor'>

    It seems to me that the author is saying that the oxidative damage and glycation occurs in protein molecules within cells, but the greatest damage occurs in the DNA strands. (see &quot;the damage to the _genome_ that undoubted has the greatest effect on the viability of the organism.&quot;)

    </span><table border="0" align="center" width="95%" cellpadding="3" cellspacing="1"><tr><td>Quote </td></tr><tr><td id="QUOTE">
    Damage to DNA accumulates not in the form of modified nucleic acids, but as chemically &quot;silent&quot; errors in repair-insertions, deletions, substitutions, transpositions, and inversions in DNA sequences-that affect the expression and structure of proteins. [/QUOTE]<span id='postcolor'>

    Here, the author seems to be saying that the errors do not arise in the form of modified nucleic acid (in other words, the damages do not happen on any of the four types of molecules that _comprise_ DNA strands), but are in their sequences in DNA. These are &quot;_silent_ errors in repair-insertion, deletions, substitutions ...&quot;; in other words, they are uncorrectable errors in the sequence.

    Consequently, since the errors are not correctable, they

    </span><table border="0" align="center" width="95%" cellpadding="3" cellspacing="1"><tr><td>Quote </td></tr><tr><td id="QUOTE">
    ... are passed forward from one cell generation to another.[/QUOTE]<span id='postcolor'>

    At least in the abstract, the author does not specifically address whether one of the error consists of glycation -- but just talks in general about &quot;silent&quot; (uncorrectable/ undetectable) errors.


    In any case, let me do more research, and try to dig up and present something that is accurate and reliable. I am embarassed to admit that my posts here have been largely anecdotal, and with lots of assumptions.
  11. rgallucci

    rgallucci New Member

    In the paper the author does directly address glycation of nucleic acid and merely says that the attachment of a sugar to a DNA strand has never been seen, and as I said before probably because the adducted nucleic acid is removed and replaced very quickly.

    It seems were are arguing the same point of view, really. You mention that the errors are silent, and so do I. As I stated before if the DNA repair enzyme (removing a nucleotide that is adducted to a sugar--lets say) makes a mistake (lack of &quot;fidelity&quot;), in both strands (ie. A-T) where there was a G-C before, that is a stable silent mutation. That, however, has nothing to do necessarily directly with glycation, but rather with the fact that there was damage to the DNA that wasn't repaired correctly. This could happen from UV damage, or from a toxin, or (possibly) glycation. The problem is, and it is a big problem with the theory, is that damage from UV and toxins has been shown, whereas glycation of DNA has not. The author just speculates that it happens. The author puts us in a UFO situation--you can't prove it does exist, but you can't prove it doesn't either.

    If you would like I can send the article to you. I have it in a .pdf file (the reason why I am not directly quoting it).
  12. virtualcyber

    virtualcyber New Member

    I have been looking at a number of papers, as you probably have, at PubMed. It seems that most papers on glycation does _NOT_ talk about glycation of DNA.

    I did find one paper (there is probably more) which seems (to me) to talk about it (does it really?): Specific non-enzymatic glycation of the rat histone H1 nucleotide binding site in vitro in the presence of AlF4-. A putative mechanism for impaired chromatin function.
    Tarkka T, Yli-Mayry N, Mannermaa RM, Majamaa K, Oikarinen J. Related Articles

    In general, if a paper talks about DNA damages, the damages seem to be introduced via glycation _products_.

    As for &quot;non-detectibility&quot; of DNA glycation, as I said earlier, I picked that up from my sister-in-law. I like to retract that statement :)

    So, I stand corrected on that issue.
  13. rgallucci

    rgallucci New Member

    Yes, there are a number of papers dealing with glycation of histones. Histones, as you probably know, are proteins with which chromosomal DNA associates that help pack the DNA into chromatin. I assume what this paper is saying is that glycation of histones can modulate how a histone associates with DNA. If it doesn't coil and pack properly, this could affect gene expression and/or DNA replication. Perhaps this is what the originator of this theory meant, since it would be along the same lines as telomere shortening (similar...but different).

    This paper does sound interesting, but I will have to get to it later. I have a grant to write, which sucks. The writing that is, hopefully not the grant. :)

Share This Page