cron-web.org

[A1CR]

[Posted on behalf of CRON4healthyfuture]

On 29 Jun 2003 a CRONie noted:

>>Anyway, I'm the one who's the complete incompetent when it comes to

biology,

>>biochemistry, etc., so I wish you'd read the damn book and explain it to me
>>in that cool way you have of making utterly over-my-head things at least
>>semi-understandable.

Heh, the book is sitting in a library I will be going by relatively soon,
but it would take time to peruse completely. *If* I get a chance to read
it, I will comment about its conctents. But, from what I understand, this
is the current iteration of de Grey's theory...........

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=--=

1) Your mitochondria accumulate what is known as the "common deletion"
with age. It is 4977 base pairs long, and it is essentially a chunk of
your mtDNA that "falls off" with age.

2) When your mitochondria lose this chunk, they actually start to "divide"
faster than intact mitochondria, and so they can spread out and make the
cell sick. This process is known as "clonal expansion".

3) In essence, because of this process, all of your cells have a certain
ratio of intact mitochondria and "mutated" mitchondria. This state
of "both good and bad" is termed heteroplasmy.

4) When the "bad mitchondria" start dividing faster than the regular
mitochondria, then the cell begins progressing towards a "loss of
heteroplasmy". The term for a cell with only defunct, mutated mitchondria
is called "homoplasmy".

5) This means that across the lifespan of an organism, the mitochondria in
your cells are progressing the following manner....

Mitochondria

-------------------------------
/ \
/ Aging \
( Heteroplasmic----> Homoplasmic-- )---> Increased ROS
\ / Decreased ATP
\--------------------------------

=-=-=-=-=-=-=-=-=-=-=-=-=-=--=-=-=-==--=

Recent addition to the theory:

Increased ROS oxidizes circulating LDL particles in the plasma. (This is
significant that de Grey decided to take this extra step conceptually, and
I comment on it below)

=-=-=-=-=-=-=-=-=-=-=-=-=-

This theory is beautiful....except for the fact that they are having
trouble finding

1) Increased ROS
2) Decreased ATP
3) A physiologically significant loss of heteroplasmy

If you can show me *recent* studies detailing 1, 2, 3, then I will gladly
write de Grey a recommendation at the Karolinska Institute.

The *best* stuff I can come up with regarding this theory involves loss of
peripheral nerves. But that's it.

=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-

Additionally, there are substantial conceptual problems with his recent
addition to the theory.

Up until this point, *no* exogenous antioxidants have been capable of
producing maximum lifespean extension. If the ROS that were escaping these
rogue mitochondria were to blame for "systemic" aging through oxidation of
circulating LDL particles, then surely these antioxidants should have been
capable of "intercepting" them.

Vitamin E, Vitamin C, alpha-lipoic, coenzyme q10. Sure, they increase
stress resistance of post-mitotic tissues, but whatever they are doing
doesn't seem to be making an impact on maximum lifespan. And they even
seem to be hurting just a little bit. This observation is not congruent
with the theory base.

=-=-=-=-=-=-=-=-=-

My frustration with this theory is that it does not seem to bear out
experimentally. Although the common deletion does seem to accumulate with
age, its physiologic significance is not only uncertain, but highly
doubtful. I would liken common deletions to something like "skin
wrinkles". Sure, it looks bad, but it isn't really hurting you.

=-=-=-=-=-=-==-=-=-

Ways de Grey can fix his theory

1) Abandon the significance of the common deletion

-- de Grey "latched on" this one type of mutation and attached almost
mystical significance to it. It turns out that deletion mutations
are not the only significant type. "Point" mutations, which are
alterations of a single nucleotide along a sequence, are also
featuring very prominently in more contemporaneous mitochondrial
mutation research

2) Focus more on the contribution of nuclear genes to mitochondrial
dysfunction seen with aging

-- He attempts to sequester aging to the mitochondria compartment.
Although oxidative modification of proteins and nucleic acids seems
to increase in all compartments, it is not entirely clear that the
progressive deterioration of redox balance should be entirely
confined to events in the mitochondria. The deterioration of
nuclear gene expression and the progressive loss of nuclear genomic
integrity is probably underemphasized in the present
conceptualizations of age-associated mitochondrial pathology.

3) Emphasize the contribution of endogenous repair and maintenance enzymes

-- The maintenance of the mitochondrial genome depends on team work
from a variety of sources, and the common deletion need not be
invoked to see those "support" systems fail

4) De-emphasize the significance of ROS to the aging process

-- This one is the hardest for most contemporary bioscientists to
swallow, but I think it is an important step to take. Although ROS
are capable of degrading all manner of biomolecules, we must take
comfort in the fact that evolution "solved" the problem of ROS a
long time ago, and that it is woven into the fabric of our
existence. To try to ablate them entirely it to invite disaster,
in my opinion. A more intelligent strategy to optimize the
biologically-mediated "control" of reactive oxygen species, rather
than trying in some sort of "top-down" manner to eradicate them
entirely.

[A1CR]

[posted on behalf of MR and CRON4healthyfuture]

CRON4healthyfuture wrote:

>> On 29 Jun 2003 a CRONie1 wrote:
>>
>
>>> >Anyway, I'm the one who's the complete incompetent when it comes to
>
>> biology,
>
>>> >biochemistry, etc., so I wish you'd read the damn book and explain it to me
>>> >in that cool way you have of making utterly over-my-head things at least
>>> >semi-understandable.
>
>>
>> Heh, the book is sitting in a library I will be going by relatively soon,
>> but it would take time to peruse completely. *If* I get a chance to read
>> it, I will comment about its conctents. But, from what I understand, this
>> is the current iteration of de Grey's theory...........

Rather than guessing secondhand, why don't you read the book or his
papers? You are free to form any opinion you like, but you can't expect
to have your "refutations" of a theory taken seriously when they aren't
founded in knowlege thereof -- esp when the arguments themselves are
based on those misunderstandings, and thus (a) unintentionally deceptive
to those bystanders who THEMSELVES don't know the theory, and (b) are
simply a waste of bandwidth. I'm pretty sure (I say, because your
replies to them seemed not to grasp the point) that this is the essence
of [CRONie1's] and [CRONie2's] recent messages to you on the subject.


>> But, from what I understand, this
>> is the current iteration of de Grey's theory...........

>> 1) Your mitochondria accumulate what is known as the "common deletion"
>> with age.

No, tho' I suspect you just phrased this improperly rather than
misunderstood. Rather, a small minority of individual cells or (in the
case of skeletal muscle) individual muscle fiber segments accumulate
micochoondria which have the common deletion. Unclear? Read the book.
(BTW, this isn't part of the theory: it's a well-established fact).

>> 2) When your mitochondria lose this chunk, they actually start to "divide"
>> faster than intact mitochondria, and so they can spread out and make the
>> cell sick. This process is known as "clonal expansion".


No. Read the book.

>> 3) In essence, because of this process, all of your cells have a certain
>> ratio of intact mitochondria and "mutated" mitchondria.


No!! Read the book.


>> 4) When the "bad mitchondria" start dividing faster than the regular
>> mitochondria,


... which they don't, which de Grey doesn't claim that they do, & which
nonevent indeed is one of the puzzles which MiFRA resolves (read the
book) ...


>> then the cell begins progressing towards a "loss of
>> heteroplasmy". The term for a cell with only defunct, mutated mitchondria
>> is called "homoplasmy".


Yes. (But you should really still read the book).

>>
>> 5) This means that across the lifespan of an organism, the mitochondria in
>> your cells are progressing the following manner....
>>
>> Mitochondria
>>
>> -------------------------------
>> / \
>> / Aging \
>> ( Heteroplasmic----> Homoplasmic-- )---> Increased ROS
>> \ / Decreased ATP
>> \--------------------------------


You appear to mean this more or less globally, in which case: no. Read
the book.


>> =-=-=-=-=-=-=-=-=-=-=-=-=-=--=-=-=-==--=
>>
>> Recent addition to the theory:


I'll niggle here: the addition was not really "recent," tho' not present
in the very first (1996) paper. It's key to That Damned Book, most
notably -- as you'd know, if you'd read it.


>> Increased ROS oxidizes circulating LDL particles in the plasma.


No. Read the book.


>> (This is
>> significant that de Grey decided to take this extra step conceptually, and
>> I comment on it below)
>>
>> =-=-=-=-=-=-=-=-=-=-=-=-=-
>>
>> This theory is beautiful....except for the fact that they are having
>> trouble finding
>>
>> 1) Increased ROS
>> 2) Decreased ATP
>> 3) A physiologically significant loss of heteroplasmy


... all of which only seem to be objections because you don't understand
the theory. These points are either among the very data which led de
Grey to propose the theory in the first place (in the face of theorists
that depended on a more simple-minded mt free radical theories which
don't mesh with same), or are covered by the theory itself, as you'd
know if you'd only read the book.

>>
>> If you can show me *recent* studies detailing 1, 2, 3, then I will gladly
>> write de Grey a recommendation at the Karolinska Institute.


Actually, plenty of recent papers report (1) & (2) above (Hagen & Ames
have reported much of the above, eg); a stronger objection to de Grey's
theory would be to say that it isn't necessary, because (one could
plausibly argue) (1) & (2), if more global, would be more than enough to
form a consistent aging theory.


>> The *best* stuff I can come up with regarding this theory involves loss of
>> peripheral nerves. But that's it.


De Grey can save you the trouble: his papers and book have footnotes.
All you'd have to do to find these references is read them.

>> =-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-=-
>>
>> Additionally, there are substantial conceptual problems with his recent
>> addition to the theory.
>>
>> Up until this point, *no* exogenous antioxidants have been capable of
>> producing maximum lifespean extension.


... as de Grey's theory emphasises. This isn't a contradiction, it's a
key argument in faavor of the theory -- as you'd know, if you read the book.

>> Vitamin E, Vitamin C, alpha-lipoic, coenzyme q10. Sure, they increase
>> stress resistance of post-mitotic tissues, but whatever they are doing
>> doesn't seem to be making an impact on maximum lifespan. And they even
>> seem to be hurting just a little bit. This observation is not congruent
>> with the theory base.

NO, it does NOT -- read the book!! Indeed, the results with C & E are
key elements of, and *reinforce,* MiFRA.

The racemic ALA used in LS studies to date is 50% deleterious S(-)-LA,
so ts Janus nature might easily just result in a null effect; and in any
case ALA has not been tried in a LS study at doses high enough to
reeflect the "clinical" benefits reported in short-term studies by Hagen
& Ames, or human clinical benefits in NIDDM, or the actual reduction of
the "common deletion" in one tissue reported by Seidman (1) (which would
certainly be predicted to extend LS in de G's theory if it is really due
to reduced deletions IN THE FIRST PLACE, & probably would even after the
fact). De Grey finds the details of thee result incredible. In any case,
even a failure with R(+) would not CERTAINLY refute the theory, as it
would depend on how R(+) reduces mtROS -- a mechanism which is not yet certain.

CoQ HAS increased LS at v. high doses, per Steve Harris, (2) and a
plausible antioxidant mechanism pproposed by Lawen et al (3) would
reconcile this with the general prediction by de Grey that AOs operating
via conventional mechanisms would not increase LS. Harris' study used
scaled human equivalents of 750 mg/day; the various failed studies used
the equivalent of 150. And again, a failure with CoQ would not CERTAINLY
refute the theory, as it would depend on whether CoQ can really,
effectively do what (3) proposes -- a mechanism which is not yet certain.

>> =-=-=-=-=-=-=-=-=-
>>
>> My frustration with this theory is that it does not seem to bear out
>> experimentally.

You don't know this, as you don't know what the theory predicts &
therefore what constitutes evidence against it. One of its key strengths
is that it explains some puzzles in the experimental data; another is
that things PREDICTED by de Grey on the basis of the theory (such as the
fact that CR lowers mtROS by reducing the reduction of Complex I, or the
"Survival of the Slowest" (in isolated cells, NB -- no full in vivo
studies AFAIK)).


>> =-=-=-=-=-=-==-=-=-
>>
>> Ways de Grey can fix his theory
>>
>> 1) Abandon the significance of the common deletion


That wouldn't fix the theory, it would eliminate it. Not understanding
the theory, you are asking him to simply abandon it in favor of your own
(which itself rather misses the point: you keep saying how important
repair & maintenance systems are, but the question of what causes agins
is what exactly it is that repair & maintenance systems are failing to
repair, which drives aging. The best candidates we have -- mtROS and
glycation -- you seem unwilling to accept).

>>
>> -- de Grey "latched on" this one type of mutation

No, he didn't. He "latched on" to a deletion. Read the book.


>> and attached almost
>> mystical significance to it. It turns out that deletion mutations
>> are not the only significant type.


That's uncontroversial: any time you get a true MUTATION (as opposed,
here, to eg. damage to junk DNA), clearly that's going to have some kind
of significance. The question is what evidence there is that they drive
aging, as opposed to being aging's downstream pathological sequelae,
causing eg. dysfunction of particular cells or cancer.

Indeed, de Grey's proposed solution to the problem posed by MiFRA is to
express ALL 13 mt-coded proteins coded allotopically in the DNA (5, and
That Damned Book).


>> "Point" mutations, which are
>> alterations of a single nucleotide along a sequence, are also
>> featuring very prominently in more contemporaneous mitochondrial
>> mutation research


Yes, but there isn't any clear connection of point mutations with aging.

>>
>> 2) Focus more on the contribution of nuclear genes to mitochondrial
>> dysfunction seen with aging


Again, that wouldn't fix the theory, it would eliminate it.

>>
>> 3) Emphasize the contribution of endogenous repair and maintenance enzymes


That wouldn't address anything. To say that endogenous repair and
maintenance enzymes don't fix age-causing damage is self-evident (if
they did, we wouldn't age, by definition); the question is what's
driving the damage that isn't being repaired.


>> 4) De-emphasize the significance of ROS to the aging process


Again, that wouldn't fix the theory, it would eliminate it. And since
mtROS are the strongest single candidate for a determinant of max LS (&
thus, as a driver of aging (that which imposes a max LS -- by
definition), that'd be very silly.

Hey, CRON4healthyfuture: whyncha read the book?

-MR

1: Seidman MD, Khan MJ, Bai U, Shirwany N, Quirk WS.
Biologic activity of mitochondrial metabolites on aging and age-related hearing
loss.
Am J Otol. 2000 Mar;21(2):161-7.
PMID: 10733178 [PubMed - indexed for MEDLINE]

2. Coles SL, Harris SB.
Coenzyme Q10 and lifespan extension.
In Klatz RM, Kovarik FA, Goldman R (eds). Advances in Anti-Aging
Medicine. Vol 1. 1996; Mary Ann Liebert: Larchmont, NY.

3. Lawen A, Martinus RD, McMullen GL, Nagley P, Vaillant F, Wolvetang EJ,
Linnane AW.
The universality of bioenergetic disease: the role of mitochondrial mutation
and the putative inter-relationship between mitochondria and plasma membrane
NADH oxidoreductase.
Mol Aspects Med. 1994;15 Suppl:s13-27. Review. No abstract available.
PMID: 7752823 [PubMed - indexed for MEDLINE]

5. de Grey AD.
Mitochondrial gene therapy: an arena for the biomedical use of inteins.
Trends Biotechnol. 2000 Sep;18(9):394-9. Review.
PMID: 10942964 [PubMed - indexed for MEDLINE]