Methuselah Mouse Prize Alternative
Prometheus
drosophila melanogaster (the fruit fly) as a model organism would be a
more viable alternative to using the mouse for the Methuselah Prize
competition. We could do with some added opinions on this topic as
some of us are looking at starting a drosophila based prize should the
Methuselah Foundation people choose to just stay with the mouse.
What do you think: mouse, fly or both?
Michael C Price
I suggested the same thing to Aubrey de Grey
a couple of days ago and he suggested two things.
Choose an insect that was not post-mitotic in the
adult form (which basically means one without
a distinct larval stage) and one that doesn't
"hibernate" in response to food shortages.
Cheers,
Michael C Price
----------------------------------------
http://mcp.longevity-report.com
http://www.hedweb.com/manworld.htm
"Prometheus" <theo...@gmail.com> wrote in message
news:be1135d6.04080...@posting.google.com...
Reason
A link to the discussion:
http://www.imminst.org/forum/index.php?act=ST&f=44&t=4048&hl=&s=
I'm of the opinion that it's a good plan technically and economically,
but very hard to sell to the public. They like fuzzy long-lived mice,
but are not going to go for flies. I have encouraged Prometheus to
prove me wrong on that score, and feel that the more the merrier
insofar as any activism and encouragement of serious anti-aging
research goes. There's no shortage of good ideas, but a definite
shortage of people willing to get behind them and devote serious
resources to making it happen...
Reason
Founder, Longevity Meme
rea...@longevitymeme.org
http://www.longevitymeme.org
Philippic
> but very hard to sell to the public. They like fuzzy long-lived mice,
> but are not going to go for flies.
Maybe you've not chosen the right insect: my suggestion is that you go for
the public's *all-time-favourite* insect -- the *ladybird* (US:
'ladybug'...?). People love them: you see them treating them almost like
*cats*...!
Hope that helps!
Philippic
Prometheus
> I think it is a great idea!
>
> I suggested the same thing to Aubrey de Grey
> a couple of days ago and he suggested two things.
> Choose an insect that was not post-mitotic in the
> adult form (which basically means one without
> a distinct larval stage) and one that doesn't
> "hibernate" in response to food shortages.
>
> Cheers,
> Michael C Price
If Aubrey means ametabolous types of insects (such as silverfish =
Lepisma saccharina) we come across two problems:
1. we do not have their genome sequenced as we do with drosophila
2. their lifespan tends to be considerably longer than the fruit fly
Michael C Price
I don't see the problem with the genome not being
sequenced -- since we don't understand the genome
anyway! The lifespan is a problem. I suggest you try
mites -- there are hundreds of species to choose from,
some feed on plants and only live a few weeks. They go
through a succession of molts.
http://www.pested.msu.edu/BullSlideNews/bulletins/pdf/2492/E2492chap9.pdf
Tim Tyler
A nice political suggestion - but ladybirds live for one or two years.
I should think that one of the attractions of using insects in the first
place is the shorter lifespan allowing more sequential iterations - with
the results of each previous trial informing the next one.
Of course shorter lifespans also result in lower costs.
--
__________
|im |yler http://timtyler.org/ t...@tt1lock.org Remove lock to reply.
Prometheus
Knowing the genome of an organism is like knowing the periodic table
in chemistry. The value of the information is huge. You must be
joking!
Did Aubrey tell you the need for an ametabolous insect?
Philippic
"Tim Tyler" <t...@tt1lock.org> wrote in message news:I1wv...@bath.ac.uk...
> Philippic <jhdddsdsfgid?@1cddfgjsbcfcak.com> wrote or quoted:
>
> > > I'm of the opinion that it's a good plan technically and economically,
> > > but very hard to sell to the public. They like fuzzy long-lived mice,
> > > but are not going to go for flies.
> >
> > Maybe you've not chosen the right insect: my suggestion is that you go
for
> > the public's *all-time-favourite* insect -- the *ladybird* (US:
> > 'ladybug'...?). People love them: you see them treating them almost like
> > *cats*...!
>
> A nice political suggestion - but ladybirds live for one or two years.
Ah! I see the problem! Thanks!
Philippic
jayd...@aol.com
>
> I should think that one of the attractions of using insects in the first
> place is the shorter lifespan allowing more sequential iterations - with
> the results of each previous trial informing the next one.
>
> Of course shorter lifespans also result in lower costs.
The point of this exercise was to create a prize to complement the
Mouse prize. We need something that will produce rapid results that
can be fed into the Mouse prize, plus help establish that longevity
prizes work. This will draw more competitors to the Mouse prize, as
well as increase their level of success.
There are a few items I identify as being important:
1) Short lifespan. I'm thinking at least an order of magnitude shorter
than mice: 3 months or less for the top decile.
2) Low cost to conduct experiments: Cost per organism, as well as cost
per genetic subgroup. Cost will be attributable to several factors,
of which lifespan is only one. Others include: maintenance (space and
food requirements, etc.), difficulty and cost of controlled genetic
mutations, etc.
3) Well-researched. Basically, if poorly researched, then items 1 and
2 become more critical. Because of the steep learning curve involved
with a poorly-researched species, the lifespan and experiment costs
will need to be much lower.
4) That post-mitotic or ametabolic thingy that the scientists (Dr. de
Grey and Prometheus) mentioned.
5) The "cuteness" factor.
Item 5 is really more an issue of having a relatively lower "ewww!"
factor than a higher "cuteness" factor. Bugs are bugs. There isn't
really much of a cuteness factor.
Fruit flies already fit items 1-3 very well. Item 4 is a wildcard:
I'll admit I don't understand it enough. I'm heading over to
Wikipedia and Google later today to due some research, get a little
primer. However, I do see some logic to the "no larval state"
argument.
I'm sure there are lots and lots of bugs that fit item 5. My personal
favorites are butterflies and dragonflies; they've fascinated me since
I was a child. However, I'm guessing they fail item 4. I'm also
quite partial to pills bugs (potato bugs, rolly polies, whatever
they're called...).
So, what insects fit items 1-4? Let's at least generate that list.
We can worry about the cuteness factor when we have a better list.
Jay Fox
Michael C Price
> Knowing the genome of an organism is like knowing the
> periodic table in chemistry. The value of the information
> is huge. You must be joking!
Since we'll be testing therapies we hope will also
work on humans, I don't think we need to know
their genomes at all. (And I'm not joking!)
Quit theorisng and just see if the frigging drugs/nutrients
will extend their LS!!!
> Did Aubrey tell you the need for an ametabolous insect?
Not directly, that's something I worked out for myself.
Ametabolous insects are not post-mitotic, which was
Aubrey's concern. It makes sense to me as well.
Prometheus
Aubrey commented on Imminst.org that diapause - which is a state of
dormancy to avoid periods of unfavorable condition - could be a
problem when confirming drosophila age for the purposes of awarding
prizes. I suspect the suggestion is that by manipulating the diapause
period longevity could be extended irrespective of the longevity
enhancement intervention leading to interpretational ambiguity. If
this is an issue, it has not been a point of contention with other
researchers who have used, and continue to use drosophila as a model
organism for aging studies.
Prometheus
It is highly unlikely that it will be a single and simple drug or
nutrient that would be able to sufficiently alter gene regulation and
expression in order to mitigate aging processes. Research to date
indicates we would be looking at a long-term expression, non genome
recombinant, inducible genetic construct of some kind.
Consequently, knowledge of the host genome would come in handy, don't
you think?
Would you be so kind as to explain exactly what it is that makes sense
about using ametabolous insects?
Michael C Price
> It is highly unlikely that it will be a single and simple drug or
> nutrient that would be able to sufficiently alter gene regulation
> and expression in order to mitigate aging processes.
Nice theory, eh, what about the experiments?
Vitamins B5, B6, dietary RNA & selenium have extended
lifespan. Perhaps we should try to replicate what already
has worked before we start spinning theories about why they
can't work.
[1a] The Use of Drosophila Melanogaster as a Screening Agent for Longevity
Factors. I. Pantothenic Acid as a Longevity Factor in Royal Jelly. Thomas
S Gardner, Journal of Gerontology 1(3) (1948): 1-8.
Mean lifespan increase of 27.8% with dietary B5.
[1b] The Use of Drosophila Melanogaster as a Screening Agent for Longevity
Factors. II. The Effects of Biotin, Pyridoxine, Sodium Yeast Nucleate, and
Pantothenic Acid on the Life Span of the Fruit Fly. Thomas S Gardner,
Journal of Gerontology 1(3) (1948): 9-13
Mean lifespan increases of 27.8%, 10.5%, 11.3%, 20.3% and 46.6% with dietary
B5, B6, RNA, B6+biotin+RNA, B5+B6+biotin+RNA respectively.
[2a] The Effect of Yeast Nucleic Acid on the Survival Time of 600-Day-Old
Albino Mice. Thomas S Gardner, Journal of Gerontology 3(?) (1946): 445-452.
This reproduces the work of Robertson2b on lifelong administration of
nucleic acid enriched diets, at a lower dosage.
[2b] Influence of Nucleic Acids of Various Origin upon the Growth and
Longevity of the white mouse. TB Robertson in the Australian J of
Experimental Biology and Medical Science, 5, (1928): 46-67
16% mean life span extension. Maximum lifespan (last 10%) extended by
approximately 8-16%.
[3a] Effect of pantothenic acid on the longevity of mice. Richard B Pelton
and Roger J Williams in Proceedings of the Society Experimental Biology &
Medicine 99 632-633, 1958.
Mean lifespan extension of 19.5%. No maximum lifespan data reported.
[4] How to re-energise old mitochondria without shooting yourself in the
foot. Driver C, Georgiou A in Biogerontology 2002;3(1-2):103-6 PMID:
12014827
Nicotinamide at 250mg/L of food medium increased mean lifespan in drosophila
by 15%. (Private communication: Maximum lifespan (last 10%) also increased.)
[6] Favorable Effects of Pyridoxine HCl on the aging process. Lindseth K,
Dictor M & Miquel J in AGE 5(4), 143, 1982.
Late middle-age intervention gave mean total lifespan extension of 11%. No
maximum lifespan data reported.
[7a] Effect of sodium selenite on antioxidative enzymes of banana fruitfly.
Kaur M, Wadhwa R, Sharma SP in Gerontology 1989;35(4):188-91 PMID: 2583532
"Sodium selenite (SS), an antioxidant, feeding prolongs the median as well
as maximum life span of both the sexes."
[7b] [Effects of sodium selenite on the activity of GSH-Px and the life-span
of Drosophila] Zhang X, Wang X, Bai L, Li Z in Wei Sheng Yan Jiu 2000 May
30;29(3):166-7. PMID: 12725065
"The average life-span and the average maximum life-span of flies in
selenium groups were increased significantly as compared with control group
(P < 0.05)."
[7c] Selenium and tellurium in mice. Effects on growth, survival, and
tumors. Schroeder HA, Mitchener M in Arch Environ Health. 1972 Jan; 24(1):
66-71. PMID: 4500615.
The dose used (3ppm) was toxic (carcinogenic); despite this the mean LS was
extended by 8% (selenate), 16% (selenite), the maximum cohort LS by -4%
(selenate), 33% (selenite). For selenite the ratio of max cohort LS /
control mean LS was 2.46. (cf: control max/mean LS = 1.845) Tellurite
(chemically similar to selenite) also extended mean (4%) and max LS (41%).
The controls received 60ug/kg selenium / diet wet weight
[7d] Selenium and tellurium in rats: effect on growth, survival and tumors.
Schroeder HA, Mitchener M in J Nutr. 1971 Nov; 101(11): 1531-40 PMID:
5124041. The selenate dose used (3ppm) was toxic (carcinogenic); despite
this the mean LS was extended by 9%, maximum cohort LS by 48%., which at 60
months beat the previous species maximum of 42 months by 43%. (Selenite at
3ppm was highly toxic and not pursued.) The ratio of max cohort LS /
control mean LS was 2.25. (cf: control max/mean LS = 1.52) The controls
received 50ug/kg selenium / diet wet weight
Michael C Price
> that makes sense about using ametabolous insects?
We resemble ametabolous insects more than
metabolous insects. Mites aren't insects but the
same argument applies
Tim
extreme longevity in regards to that species will be much more readily
achievable by manipulation in insects than mammals, but then there is
the question of relevance. But, look whats already been done with
nematodes.
A Harvard biologist, Dr. Carroll Williams back in the 1940's did some
fascinating work on metamorphosis.
"Just behind the insect brain, investigators have found a pair of
glands called the corpora allata. Dissection has revealed these glands
in every metamorphosing insect thus far examined. By delicate surgery
scientists have been able to remove them from living larvae. Wherever
this was done, the caterpillars ended their larval life immediately.
No matter what their stage of development, at their next molt they
spun midget-sized cocoons and emerged as dwarf adults. Thus removal of
the corpora allata cuts short the youth of an insect and thrusts it
prematurely into the adult world. Since it maintains insect
immaturity, the secretion of these glands has been named the
"juvenile" hormone.
Just as removal of the corpora allata causes a larva to become a
pupa prematurely, the artificial implanting of these glands in a
mature larva on the brink of pupation, rejuvenates it. The larva
postpones metamorphosis and continues to grow, until finally it turns
into a giant adult. It is believed that this sort of thing happened
naturally during the time some 300 million years ago when insects with
two-and-a-half-foot wingspans existed. The corpora allata of these
giants must have continued to pour out juvenile hormone for a long
period, resulting in a longer larval stage and consequently a larger.
adult.
As a normal larva matures, the corpora allata halt their production
of juvenile hormone and the insects array of pupal-adult cells is
liberated. These immediately respond by growing and differentiating
into pupal organs. At the same time the larval cells receive their own
hormone from the thorax, signaling that it is time for them to reach
biological death and transfiguration into the raw material of the
adult."
I suspect these large insects like the large dragonflylike Meganeura
were quite long-lived in comparison to todays species ( I meant to
check if there was any data, as at least pieces must have been
preserved in amber that might give some clue). Metamorphosis does
appear to be related to temperature and lemgth of day. As far as I
know the longest lived insect is the Queen Termite at about 50 years
and some Cicada species live at least 17. Even so who wants a 20 foot
cockroach :-). One thing to note I guess is that negligible senescing
organisms often never stop growth completely. Personally I's stick
with a shorter lived mammal like the shrew or even a marsupial like
the American Oppossum. It seems to me they are more relevant as to
mortality in humans and results could be obtained faster.
Tim
jayd...@aol.com
> > Mouse prize. We need something that will produce rapid results that
> > can be fed into the Mouse prize, plus help establish that longevity
> > prizes work. This will draw more competitors to the Mouse prize, as
> > well as increase their level of success.
> >
> > There are a few items I identify as being important:
> > 1) Short lifespan. I'm thinking at least an order of magnitude shorter
> > than mice: 3 months or less for the top decile.
> > 2) Low cost to conduct experiments: Cost per organism, as well as cost
> > per genetic subgroup. Cost will be attributable to several factors,
> > of which lifespan is only one. Others include: maintenance (space and
> > food requirements, etc.), difficulty and cost of controlled genetic
> > mutations, etc.
> > 3) Well-researched. Basically, if poorly researched, then items 1 and
> > 2 become more critical. Because of the steep learning curve involved
> > with a poorly-researched species, the lifespan and experiment costs
> > will need to be much lower.
> > 4) That post-mitotic or ametabolic thingy that the scientists (Dr. de
> > Grey and Prometheus) mentioned.
> > 5) The "cuteness" factor.
> >
> > Item 5 is really more an issue of having a relatively lower "ewww!"
> > factor than a higher "cuteness" factor. Bugs are bugs. There isn't
> > really much of a cuteness factor.
> >
> >
>
> Aubrey commented on Imminst.org that diapause - which is a state of
> dormancy to avoid periods of unfavorable condition - could be a
> problem when confirming drosophila age for the purposes of awarding
> prizes. I suspect the suggestion is that by manipulating the diapause
> period longevity could be extended irrespective of the longevity
> enhancement intervention leading to interpretational ambiguity. If
> this is an issue, it has not been a point of contention with other
> researchers who have used, and continue to use drosophila as a model
> organism for aging studies.
Prometheus,
Would you at least agree with the items on my list, as I've stated
them? Any changes? Would you add any other items?
So far, I haven't seen a viable alternative to the fruit fly. (Though
one suggestion by Dr. de Grey has come close: Nothobranchius furzeri,
an African fish.
URL: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14667379
)
Jay Fox
Prometheus
with the use of nutritional supplementation. I am not suggesting
supplementation does not have any effect - fabulous effects are
observed on nutritionally deficient animals when they are supplemented
with the nutritional factors that are absent from their diet.
Please bear in mind however that at the end of the day it is just that
- supplementation. Increasing the dosage of the supplement invariably
results in no further effect once the deficiency is compensated. When
considering the modulation of the mechanism of senescence we need to
address a lot more than just nutritional deficiencies.
No amount of supplementation is going to extend lifespan beyond the
maximum normal range unless fundamental alterations in gene regulation
take place that instruct the cell to behave in a manner entirely
different to what it is predestined for. For instance no supplement
that I am aware of will cause a cell to become immortalized unless the
supplement is mutagenic.
"Michael C Price" <michaelEXCI...@ntlworld.com> wrote in message news:<EppQc.109$Ua2...@newsfe2-gui.ntli.net>...
Prometheus
Michael if you ask Aubrey about the ametabolous issue I think you will
find he was referring to the problem of differentiating between the
lifespan extension mediated between diapause and the experimental
intervention.
Michael C Price
>>> Would you be so kind as to explain exactly what it is
>>> that makes sense about using ametabolous insects?
>>
>> We resemble ametabolous insects more than
>> metabolous insects. Mites aren't insects but the
>> same argument applies
> Michael if you ask Aubrey about the ametabolous issue I think
> you will find he was referring to the problem of differentiating
> between the lifespan extension mediated between diapause and
> the experimental intervention.
I will ask, but the distinction strikes me as irrelevant.
Aren't these all different sides of the same coin??
Michael C Price
> Thanks for the info Michael. I appreciate the point you are making
> with the use of nutritional supplementation. I am not suggesting
> supplementation does not have any effect - fabulous effects are
> observed on nutritionally deficient animals when they are
> supplemented with the nutritional factors that are absent from their
> diet.
The LS studies I cited all had non-deficient controls.
You are making the same assumption that almost everyone
else makes (for a variety of ill-thought out reasons), namely
that any nutritional experiment that shows a positive result
must have had classically deficient controls. Tell me why
you believe this and I'll tell you why you're wrong :-)
You are new to sci.life-extension, I believe, so you probably
haven't seen the studies I've collected that demonstrate supra-
RDA benefits on nutritionally replete (= non classically
deficient) humans.
Have a look at
http://mcp.longevity-report.com
If you want a more up to date version, I'll email you my working
copy.
> Please bear in mind however that at the end of the day it is just that
> - supplementation. Increasing the dosage of the supplement invariably
> results in no further effect once the deficiency is compensated.
Incorrect. Lots of experiments show further benefits (in both humans
and other animals) as nutritional supplements are increased beyond
the level that suppresses the classical vitamin deficiency syndromes.
See studies at end of post.
> When considering the modulation of the mechanism of senescence
> we need to address a lot more than just nutritional deficiencies.
Again, this is an assumption. You are being confused by the
word "deficiencies".
> No amount of supplementation is going to extend lifespan beyond the
> maximum normal range unless fundamental alterations in gene regulation
> take place that instruct the cell to behave in a manner entirely
> different to what it is predestined for.
How do you know that? You are assuming zero cost in evolutionary
terms for the foraging of nutrients and biosynthesis of coenzymes.
Something we know is incorrect.
> For instance no supplement
> that I am aware of will cause a cell to become immortalized unless the
> supplement is mutagenic.
Immortalised?? Straw-man argument. All we talking about here is
*slowing* the aging process not turning them into supermites.
From my longevity report
"The health benefits to already healthy humans of supra-RDA levels of
micronutrients - as demonstrated by many placebo-controlled trials[47-61]
and epidemiological studies[11-14], [136], a view finally endorsed in a JAMA
review[82] - are further circumstantial evidence that their anti-aging
effects will extrapolate onto humans."
[11a] Multivitamin use, folate, and colon cancer in women in the Nurses'
Health Study. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C,
Rosner BA, Speizer FE, Willett WC in Ann Intern Med 1998 Oct 1;129(7):517-24
PMID: 9758570
Long-term use (>15 years) of folate supplements produced a 4-fold reduction
in the incidence of colon cancer. Other cancers not analysed.
[11b] Are dietary factors involved in DNA methylation associated with colon
cancer? Slattery ML, Schaffer D, Edwards SL, Ma KN, Potter JD in Nutr
Cancer 1997;28(1):52-62 PMID: 9200151
"We did not observe strong independent associations between folate, vitamin
B6, vitamin B12, methionine, or alcohol and risk of colon cancer after
adjusting for body size, physical activity, cigarette smoking patterns,
energy intake, and dietary intake of fiber and calcium. However, when
assessing the associations between colon cancer and a composite dietary
profile based on alcohol intake, methionine, folate, vitamin B12, and
vitamin B6, we observed a trend of increasing risk as one moved from a low-
to a high-risk group"
[11c] Dietary intake of folic acid and colorectal cancer risk in a cohort of
women. Terry P, Jain M, Miller AB, Howe GR, Rohan TE in Int J Cancer 2002
Feb 20;97(6):864-7 PMID: 11857369
Folate is crucial for normal DNA methylation, synthesis and repair, and
deficiency of this nutrient is hypothesized to lead to cancer through
disruption of these processes. There is some evidence to suggest that
relatively high dietary folate intake might be associated with reduced
colorectal cancer risk, especially among individuals with low methionine
intake. A case-cohort analysis was undertaken within the cohort of 56,837
women who were enrolled in the Canadian National Breast Screening Study and
who completed a self-administered dietary questionnaire. During follow-up to
the end of 1993, a total of 389 women were diagnosed with colorectal cancer,
identified by linkage to the Canadian Cancer Database. For comparative
purposes, a subcohort of 5,681 women was randomly selected from the full
dietary cohort at baseline. After exclusions for various reasons, the
analyses were based on 295 cases and 5,334 non-cases. Folate intake was
inversely associated with colorectal cancer risk (IRR = 0.6, 95% CI =
0.4-1.1, p for trend = 0.25). The inverse association was essentially
similar among individuals with low and high methionine intake, and was
similar for colon and rectal cancers when those endpoints were analyzed
separately. Among individuals with low methionine intake, folate intake did
not appear to lower the risk of rectal cancer, a finding that may be due, in
part, to the low number of cases in the subgroup analysis. Overall, our data
lend some support to the hypothesis that high folate intake is associated
with a reduced risk of colorectal cancer. Copyright 2001 Wiley-Liss, Inc.
[12a] Long-term nutrient intake and early age-related nuclear lens
opacities. Jacques PF, Chylack LT Jr, Hankinson SE, Khu PM, Rogers G,
Friend J, Tung W, Wolfe JK, Padhye N, Willett WC, Taylor A in Arch
Ophthalmol 2001 Jul;119(7):1009-19 PMID: 11448323
"These results provide additional evidence that antioxidant nutrients play a
role in the prevention of age-related nuclear lens opacities."
[12b] Long-term intake of vitamins and carotenoids and odds of early
age-related cortical and posterior subcapsular lens opacities. Taylor A,
Jacques PF, Chylack LT Jr, Hankinson SE, Khu PM, Rogers G, Friend J, Tung W,
Wolfe JK, Padhye N, Willett WC in Am J Clin Nutr 2002 Mar;75(3):540-9
PMID: 11864861
Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University,
Boston, MA 02111, USA. ata...@hnrc.tufs.edu
BACKGROUND: Proper nutrition appears to protect against cataracts. Few
studies have related nutrition to the odds of developing cortical or
posterior subcapsular (PSC) cataracts. OBJECTIVE: We assessed the relation
between usual nutrient intakes and age-related cortical and PSC lens
opacities. DESIGN: We studied 492 nondiabetic women aged 53-73 y from the
Nurses' Health Study cohort who were without previously diagnosed cataracts.
Usual nutrient intake was calculated as the average intake from 5
food-frequency questionnaires collected over a 13-15-y period before the eye
examination. Duration of vitamin supplement use was determined from 7
questionnaires collected during this same period. We defined cortical
opacities as grade > or = 0.5 and subcapsular opacities as grade > or =0.3
of the Lens Opacities Classification System III. RESULTS: Some lenses had
more than one opacity. No nutrient measure was related to prevalence of
opacities in the full sample, but significant interactions were seen between
age and vitamin C intake (P = 0.02) for odds of cortical opacities and
between smoking status and folate (P = 0.02), alpha-carotene (P = 0.02),
beta-carotene (P = 0.005), and total carotenoids (P = 0.02) for odds of PSC
opacities. For women aged <60 y, a vitamin C intake > or = 362 mg/d was
associated with a 57% lower odds ratio (0.43; 95% CI: 0.2, 0.93) of
developing a cortical cataract than was an intake <140 mg/d, and use of
vitamin C supplements for > or = 10 y was associated with a 60% lower odds
ratio (0.40; 0.18, 0.87) than was no vitamin C supplement use. Prevalence of
PSC opacities was related to total carotenoid intake in women who never
smoked (P = 0.02). CONCLUSIONS: Our results support a role for vitamin C in
diminishing the risk of cortical cataracts in women aged <60 y and for
carotenoids in diminishing the risk of PSC cataracts in women who have never
smoked.
[13] Vitamin E and vitamin C supplement use and risk of all-cause and
coronary heart disease mortality in older persons: the Established
Populations for Epidemiologic Studies of the Elderly. Losonczy KG, Harris
TB, Havlik RJ in Am J Clin Nutr 1996 Aug;64(2):190-6 PMID: 8694019
34% reduction in mortality over 9 years from vitamin E use
42% reduction in mortality over 9 years from vitamin C & E
[14] Vitamin C intake and mortality among a sample of the United States
population. Enstrom JE, Kanim LE, Klein MA in Epidemiology 1992
May;3(3):194-202 PMID: 1591317
35% reduction in mortality over 10 years from vitamin C use
[47] Optimization of dietary folate or low-dose folic acid supplements lower
homocysteine but do not enhance endothelial function in healthy adults,
irrespective of the methylenetetrahydrofolate reductase (C677T) genotype.
Pullin CH, Ashfield-Watt PA, Burr ML, Clark ZE, Lewis MJ, Moat SJ, Newcombe
RG, Powers HJ, Whiting JM, McDowell IF in J Am Coll Cardiol 2001
Dec;38(7):1799-805 PMID: 11738277
"RESULTS: At baseline, homocysteine was inversely related to plasma folate
and was higher in TT homozygotes. For the whole group, plasma folate
increased by 46% after dietary folate and by 79% after supplementation, with
reductions of homocysteine of 14% and 16%, respectively. Within the
genotype, TT homozygotes exhibited the most marked changes in these
variables."
[48] Effects of vitamin B12, folate, and vitamin B6 supplements in elderly
people with normal serum vitamin concentrations. Naurath HJ, Joosten E,
Riezler R, Stabler SP, Allen RH, Lindenbaum J in Lancet 1995 Jul
8;346(8967):85-9 PMID: 7603218
"The response rate to vitamin supplements supports the notion that metabolic
evidence of vitamin deficiency is common in the elderly, even in the
presence of normal serum vitamin levels. "
[49] The effect of folic acid supplementation on plasma homocysteine in an
elderly population. Rydlewicz A, Simpson JA, Taylor RJ, Bond CM, Golden MH
in QJM 2002 Jan;95(1):27-35 PMID: 11834770
"a total daily folic acid intake of 926 microg per day would be required to
ensure that 95% of the elderly population would be without cardiovascular
risk from folate deficiency. DISCUSSION: A daily folic acid intake of 926
microg is unlikely to be achieved by diet alone. Individual supplementation
or fortification of food with folic acid will be required to reach this
target."
[50a] Vitamin supplements and cardiovascular risk: review of the randomized
trials of homocysteine-lowering vitamin supplements. Clarke R, Armitage J
in Semin Thromb Hemost 2000;26(3):341-8 PMID: 11011852
"Hence, in typical populations, daily supplementation with both 0.5 to 5 mg
folic acid and about 0.5 mg vitamin B12 would be expected to reduce
homocysteine levels by one quarter to one third (from about 12 micromol/L to
about 8 to 9 micromol/L)."
[50b] A randomized, double-blind, placebo-controlled study of oral vitamin
B12 supplementation in older patients with subnormal or borderline serum
vitamin B12 concentrations. Seal EC, Metz J, Flicker L, Melny J in J Am
Geriatr Soc 2002 Jan;50(1):146-51 PMID: 12028259
"Cyanocobalamin supplementation of 50 microg but not 10 microg daily
produced a significant increase in serum vitamin B12. This result has
implications for the management of patients with subnormal or borderline
serum vitamin B12 concentrations and for food fortification with vitamin
B12."
[51] Multivitamin/mineral supplementation improves plasma B-vitamin status
and homocysteine concentration in healthy older adults consuming a
folate-fortified diet. McKay DL, Perrone G, Rasmussen H, Dallal G, Blumberg
JB in J Nutr 2000 Dec;130(12):3090-6 PMID: 11110875
"Plasma folate, pyridoxal phosphate (PLP) and vitamin B-12 concentrations
were increased 41.6, 36.5 and 13.8%, respectively, in the supplemented
group, whereas no changes were observed in the placebo group. The mean
homocysteine concentration decreased 9.6% in the supplemented group (P: <
0.001) and was unaffected in the placebo group."
[52a] Effects of folic acid and combinations of folic acid and vitamin B-12
on plasma homocysteine concentrations in healthy, young women. Bronstrup A,
Hages M, Prinz-Langenohl R, Pietrzik K in Am J Clin Nutr 1998
Nov;68(5):1104-10 PMID: 9808229
"These results suggest that the addition of vitamin B-12 to folic acid
supplements or enriched foods maximizes the reduction of homocysteine and
may thus increase the benefits of the proposed measures in the prevention of
vascular disease and neural tube defects."
[52b] Importance of both folic acid and vitamin B12 in reduction of risk of
vascular disease. Quinlivan EP, McPartlin J, McNulty H, Ward M, Strain JJ,
Weir DG, Scott JM in Lancet 2002 Jan 19;359(9302):227-8 PMID: 11812560
"a fortification policy based on folic acid and vitamin B12, rather than
folic acid alone, is likely to be much more effective at lowering of
homocysteine concentrations, with potential benefits for reduction of risk
of vascular disease."
[52c] Folate and vitamin B6 from diet and supplements in relation to risk of
coronary heart disease among women. Rimm EB, Willett WC, Hu FB, Sampson L,
Colditz GA, Manson JE, Hennekens C, Stampfer MJ in JAMA 1998 Feb
4;279(5):359-64 PMID: 9459468
"the relative risks (RRs) of CHD between extreme quintiles were 0.69 (95%
confidence interval [CI], 0.55-0.87) for folate (median intake, 696 microg/d
vs 158 microg/d) and 0.67 (95% CI, 0.53-0.85) for vitamin B6 (median intake,
4.6 mg/d vs 1.1 mg/d). Controlling for the same variables, the RR was 0.55
(95% CI, 0.41-0.74) among women in the highest quintile of both folate and
vitamin B6 intake compared with the opposite extreme."
[53] Folate, vitamin B12, homocysteine status and DNA damage in young
Australian adults. Fenech M, Aitken C, Rinaldi J in Carcinogenesis 1998
Jul;19(7):1163-71 PMID: 9683174
"The results from this study suggest that (i) MNC [micronucleated cells]
frequency is minimized when plasma HC [homocysteine] is below 7.5 micromol/l
and serum vitamin B12 is above 300 pmol/l and (ii) dietary supplement intake
of 700 microg folic acid and 7 microg vitamin B12 is sufficient to minimize
MNC frequency and plasma HC. Thus, it appears that elevated plasma HC, a
risk factor for cardiovascular disease, may also be a risk factor for
chromosome damage."
[54a] Supplementation with selenium and human immune cell functions. II.
Effect on cytotoxic lymphocytes and natural killer cells.
Kiremidjian-Schumacher L, Roy M, Wishe HI, Cohen MW, Stotzky G in Biol Trace
Elem Res 1994 Oct-Nov;46(1-2):183 PMID: 7946899
"The results indicated that the immunoenhancing effects of selenium in
humans require supplementation above the replete levels produced by normal
dietary intake."
[54b] Anticarcinogenic effects of selenium. Schrauzer GN in Cell Mol Life
Sci 2000 Dec;57(13-14):1864-73 PMID: 11215513
"Selenium (Se) exerts its anticarcinogenic effects by multiple mechanisms.
[.] For maximal utilization of its cancer-protective potential, Se
supplementation should start early in life and be maintained over the entire
lifespan."
[54c] Chemopreventive agents: selenium. Combs GF Jr, Gray WP in Pharmacol
Ther 1998 Sep;79(3):179-92 PMID: 2526614
"The antitumorigenic activities have been associated with Se intakes that
correct nutritionally deficient status in animals, as well as higher intakes
that are substantially greater than those associated with maximal expression
of the selenocysteine-containing enzymes. Therefore, it is proposed that
while some cancer protection, particularly that involving antioxidant
protection, involves selenoenzymes, specific Se metabolites, which are
produced in significant amounts at relatively high Se intakes, also
discharge antitumorigenic functions. According to this two-stage model of
the roles of Se in cancer prevention, individuals with nutritionally
adequate Se intakes may benefit from Se supplementation."
[55a] Evidence for synergism between chromium and nicotinic acid in the
control of glucose tolerance in elderly humans. Urberg M, Zemel MB in
Metabolism 1987 Sep;36(9):896-9 PMID: 3626867
"Sixteen healthy elderly volunteers were divided into three groups and given
either 200 micrograms Cr, 100 mg nicotinic acid, or 200 micrograms Cr + 100
mg nicotinic acid daily for 28 days and evaluated on days 0 and 28. Fasting
glucose and glucose tolerance were unaffected by either chromium or
nicotinic acid alone. In contrast, the combined chromium-nicotinic acid
supplement caused a 15% decrease in a glucose area integrated total (p less
than .025) and a 7% decrease in fasting glucose."
[55b] Effect of chromium supplementation on glucose tolerance and lipid
profile. Bahijri SM in Saudi Med J 2000 Jan;21(1):45-50 PMID: 11533750
"Improved glucose control, and lipid profile following chromium supplement
suggests the presence of low chromium status in the studied population.
However, serum chromium could not be recommended for use as an indicator of
chromium status as subjects with widely varying levels responded favorably
to the chromium supplement."
[55c] The safety and efficacy of high-dose chromium. Lamson DS, Plaza SM in
Altern Med Rev 2002 Jun;7(3):218-35 PMID: 12126463
"The beneficial effects of chromium on serum glucose and lipids and insulin
resistance occur even in the healthy."
[55d] High-dose biotin, an inducer of glucokinase expression, may synergize
with chromium picolinate to enable a definitive nutritional therapy for type
II diabetes. McCarty MF in Med Hypotheses 1999 May;52(5):401-6 PMID:
10416947
[55e] Beneficial effect of chromium-rich yeast on glucose tolerance and
blood lipids in elderly subjects. Offenbacher EG, Pi-Sunyer FX in Diabetes
1980 Nov;29(11):919-25 PMID: 7000589
"Thus, chromium-rich brewers' yeast improved glucose tolerance and total
lipids in elderly subjects, while chromium-poor torula yeast did not. An
improvement in insulin sensitivity also occurred with brewers' yeast
supplementation. This supports the thesis that elderly people may have a low
level of chromium and that an effective source for chromium repletion, such
as brewers' yeast, may improve their carbohydrate tolerance and total
lipids."
[55f] Effects of chromium supplementation on fasting insulin levels and
lipid parameters in healthy, non-obese young subjects. Wilson BE, Gondy A
in Diabetes Res Clin Pract 1995 Jun;28(3):179-84 PMID: 8529496
"However, those individuals [6/15] within the chromium group with initial
fasting IRI levels greater than 35 pmol/l had a significant decrease in IRI
level after supplementation (P < 0.03) despite no significant changes in
serum lipids. These subjects may benefit from chromium supplementation by
improving insulin sensitivity and cardiovascular risk over time."
[56] Effect of vitamin and trace-element supplementation on cognitive
function in elderly subjects. Chandra RK in Nutrition 2001 Sep;17(9):709-12
PMID: 11527656
"Cognitive functions improved after oral supplementation with modest amounts
of vitamins and trace elements. This has considerable clinical and public
health significance. We recommend that such a supplement be provided to all
elderly subjects because it should significantly improve cognition and thus
quality of life and the ability to perform activities of daily living. Such
a nutritional approach may delay the onset of Alzheimer's disease."
[57a] Vitamin supplementation for 1 year improves mood. Benton D, Haller J,
Fordy J in Neuropsychobiology 1995;32(2):98-105 PMID: 7477807
"One hundred and twenty-nine young healthy adults took either 10 times the
recommended daily dose of 9 vitamins, or a placebo, under a double-blind
procedure, for a year."... "These changes in mood after a year occurred even
though the blood status of 9 vitamins reached a plateau after 3 months: this
improvement in mood was associated in particular with improved riboflavin
and pyridoxine status. In females baseline thiamin status was associated
with poor mood and an improvement in thiamin status after 3 months was
associated with improved mood"
[57b] Improvement of fine motoric movement control by elevated dosages of
vitamin B1, B6, and B12 in target shooting. Bonke D, Nickel B in Int J
Vitam Nutr Res Suppl 1989;30:198-204 PMID: 2507698
"In both studies, marksmen in the vitamin-treated groups showed
statistically significant, considerably improved firing accuracy as measured
by the number of points achieved within a series of 20 shots at each
examination. In study 2 the degree of improvement was linearly dependent on
the duration of vitamin treatment"
[58a] The effects of an oral multivitamin combination with calcium,
magnesium, and zinc on psychological well-being in healthy young male
volunteers: a double-blind placebo-controlled trial. Carroll D, Ring C,
Suter M, Willemsen G in Psychopharmacology (Berl) 2000 Jun;150(2):220-5
PMID: 10907676
"These findings demonstrate that Berocca [a multivitamin and mineral
supplement] significantly reduces anxiety and perceived stress."
[58b] The effects of high oral magnesium supplementation on blood pressure,
serum lipids and related variables in apparently healthy Japanese subjects.
Itoh K, Kawasaka T, Nakamura M in Br J Nutr 1997 Nov;78(5):737-50 PMID:
9389897
"In a double-blind, placebo-controlled study, thirty-three subjects were
allocated to undergo either a 4-week treatment with oral Mg supplementation
(Mg(OH)2; 411-548 mg Mg/d) or a placebo. [] The total
cholesterol:HDL-cholesterol ratio decreased significantly during the last 2
weeks of Mg supplementation compared with the first 2 weeks and the run-in
periods, but this did not occur in the placebo group. These results suggest
that Mg supplementation may lower blood pressure through the suppression of
the adrenergic activity and possible natriuresis, while also improving the
serum lipids through the activation of LCAT [lecithin-cholesterol
acyltransferase] in human subjects."
[59] Effect of vitamin and trace element supplementation on immune indices
in healthy elderly. Pike J, Chandra RK in Int J Vitam Nutr Res
1995;65(2):117-21 PMID: 7591530
"Supplementation with micronutrients can play a crucial role in the
maintenance of normal immune function in the elderly."
[60a] Nucleotides as immunomodulators in clinical nutrition. Grimble GK,
Westwood OM in Curr Opin Clin Nutr Metab Care 2001 Jan;4(1):57-64 PMID:
11122561
"supplementation of infant formula milk leads to improved growth and reduced
susceptibility to infection. Animal studies have confirmed some of these
data." . "Nucleotide supplementation has also been shown to improve some
aspects of tissue recovery from ischaemia/reperfusion injury or radical
resection." . "We propose that dietary nucleotides should be considered
within a pharmacological and metabolic framework."
[60b] Dietary nucleotides prevent decrease in cellular immunity in
ground-based microgravity analog. Yamauchi K, Hales NW, Robinson SM,
Niehoff ML, Ramesh V, Pellis NR, Kulkarni AD in J Appl Physiol 2002
Jul;93(1):161-6 PMID: 12070200
"These results suggest that exogenous nucleotide supplementation, especially
uracil, of normal diet is beneficial in the maintenance and restoration of
the immune response".
[61] Plasma-Saturating intakes of vitamin C confer maximal antioxidant
protection to plasma. Johnston CS, Cox SK in J Am Coll Nutr 2001
Dec;20(6):623-7 PMID: 11771678
"Significant decreases in markers of oxidative stress were noted at the 500
mg, 1,000 mg and 2,000 mg dosages versus placebo. Antioxidant protection was
similar at the 1,000 mg and 2,000 mg dosage. CONCLUSIONS: These data
indicate that the antioxidant protection afforded by short-term vitamin C
supplementation is maximal at the 500-1,000 mg dosage range."
OBJECTIVE: Supplemental vitamin C has been shown to reduce oxidative damage
in vivo, yet the dose-response relationship between vitamin C intake and
antioxidant protection is not known. This report examined blood indicators
of oxidative stress in subjects consuming graded doses of vitamin C, from 75
to 2,000 mg/day. METHODS: Ten healthy, non-smoking men and women (26.1 +/-
2.1 years) were recruited from a campus population. During the ten-week
study, subjects limited fruit and vegetable consumption (< or = 3
servings/day) and consumed a multivitamin and mineral pill daily. Beginning
at week 3, subjects ingested either a vitamin C (n = 8) or placebo (n = 2)
capsule, which were identical in appearance and taste. The content of the
vitamin C capsule increased every two weeks (from 250 mg at weeks 3-4 to 500
mg, 1,000 mg. and 2,000 mg at weeks 5-6. 7-8. 9-10, respectively). Fasting
blood samples were collected at two-week intervals and analyzed for vitamin
C, total lipid hydroperoxides and Heinz bodies in packed erythrocytes
incubated 24 hours at 37 degrees. RESULTS: Plasma vitamin C rose 55% in
vitamin C-supplemented subjects by the end of the ten-week treatment (p <
0.05), and measures of oxidative stress decreased 60% to 90% (8.1 +/- 0.6 to
3.5 +/- 0.4 nmol/mL and 69.1 +/- 7.8% to 6.7 +/- 6.0% for total lipid
hydroperoxides and Heinz bodies, respectively). Significant decreases in
markers of oxidative stress were noted at the 500 mg, 1,000 mg and 2,000 mg
dosages versus placebo. Antioxidant protection was similar at the 1,000 mg
and 2,000 mg dosage. CONCLUSIONS: These data indicate that the antioxidant
protection afforded by short-term vitamin C supplementation is maximal at
the 500-1,000 mg dosage range.
[82a] Vitamins for chronic disease prevention in adults: clinical
applications. Fletcher RH, Fairfield KM in JAMA 2002 Jun 19;287(23):3127-9
PMID: 12069676
"Most people do not consume an optimal amount of all vitamins by diet alone.
Pending strong evidence of effectiveness from randomized trials, it appears
prudent for all adults to take vitamin supplements.[..] We recommend that
all adults take one multivitamin daily.[...] It is reasonable to consider a
dose of 2 ordinary [i.e. RDA levels] multivitamins daily in the elderly"
[82b] Vitamins for chronic disease prevention in adults: scientific review.
Fairfield KM, Fletcher RH in JAMA 2002 Jun 19;287(23):3116-26 PMID:
12069675
"Although the clinical syndromes of vitamin deficiencies are unusual in
Western societies, suboptimal vitamin status is not [unusual]."
[136] Dietary niacin and the risk of incident Alzheimer's disease and of
cognitive decline. J Neurol Neurosurg Psychiatry. 2004 Aug;75(8):1093-9 by
Morris MC, Evans DA, Bienias JL, Scherr PA, Tangney CC, Hebert LE, Bennett
DA, Wilson RS, Aggarwal N. PMID: 15258207
"BACKGROUND: Dementia can be caused by severe niacin insufficiency, but it
is unknown whether variation in intake of niacin in the usual diet is linked
to neurodegenerative decline. We examined whether dietary intake of niacin
was associated with incident Alzheimer's disease (AD) and cognitive decline
in a large, prospective study. [.] CONCLUSION: Dietary niacin may protect
against AD and age related cognitive decline."
"The protective association with higher niacin intake became stronger (p for
trend = 0.04) after further adjustment for multivitamin use and intake of
the antioxidant nutrients (vitamin C, beta-carotene, or vitamin E from food
sources) that were found in previous reports to be possibly protective
against AD.
Intake of niacin from foods had an inverse association with AD in the basic
adjusted model (p for trend = 0.002) (table 2). Participants in intake
quintiles 2-4 had 70% reductions in risk compared with those in the lowest
quintile (median intake 12.6mg/day [0.84 RDA]), whereas participants in the
highest fifth of intake (median 22.4mg/day [1.49 RDA]) had an 80% reduction
in risk; all were statistically significant. The relative risks were only
slight less protective in the multiple adjusted model [which included the
B-vitamins B1, B2, B6, B12, folate] and remained statistically significant."
So taking 1.49 of the RDA of niacin over 0.84 caused a five-fold reduction
the risk of Alzheimer's; the rate of cognitive decline (from all causes)
across the whole population was also lowest in the highest quintile, at 44%
of the rate of decline in the lowest quintile.
Lowest Quintile: 13.2-27mg niacin equivalents, higher than the RDA of
16/14mg/d and the 8.8mg/d/2000kcal below which pellagra is apparent (the
classic definition of "deficiency").
Tim Tyler
> Prometheus writes:
> > Thanks for the info Michael. I appreciate the point you are making
> > with the use of nutritional supplementation. I am not suggesting
> > supplementation does not have any effect - fabulous effects are
> > observed on nutritionally deficient animals when they are
> > supplemented with the nutritional factors that are absent from their
> > diet.
>
> The LS studies I cited all had non-deficient controls.
>
> You are making the same assumption that almost everyone
> else makes (for a variety of ill-thought out reasons), namely
> that any nutritional experiment that shows a positive result
> must have had classically deficient controls. Tell me why
> you believe this and I'll tell you why you're wrong :-)
Life extension can be difficult. Many lifespan studies with
positive results can actually be explained by the controls
exhibiting illness, genetic problems or other disorders that
produce artificially shortened lives.
One of the studies you cite - for example - used albino mice -
and it is known that albinos are more susceptable to a variety of
disorders - most notably they are likely to go deaf, get sunburn
and suffer from skin cancer.
In such cases there's the possibility that the supplementation
is correcting the disorder - and restoring more normal lifespans
to the diseased organisms. That's great - but it doesn't tell
us much about the effect of the intervention on individuals
without the disorder in question.
In other words, it isn't /just/ deficiencies of the nutrient
under study in the controls you have to check for - it's
practically anything that might artifically shorten their
lives.
Michael C Price
>
>>> Thanks for the info Michael. I appreciate the point you are
>>> making with the use of nutritional supplementation. I am not
>>> suggesting supplementation does not have any effect - fabulous
>>> effects are observed on nutritionally deficient animals when
>>> they are supplemented with the nutritional factors that are
>>> absent from their diet.
>>
>> The LS studies I cited all had non-deficient controls.
>>
>> You are making the same assumption that almost everyone
>> else makes (for a variety of ill-thought out reasons), namely
>> that any nutritional experiment that shows a positive result
>> must have had classically deficient controls. Tell me why
>> you believe this and I'll tell you why you're wrong :-)
>
> Life extension can be difficult. Many lifespan studies with
> positive results can actually be explained by the controls
> exhibiting illness, genetic problems or other disorders that
> produce artificially shortened lives.
True, but I have not included experiments where the controls
were genetically subnormal / deliberately bred for susceptibility
to certain diseases. You may have noticed I don't cite Evans'
chromium LS experiments anymore because the strain used may
have been susceptible to diabetes.
> One of the studies you cite - for example - used albino mice -
> and it is known that albinos are more susceptible to a variety
> of disorders - most notably they are likely to go deaf, get
> sunburn and suffer from skin cancer.
Cause of death was not reported, so we can only speculate.
Either way the experiment should be repeated on other
strains and species.
> In such cases there's the possibility that the supplementation
> is correcting the disorder - and restoring more normal lifespans
> to the diseased organisms. That's great - but it doesn't tell
> us much about the effect of the intervention on individuals
> without the disorder in question.
>
> In other words, it isn't /just/ deficiencies of the nutrient
> under study in the controls you have to check for - it's
> practically anything that might artifically shorten their
> lives.
I agree, with the caveat that we, also, suffer from multiple
deficiencies and disorders. Such interventions would help
us also, whether or not we believed they were slowing down
the aging process. Chromium is an example.
Tim Tyler
> > One of the studies you cite - for example - used albino mice -
> > and it is known that albinos are more susceptible to a variety
> > of disorders - most notably they are likely to go deaf, get
> > sunburn and suffer from skin cancer.
>
> Cause of death was not reported, so we can only speculate.
> Either way the experiment should be repeated on other
> strains and species.
Yes. Much as I like to see the results of LS studies, I'm conscious
that they are not the cheapest of things to perform - and I suspect
that funding issues are responsible for a lot of our current level
of ignorance in this general area.
> > In such cases there's the possibility that the supplementation
> > is correcting the disorder - and restoring more normal lifespans
> > to the diseased organisms. That's great - but it doesn't tell
> > us much about the effect of the intervention on individuals
> > without the disorder in question.
> >
> > In other words, it isn't /just/ deficiencies of the nutrient
> > under study in the controls you have to check for - it's
> > practically anything that might artifically shorten their
> > lives.
>
> I agree, with the caveat that we, also, suffer from multiple
> deficiencies and disorders. Such interventions would help
> us also, whether or not we believed they were slowing down
> the aging process. Chromium is an example.
Here it helps to know what you are doing. Because a medicine helps with
one particular disease, that doesn't say very much about it effects on
other disorders. It might be beneficial, neutral or deleterious.
Under those circumstances an approach that involves taking a nutrient
because it has extended the lifespans of a bunch of ill organisms
somewhere may not be recommended - unless you have the same illness
that they had.
Nutrients do fare a /little/ better than drugs in this context.
Tim
Larval juvenile hormone treatment affects pre-adult development, but
not adult age at onset of foraging in worker honey bees (Apis
mellifera).
Elekonich MM, Jez K, Ross AJ, Robinson GE.
Department of Entomology, University of Illinois at Urbana-Champaign,
Urbana, IL 61801, USA. elek...@ohio.edu
Previous research has shown that juvenile hormone (JH) titers increase
as adult worker honey bees age and treatments with JH, JH analogs and
JH mimics induce precocious foraging. Larvae from genotypes exhibiting
faster adult behavioral development had significantly higher levels of
juvenile hormone during the 2nd and 3rd larval instar. It is known
that highly increased JH during this period causes the totipotent
female larvae to differentiate into a queen. We treated third instar
larvae with JH to test the hypothesis that this time period may be a
developmental critical period for organizational effects of JH on
brain and behavior also in the worker caste, such that JH treatment at
a lower level than required to produce queens will speed adult
behavioral development in workers. Larval JH treatment did not
influence adult worker behavioral development. However, it made
pre-adult development more queen-like in two ways: treated larvae were
capped sooner by adult bees, and emerged from pupation earlier. These
results suggest that some aspects of honey bee behavioral development
may be relatively insensitive to pre-adult perturbation. These results
also suggest JH titer may be connected to cues perceived by the adult
bees indicating larval readiness for pupation resulting in adult bee
cell capping behavior.
PMID: 12769989 [PubMed - indexed for MEDLINE]
Interestingly a paper I read suggested that the Paleozoic gigantism
and flight both by insects and birds developed during hyperoxic
periods of earth's climatic history.
Tim
Prometheus
Not if we want to isolate the effects a lifespan intervention will
have without involving the mechanisms of diapause.
Prometheus
> haven't seen the studies I've collected that demonstrate supra-
> RDA benefits on nutritionally replete (= non classically
> deficient) humans.
> Have a look at
> http://mcp.longevity-report.com
> If you want a more up to date version, I'll email you my working
> copy.
I am aware of your report, and thank you, I would be interested in
your latest working copy.
Don't misunderstand my approach Michael. I too at one stage immersed
myself in the science of optimizing supplementation as a solution
towards modulating regenerative competence. My conclusion was that the
status quo of the cell, tissue and organism are genetically defined
and predestined to act within a defined operational boundary.
Consequently any intervention seeking to take the cell outside of
those parameters had to act upon the genome itself.
I also wish to point out that I am not contentious of your work or
your theories. I am however eager to see progress in what I see as the
most rapid way to accelerate the process of discovery in this area.
>
> > No amount of supplementation is going to extend lifespan beyond the
> > maximum normal range unless fundamental alterations in gene regulation
> > take place that instruct the cell to behave in a manner entirely
> > different to what it is predestined for.
>
> How do you know that? You are assuming zero cost in evolutionary
> terms for the foraging of nutrients and biosynthesis of coenzymes.
> Something we know is incorrect.
>
> > For instance no supplement
> > that I am aware of will cause a cell to become immortalized unless the
> > supplement is mutagenic.
>
> Immortalised?? Straw-man argument. All we talking about here is
> *slowing* the aging process not turning them into supermites.
I think it is important that you grasp my meaning here. I used cell
immortalization as a tangible but non lethal example of a fundamental
alteration in cell behavior. Do you have evidence of supplements that
will influence a cell to act in this way?
Prometheus
Points 1 -3 are of course valid in the selection of a model organism,
and providing that the objective is to address human biology and human
health the degree of conservation between the gene(s) and mechanism(s)
in the organism being studied and that of humans is also of
importance.
Ultimately in any experimental design all the pros and cons have to be
accounted for in model organism selection such as the experience that
the investigators themselves have as well the resources of the lab. In
many cases use of experimental animals have to also be approved by
ethics committees.
Michael C Price
>>>>> Would you be so kind as to explain exactly what it is
>>>>> that makes sense about using ametabolous insects?
>>>>
>>>> We resemble ametabolous insects more than
>>>> metabolous insects. Mites aren't insects but the
>>>> same argument applies
>> [...]
>>> Michael if you ask Aubrey about the ametabolous issue I think
>>> you will find he was referring to the problem of differentiating
>>> between the lifespan extension mediated between diapause and
>>> the experimental intervention.
>>
>> I will ask, but the distinction strikes me as irrelevant.
>> Aren't these all different sides of the same coin??
>>
>
> have without involving the mechanisms of diapause.
I think you must have misunderstood my meaning, since we are in
agreement about this.
If we pick an ametabolous insect (or arthopod) -- hence no
developmental diapause -- that also doesn't experience seasonal or
starvation induced diapause then we don't have to worry about
these effects that humans don't experience.
Michael C Price
>> You are new to sci.life-extension, I believe, so you probably
>> haven't seen the studies I've collected that demonstrate supra-
>> RDA benefits on nutritionally replete (= non classically
>> deficient) humans.
>> Have a look at
>> http://mcp.longevity-report.com
>> If you want a more up to date version, I'll email you my working
>> copy.
>
> I am aware of your report, and thank you, I would be interested in
> your latest working copy.
Will send it.
> Don't misunderstand my approach Michael. I too at one stage immersed
> myself in the science of optimizing supplementation as a solution
> towards modulating regenerative competence. My conclusion was that
> the status quo of the cell, tissue and organism are genetically defined
> and predestined to act within a defined operational boundary.
How did you reach that conclusion? Empirically or on the basis
of theoretical considerations? You didn't answer the question I asked:
"How do you know that? You are assuming zero cost in evolutionary
terms for the foraging of nutrients and biosynthesis of coenzymes.
Something we know is incorrect."
> Consequently any intervention seeking to take the cell outside of
> those parameters had to act upon the genome itself.
>
> I also wish to point out that I am not contentious of your work or
> your theories. I am however eager to see progress in what I see as the
> most rapid way to accelerate the process of discovery in this area.
>>
>>> No amount of supplementation is going to extend lifespan beyond the
>>> maximum normal range unless fundamental alterations in gene regulation
>>> take place that instruct the cell to behave in a manner entirely
>>> different to what it is predestined for.
>>
>> How do you know that? You are assuming zero cost in evolutionary
>> terms for the foraging of nutrients and biosynthesis of coenzymes.
>> Something we know is incorrect.
>>
>>> For instance no supplement that I am aware of will cause
>>> a cell to become immortalized unless the supplement is
>>> mutagenic.
>>
>> Immortalised?? Straw-man argument. All we talking about here is
>> *slowing* the aging process not turning them into supermites.
>
> I think it is important that you grasp my meaning here. I used cell
> immortalization as a tangible but non lethal example of a fundamental
> alteration in cell behavior. Do you have evidence of supplements that
> will influence a cell to act in this way?
No, and why do you ask? Do you think that any LE requires cell
immortalisation? Why do you believe that slowing the aging process
requires "a fundamental alteration in cell behavior."
Prometheus
> > I think it is important that you grasp my meaning here. I used cell
> > immortalization as a tangible but non lethal example of a fundamental
> > alteration in cell behavior. Do you have evidence of supplements that
> > will influence a cell to act in this way?
>
> No, and why do you ask? Do you think that any LE requires cell
> immortalisation? Why do you believe that slowing the aging process
> requires "a fundamental alteration in cell behavior."
>
Let me explain by using one of the known effects of aging as an
example - age related stem cell depletion.
We know that somatic cells are constrained by the Hayflick limit and
were it not for stem cell reservoirs in various organ niches most
tissues would begin to degenerate far quicker - in some cases such as
certain epithelial regions of the gastrointestinal system - within
days. Over time the stem cell reservoirs dry up and there is a
decrease in the rate of regeneration. An "improved" stem cell system
would require that (a) it sustain a normal rate of stem cell
production for a longer period of time and that (b) stem cell targets
could be diversified such that tissues that are stem cell "starved"
would also benefit from regeneration.
The facilitation of (a) would be an brought about by an analysis of
the regulatory systems associated with age related stem cell depletion
such as microarray expression studies. Having isolated the regulatory
cause, say DNA damage, a solution could be engineered to compensate
for the deficiency, by perhaps increased expression of specific DNA
repair genes. The facilitation of (b) would require that the stem cell
express new or additional cell surface proteins to enable it to
localize to areas that it normally would not go to.
In both cases we would be looking at changing the regulation and
expression of specific genes. Presently, the only way we know to do
that in a safe way is to insert a non-recombining DNA construct in the
cell.
I have gone to this length so that I can illustrate what I mean by a
fundamental alteration in cell behavior. With increased understanding
of cell physiology and genetics, we can discover novel solutions for
modulating cell function. The more precise our understanding is, the
more specific the technical solution potentially becomes. I agree it
would be terrific and effortless to be able to ingest a nutritional
substance that can find its way into most cells and trigger a cascade
that unleashes substantive longevity function. But I don't think such
a substance has been discovered and neither do I feel it will ever be
discovered. It would imply that cells have evolved with receptors that
could potentially trigger dramatic yet highly specific changes in gene
regulation from commonly found molecules. The only such known
substances are teratogens and carcinogens and their changes are far
from subtle.
On the one end of the spectrum of influencing cell behavior we have
nutritional interventions, which have a limited scope of effect and
very little or no influence of gene regulation and on the other side
we have substances such as carcinogens which have a dramatic influence
on gene regulation - like a sledge hammer. What we need lies between
these two extremes.
Michael C Price
>>> immortalization as a tangible but non lethal example of a fundamental
>>> alteration in cell behavior. Do you have evidence of supplements that
>>> will influence a cell to act in this way?
>>
>> No, and why do you ask? Do you think that any LE requires cell
>> immortalisation? Why do you believe that slowing the aging process
>> requires "a fundamental alteration in cell behavior."
>>
> Thanks for the doc.
You're welcome.
> Let me explain by using one of the known effects of aging as an
> example - age related stem cell depletion.
I understand your meaning. The problem I have with it that your example
is full of unverified hypotheses and assumptions. For instance how do
you know that stem cell vitality can't be extended by simple vitamin
supplementation? You mention the GI tract as possibility the most
dependent (over a time scale of weeks) on stem cell replenishment
-- yet colon cancer is reduced by 75% with 15 years of folate
supplementation [11]. This suggests that the master stem cell
DNA integrity is preserved or radically enhanced with extra folate
(probably via suppression of inappropriate uraecil misincorporation
into the DNA during stem cell replication).
You say
> Having isolated the regulatory cause, say DNA damage,
I have no problem with the putative cause. But why do you
propose such complex, unavailable interventions as:
> a solution could be engineered to compensate for the deficiency,
> by perhaps increased expression of specific DNA repair genes.
when the obvious solution is to simply take extra folate[11,25].
Extra niacin would also help maintain DNA integrity through up-
regulation of PARP activity [27], along no doubt :-), with the other
B-vitamins and minerals.
> I agree it
> would be terrific and effortless to be able to ingest a nutritional
> substance that can find its way into most cells and trigger a cascade
> that unleashes substantive longevity function. But I don't think such
> a substance has been discovered and neither do I feel it will ever be
> discovered. It would imply that cells have evolved with receptors that
> could potentially trigger dramatic yet highly specific changes in gene
> regulation from commonly found molecules.
No, all it implies is that our metabolism operates in environment that is
sub-optimal with respect to the levels of enzymic cofactors derived from a
natural diet (modern and paleolithic). That we have evolved to optimise
our gathering and processing of micronutrients does *not* imply that the
levels of micronutrients in our diet (modern and paleolithic) are optimal.
Especially nowadays that we can just buy such micronutrients with
very little associated downside. I no longer have to kill (and risk being
killed by) a woolly mammoth to get my vitamin B12.
You have prompted me to update a section of my report:
Natural Diet is not Optimal
The switch from a hunter-gather diet (nuts, berries, wild game, roots) to
one based on agriculture, about 7000 years ago in the Middle East, was
accompanied by a drop in average height of up to 6 inches (only regained in
the West during the 20th Century28a); a compelling sign that the reduced
food diversity that accompanies agricultural abundance resulted in
widespread chronic malnourishment. What about modern diets, are they
optimally healthy? Supplying more than the RDA of many micronutrients to
already healthy people further improves their health, as demonstrated by
many placebo-controlled trials47-61 and epidemiological studies11-14, a view
finally endorsed in a JAMA review82. This demonstrates that our modern
diet, although superior to any since hunter-gatherer days, still borders on
malnourishment.
What about the pre-agricultural-farming Palaeolithic hunter-gatherer diet,
perhaps that diet (nuts, berries, wild game, roots) was optimal? That we
have deviated from this 'natural' diet is beyond dispute. If only, the myth
says, we would eat like cavemen, we would be much healthier. The belief
that the 'natural' diet is optimal seems to arise from a misunderstanding of
evolution. The argument runs thus: we have evolved to optimise the
metabolising of dietary micronutrients; therefore the amounts of various
micronutrients in our natural diet must be optimal. This is a simply faulty
logic - the conclusion (amounts of various micronutrients in our diet must
be optimal) doesn't follow from the premise (we have evolved to optimise the
metabolising of dietary micronutrients). That we have evolved to optimise
our gathering and processing of micronutrients does *not* imply that the
levels of micronutrients in our diet (modern and paleolithic) are optimal.
Especially nowadays that we can just buy such micronutrients with very
little associated downside risk. I no longer have to kill (and risk being
killed by) a woolly mammoth to get my vitamin B12, for instance. This is an
elementary error of logic that evolutionary biologists and nutritionists
continue to make.
The same illogic applies to macronutrients, where it is easier to
demonstrate this fallacy. Water is a macronutrient, which our thirst
mechanism fails to regulate optimally, leaving us marginally, chronically
dehydrated76. For our savannah ancestors paying a visit to the watering
hole was an expensive, time-consuming and risky activity due to increased
exposure to waterhole predation, water-borne parasites and diseases; under
these circumstances partial dehydration is a worthwhile trade-off. Our
thirst mechanism is not adjusted, in the evolutionary sense, to the
availability of clean, cheap water in the modern world; drinking more water
than we naturally feel inclined to may be beneficial to our health75.
The same is true for feeding. Feeding, for most of our evolutionary
history, has been an expensive, risky activity, involving a number of
trade-offs, forcing a compromise with marginal malnutrition. Herbivores
face increased predation whilst grazing and carnivores risk injury whilst
hunting, for example. This makes feeding a risky activity. Feeding halts
when the marginal benefit of the extra calories is outweighed by the
associated foraging risks; marginal malnourishment, due to inadequate
amounts of some or all micronutrients in the diet, will not necessarily
generate a feeling of hunger.
[11a] Multivitamin use, folate, and colon cancer in women in the Nurses'
Health Study. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C,
Rosner BA, Speizer FE, Willett WC in Ann Intern Med 1998 Oct 1;129(7):517-24
PMID: 9758570
Long-term use (>15 years) of folate supplements produced a 4-fold reduction
in the incidence of colon cancer. Other cancers not analysed. The
protective effect (relative to age-matched controls) increased with the
duration of supplementation.
[11b] Are dietary factors involved in DNA methylation associated with colon
cancer? Slattery ML, Schaffer D, Edwards SL, Ma KN, Potter JD in Nutr
Cancer 1997;28(1):52-62 PMID: 9200151
"We did not observe strong independent associations between folate, vitamin
B6, vitamin B12, methionine, or alcohol and risk of colon cancer after
adjusting for body size, physical activity, cigarette smoking patterns,
energy intake, and dietary intake of fiber and calcium. However, when
assessing the associations between colon cancer and a composite dietary
profile based on alcohol intake, methionine, folate, vitamin B12, and
vitamin B6, we observed a trend of increasing risk as one moved from a low-
to a high-risk group"
[11c] Dietary intake of folic acid and colorectal cancer risk in a cohort of
women. Terry P, Jain M, Miller AB, Howe GR, Rohan TE in Int J Cancer 2002
Feb 20;97(6):864-7 PMID: 11857369
"Folate is crucial for normal DNA methylation, synthesis and repair, and
deficiency of this nutrient is hypothesized to lead to cancer through
disruption of these processes. There is some evidence to suggest that
relatively high dietary folate intake might be associated with reduced
colorectal cancer risk, especially among individuals with low methionine
intake. [.] Folate intake was inversely associated with colorectal cancer
risk (IRR = 0.6, 95% CI = 0.4-1.1, p for trend = 0.25). The inverse
association was essentially similar among individuals with low and high
methionine intake, and was similar for colon and rectal cancers when those
endpoints were analyzed separately. Among individuals with low methionine
intake, folate intake did not appear to lower the risk of rectal cancer, a
finding that may be due, in part, to the low number of cases in the subgroup
analysis. Overall, our data lend some support to the hypothesis that high
folate intake is associated with a reduced risk of colorectal cancer.
Copyright 2001 Wiley-Liss, Inc."
[25a] Folate deficiency causes uracil misincorporation into human DNA and
chromosome breakage: Implications for cancer and neuronal damage. Blount
BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G, Wickramasinghe SN,
Everson RB, Ames BN in Proc Natl Acad Sci USA 94 (1997) pp 3290-3295 PMID:
9096386
"Folate deficiency causes massive incorporation of uracil into human DNA (4
million per cell) and chromosome breaks. The likely mechanism is the
deficient methylation of dUMP to dTMP and subsequent incorporation of uracil
into DNA by DNA polymerase. During repair of uracil in DNA, transient nicks
are formed; two opposing nicks could lead to chromosome breaks. Both high
DNA uracil levels and elevated micronucleus frequency (a measure of
chromosome breaks) are reversed by folate administration. A significant
proportion of the U.S. population has low folate levels, in the range
associated with elevated uracil misincorporation and chromosome breaks. Such
breaks could contribute to the increased risk of cancer and cognitive
defects associated with folate deficiency in humans."
[25b] DNA damage in folate deficiency. Blount BC, Ames BN in Baillieres
Clin Haematol 1995 Sep;8(3):461-78 PMID: 8534957
"Folate deficiency significantly increases uracil content and chromosome
breaks (as measured by micronucleated cells) in human leukocyte DNA. Folate
supplementation reduces both the uracil content of DNA and the frequency of
micronucleated cells, indicating that uracil misincorporation may play a
causative role in folate deficiency-induced chromosome breaks. A calculation
is presented to explain how the levels of uracil found in DNA could cause
chromosome breaks. Based on this calculation, the frequency of uracil repair
events that might result in double-strand DNA breaks increases by 1752-fold.
These results are consistent with clinical and epidemiological evidence
linking folate deficiency to DNA damage and cancer."
[27a] Requirement of NAD and SIR2 for life-span extension by calorie
restriction in Saccharomyces cerevisiae. Lin SJ, Defossez PA, Guarente L in
Science 2000 Sep 22;289(5487):2126-2128 PMID: 11000115
[27b] Manipulation of a Nuclear NAD+ Salvage Pathway Delays Aging without
Altering Steady-state NAD+ Levels. Anderson RM, Bitterman KJ, Wood JG,
Medvedik O, Cohen H, Lin SS, Manchester JK, Gordon JI, Sinclair DA in J Biol
Chem 2002 May 24;277(21):18881-90. PMID: 11884393
[27c] Oral Niacin Prevents Photocarcinogenesis and Photoimmunosuppression in
mice. Gensler HL, Williams T, Huang AC, Jacobson EL in Nutrition and Cancer
34(1) (1999), pg 36-41. PMID: 10453439
The relationship between dietary intake of niacin and tissue NAD elevation
is detailed in the main body of the article. The UV-irradiated mice on a
diet with 0.003%, 0.1%, 0.5% & 1.0% niacin had a 0.72, 0.60, 0.48 & 0.40
tumours/mouse, respectively; a 44% reduction. The authors hypothesize that
the cancer-protective effect is mediated by NAD-induced PARP activity.
[27d] Mapping the role of NAD metabolism in prevention and treatment of
carcinogenesis. Jacobson EL, Shieh WM, Huang AC in Mol Cell Biochem 1999
Mar;193(1-2):69-74 PMID: 10331640
NAD is elevated by niacin in many human tissues.
[27e] Evaluating the role of niacin in human carcinogenesis. Jacobson EL,
Dame AJ, Pyrek JS, Jacobson MK. Biochimie 1995;77(5):394-8 PMID: 8527495
"NAD content varies by as much as 12-fold within a [human] population and
can be modulated readily by supplementation [with niacin]"
[27f] Protective effect of nicotinamide on bracken fern induced
carcinogenicity in rats. Pamukcu AM, Milli U, Bryan GT in Nutr Cancer
1981;3(2):86-93 PMID: 6213941
0.5% nicotinamide in diet cut the induced cancer rate by 40%
[27g] Fifteen year mortality in Coronary Drug Project patients: long-term
benefit with niacin. Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L,
Prineas RJ, Friedewald W in J Am Coll Cardiol 1986 Dec;8(6):1245-55 PMID:
3782631
"With a mean follow-up of 15 years, nearly 9 years after termination of the
trial, mortality from all causes in each of the drug groups, except for
niacin, was similar to that in the placebo group. Mortality in the niacin
group was 11% lower than in the placebo group (52.0 versus 58.2%; p =
0.0004)."
[27h] Pharmacological intakes of niacin increase bone marrow
poly(ADP-ribose) and the latency of ethylnitrosourea-induced carcinogenesis
in rats. Boyonoski AC, Spronck JC, Jacobs RM, Shah GM, Poirier GG, Kirkland
JB in J Nutr 2002 Jan;132(1):115-20 PMID: 11773517
"This study was designed to test the effects of supplementing an already
high quality diet with pharmacologic levels of niacin. [...] Supplementation
with NA or Nam at 4.0 g/kg diet (combined analysis) increased the latency of
the ENU-induced morbidity curve, relative to niacin-adequate controls.
Morbidity could be attributed in almost all cases to some form of neoplasm,
with leukemias the predominant form. In short-term studies, supplementation
with either NA or Nam caused dramatic increases in bone marrow NAD(+) (1- to
1.5-fold), basal poly(ADP-ribose) (3- to 5-fold) and ENU-induced
poly(ADP-ribose) levels (1.5-fold). These data show that supplementation of
a niacin-adequate, high quality diet with pharmacologic levels of nicotinic
acid or nicotinamide increases NAD(+) and poly(ADP-ribose) levels in bone
marrow and may be protective against DNA damage."
Michael C Price
> You mention the GI tract as possibility the mostdependent
> (over a time scale of weeks) on stem cell replenishment
> -- yet colon cancer is reduced by 75% with 15 years of
> folate supplementation [11].
Re-reading one of the references [11a] I see that the protective
effect against colon cancer (which is actually higher, at 78%, compared
with controls who already folate-RDA-replete) could have been due to
other components in the multivitamin supplements.
I have re-summarised the study:
[11a] Multivitamin use, folate, and colon cancer in women in the Nurses'
Health Study. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C,
Rosner BA, Speizer FE, Willett WC in Ann Intern Med 1998 Oct 1;129(7):517-24
PMID: 9758570
Long-term use (>15 years) of folate-containing multivitamin supplements
produced an almost 5-fold reduction in the incidence of colon cancer. Other
cancers not analysed. The protective effect (relative to age-matched
controls) increased with the duration of supplementation. The relative risk
of colon cancer over the period 1980-1994 (against folate intake in 1980,
without adjusting for other vitamins) was: 1.0 (<= 200 ug/d), 0.92 (201-300
ug/d), 0.79 (301-400 ug/d) & 0.69 (>400 ug/d). This risk declined with
time: comparing the >400 with the <=200 folate ug/d group the risk declined
from 0.85 (1980-mid1988) to 0.56 (mid1988-1994).
Amongst multivitamin users (pooling all folate categories) the risk declined
with duration of use: 1.02 (4 years use), 0.83 (5-9yrs), 0.80 (10-14 yrs) &
0.25 (15+ yrs). Women who had 15+ years of multivitamin use and >300 ug/d
energy-adjusted folate (in 1980) had a RR of only 0.22[CI: 0.05-0.88]
compared with users with <15 years multivitamin use and 201-300 ug/d (>RDA)
of energy-adjusted folate. FDA regulations forbad the use of 400ug of
folate in multivitamin supplements prior to 1973, which limited the ability
for a longer -term follow-up. The study abstract concludes: "Long-term use
of multivitamins may substantially reduce risk for colon cancer. This effect
may be related to the folic acid contained in multivitamins."
Cheers,
Michael C Price
----------------------------------------
http://mcp.longevity-report.com
http://www.hedweb.com/manworld.htm
"Michael C Price" <michaelEXCI...@ntlworld.com> wrote in message
news:HTJRc.70$Bo5...@newsfe4-gui.ntli.net...
Prometheus
Thanks for the presentation of your arguments and the supporting
evidence.
Please consider the following and respond: in the case of the
accelerated aging disorder, Werner's Syndrome, where the causative
factor is known to be an increased incidence of DNA replication errors
due to an inherited mutation of the the RecQ helicase gene, what is
the extent of benefits that nutritional support would offer above and
beyond diet regimes followed by patients of similar disposition?
I suspect that the difference between supplement megadosing and
optimal nutritional support may not be all that different and
furthermore, supplement megadosing would have to take into
consideration the individuals unique genetic profile to attempt to
compensate for inborn deficiencies. Ultimately, however, the
limitation is in moving beyond the constraints imposed by the genome
and in my opinion this can only be induced by genomic interventions.
>
> You have prompted me to update a section of my report:
>
> Natural Diet is not Optimal
>
> The switch from a hunter-gather diet (nuts, berries, wild game, roots) to
> one based on agriculture, about 7000 years ago in the Middle East, was
> accompanied by a drop in average height of up to 6 inches (only regained in
> the West during the 20th Century28a); a compelling sign that the reduced
> food diversity that accompanies agricultural abundance resulted in
> widespread chronic malnourishment. What about modern diets, are they
> optimally healthy? Supplying more than the RDA of many micronutrients to
> already healthy people further improves their health, as demonstrated by
> many placebo-controlled trials47-61 and epidemiological studies11-14, a view
> finally endorsed in a JAMA review82. This demonstrates that our modern
> diet, although superior to any since hunter-gatherer days, still borders on
> malnourishment.
I entirely agree that nutritional optimization, particularly taking
into account genetic typing is of read benefit to individuals. I
question, however, the degree of LE that can be achieved using this
strategy alone.
Agree.
>
> The same is true for feeding. Feeding, for most of our evolutionary
> history, has been an expensive, risky activity, involving a number of
> trade-offs, forcing a compromise with marginal malnutrition. Herbivores
> face increased predation whilst grazing and carnivores risk injury whilst
> hunting, for example. This makes feeding a risky activity. Feeding halts
> when the marginal benefit of the extra calories is outweighed by the
> associated foraging risks; marginal malnourishment, due to inadequate
> amounts of some or all micronutrients in the diet, will not necessarily
> generate a feeling of hunger.
Agree.
>
> [11a] Multivitamin use, folate, and colon cancer in women in the Nurses'
> Health Study. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C,
> Rosner BA, Speizer FE, Willett WC in Ann Intern Med 1998 Oct 1;129(7):517-24
> PMID: 9758570
> Long-term use (>15 years) of folate supplements produced a 4-fold reduction
> in the incidence of colon cancer. Other cancers not analysed. The
> protective effect (relative to age-matched controls) increased with the
> duration of supplementation.
Yes folate in my opinion deserves more investigation, particularly in
patients where homocysteine levels are elevated. It is possible that
many people are folate starved.
Michael C Price
>> That we have evolved to optimise our gathering and processing
>> of micronutrients does *not* imply that the levels of
>> micronutrients in our diet (modern and paleolithic) are optimal.
>> Especially nowadays that we can just buy such micronutrients
>> with very little associated downside. I no longer have to kill
>> (and risk being killed by) a woolly mammoth to get my vitamin
>> B12.
>
> Thanks for the presentation of your arguments and the supporting
> evidence.
> Please consider the following and respond: in the case of the
> accelerated aging disorder, Werner's Syndrome, where the causative
> factor is known to be an increased incidence of DNA replication
> errors due to an inherited mutation of the RecQ helicase gene,
> what is the extent of benefits that nutritional support would offer
> above and beyond diet regimes followed by patients of similar
> disposition?
My guess is that megadosing will offer some benefits to WS patients,
-- although I know and care more about the effect on normals --
but that their condition will still progress unfavourably. As it will for
normal patients who suffer from 'normal' aging. Megadosing will
not stop either WS or 'normal' aging, but it may slow the progression
of both.
> I suspect that the difference between supplement megadosing
> and optimal nutritional support may not be all that different
The use of the word 'optimal' is begging the question.
I believe that megadosing in the appropriate supplements is
optimal, but I doubt that is what you mean by it.
> and
> furthermore, supplement megadosing would have to take into
> consideration the individuals unique genetic profile to attempt to
> compensate for inborn deficiencies.
Of course. We are all genetic individuals.
> Ultimately, however, the limitation is in moving beyond the
> constraints imposed by the genome and in my opinion this can
> only be induced by genomic interventions.
Of course, but that's not a reason not to megadose in the
meantime.
Ultimately we are talking about uploading, but what I'm
concerned about *now* is what I can take *now*,
which seems to just be megadoses of B-vitamins and
some minerals and other dietary coenzyme precursors.
Plus, perhaps, a few xenobiotics, such ALT-711.
[...]
>
> I entirely agree that nutritional optimization, particularly taking
> into account genetic typing is of rea[l] benefit to individuals. I
> question, however, the degree of LE that can be achieved using
> this strategy alone.
Scepticism is always healthy, but even healthier if it has an
empirical basis. Do you have any studies that demonstrate that
megadosing with the appropriate supplements *wont'* extend LS
considerably? i.e. data that would actually falsify my hypothesis?
[.. why we have evolved to be malnourished...]
> Agree.
Thanks.
Re the folate and nurses study
[....]
>
> Yes folate in my opinion deserves more investigation, particularly in
> patients where homocysteine levels are elevated. It is possible that
> many people are folate starved.
Note, my re-analysis of this study, which indicates that the 78%
reduction in colon cancer incidence after long term supplementation
(relative to RDA-replete subjects) may have been due to a synergistic
effect of all the vitamins in the supplements, not just the folate, that
the nurses were taking. Perhaps we are not just folate starved, but
generally malnourished across the entire micronutrient spectrum.
[11a] Multivitamin use, folate, and colon cancer in women in the Nurses'
Health Study. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C,
Rosner BA, Speizer FE, Willett WC in Ann Intern Med 1998 Oct 1;129(7):517-24
PMID: 9758570
Long-term use (>15 years) of folate-containing multivitamin supplements
produced an almost 5-fold reduction in the incidence of colon cancer. Other
cancers not analysed. The protective effect (relative to age-matched
controls) increased with the duration of supplementation. The relative risk
of colon cancer over the period 1980-1994 (against folate intake in 1980,
without adjusting for other vitamins) was: 1.0 (<= 200 ug/d), 0.92 (201-300
ug/d), 0.79 (301-400 ug/d) & 0.69 (>400 ug/d). This risk declined with
time: comparing the >400 with the <=200 folate ug/d group the risk declined
from 0.85 (1980-mid1988) to 0.56 (mid1988-1994).
Amongst multivitamin users (pooling all folate categories) the risk declined
with duration of use: 1.02 (4 years use), 0.83 (5-9yrs), 0.80 (10-14 yrs) &
0.25 (15+ yrs). Women who had 15+ years of multivitamin use and >300 ug/d
energy-adjusted folate (in 1980) had a RR of only 0.22[CI: 0.05-0.88]
compared with users with <15 years multivitamin use and 201-300 ug/d (>RDA)
of energy-adjusted folate. FDA regulations forbad the use of 400ug of
folate in multivitamin supplements prior to 1973, which limited the ability
for a longer -term follow-up. The study abstract concludes: "Long-term use
of multivitamins may substantially reduce risk for colon cancer. This effect
may be related to the folic acid contained in multivitamins."
Cheers,
jayd...@aol.com
True, true... I would assume that the African fish Dr. de Grey
pointed out would win on this issue (genetic relevance), if only
because they are vertebrates. What are the relevances of the various
types of bugs (insects, arachnids (Michael's proposed mites), etc.)?
As for the wide variety of insects, has there been much in the way of
studies to show which orders (or indeed families) of insects tend to
be more geneticly related to humans? Is it pretty much the same across
the board? Are there any that are substantially better than diptera
(Drosophilidae) when it comes to genetic relevance?
> Ultimately in any experimental design all the pros and cons have to be
> accounted for in model organism selection such as the experience that
> the investigators themselves have as well the resources of the lab.
I think this factor more than any other weighs heavily in favor of
fruit flies. Discussion of mites, ladybugs, fish, etc., might be
interesting from a scientific standpoint. However, the point of this
prize isn't to launch a whole new field of study by making yet another
species get widespread scientific attention: we don't have the time or
resources for that. We need to focus on what we already know, and
build upon that.
Even if good results were made in a previously understudied species,
it would be harder for the scientific community to analyze the results
or to appreciate the accomplishment, given the lack of past
precedents. An extension of mice lifespan by 50% over the current
record would be considered *HUGE* (by past predecent), and would send
waves through the research community. A similar extention in flies
would be still be big, but not nearly as much of a surprise (given
past precedent); at least it would be quantifiable in some nebulous
sense.
However, the reaction in an understudied species would be more of "Was
this really a substantial result?". In essence, there would need to
be a lot of catch-up, not just in the understanding possessed the
scientists performing the experiments, but in the scientific
community's ability to judge the importance of those experiments.
> In many cases use of experimental animals have to also be approved by
> ethics committees.
Given the "low-end" species we're discussing, I don't see this being
an issue: at worst, the fish might be, because recent studies have
drawn the conclusion that fish do experience pain in a real sense.
However, I assume we're not going to be abusing them; at any rate, I
think mice would pose a more substantial ethical question than any of
the species we're considering. However, I assume you had something
specific in mind when pointing this out, Prometheus?
Jay Fox
Michael C Price
>
> True, true... I would assume that the African fish Dr. de Grey
> pointed out would win on this issue (genetic relevance), if only
> because they are vertebrates. What are the relevances of the various
> types of bugs (insects, arachnids (Michael's proposed mites), etc.)?
>
> As for the wide variety of insects, has there been much in the way of
> studies to show which orders (or indeed families) of insects tend to
> be more geneticly related to humans? Is it pretty much the same across
> the board?
We humans are equally related to all insects (& arthopods), since they
diversified within the arthropod phylum after the chordates had gone their
own way. All the *major* triploblastic (three-layered) phyla diverged from
each other at about the same time in the Cambrian explosion.
(Diploblasts = sponges, jellyfish...)
There are some surprising relationships. We are more closely related to
trout than trout are to lungfishes. Fungi are more closely related to us
than to higher plants.
jayd...@aol.com
> drosophila melanogaster (the fruit fly) as a model organism would be a
> more viable alternative to using the mouse for the Methuselah Prize
> competition. We could do with some added opinions on this topic as
> some of us are looking at starting a drosophila based prize should the
> Methuselah Foundation people choose to just stay with the mouse.
>
> What do you think: mouse, fly or both?
For those still interested in this thread,
I came across this article at Better Humans:
http://www.betterhumans.com/News/news.aspx?articleID=2004-08-09-3
Here's the "abstract" (I "quoted" it, not sure what the best method is
for these groups):
>> Looking for genes regulated by environmental stress has proven a
>> useful strategy for revealing genetic aspects of longevity.
>>
>> Using a gene-screening technique to find genes regulated by heat,
>> oxidants and starvation, researcher Seymour Benzer and colleagues
>> at the California Institute of Technology in Pasadena, California
>> found 13 candidate longevity genes and tweaked two to increase the
>> lifespan of fruit flies.
While these sorts of gene screening techniques could be applied to
mice, how long would it take to get the results? Luckily, negative
results would only take about.. oh, say, three years. Positive
results? A little longer...
The answer for fruit flies is simple: a couple months. And what were
the results in this study?
>> The researchers found 13 genes regulated by environmental stresses
>> whose functions are known to include free radical scavenging,
>> chaperoning and detoxification. Based on their responses to the
>> stresses, genes encoding the heat shock proteins hsp26 and hsp27
>> were chosen to test for their effects on lifespan.
>>
>> For this, the researchers generated a line of flies genetically
>> altered to overexpress the proteins. Overexpression of either
>> hsp26 or hsp27 extended the mean lifespan of the flies by 30%, and
>> the flies also displayed increased stress resistance.
>>
>> The findings show that stress screening can be used to find
>> longevity genes...
It is these sorts of things that convince me that a fly prize is
really the only viable option to complement the mouse prize.
Literally dozens of experiments are being performed at any given time
on fruit flies that relate directly or indirectly to longevity
enhancement at the genetic level. These experiments are all potential
competitors.
The tools are available: the process of manipulating genes in fruit
flies is long established. The groundwork has been laid: dozens of
candidate genes have been identified, with studies like this revealing
more on a regular basis. Moving forward with fruit flies will happen
more quickly than with any other species (except perhaps yeast and
worms; that brings us back to relevance...).
In addition to the available potential competitors, research labs with
more discretion in their study proposals can take this to the next
level: test the effects of combining multiple gene
modifications--testing two or three at a time of the successful genes
already identified. (A lot of these current studies are
identifying/testing individual genes--such is the nature of research
in its purest form.)
I wanted to bring this up at the Immortality Institute as well, but
their forum database seems to be down, and has been for almost two
days.
Prometheus,
You asked at imminst that I not give up on the venerable fruit fly. I
haven't; I was simply keeping my options open. However, the more that
alternatives to the fruit fly are brought forward, the more I realize
that they truly are the best alternative. I see no better way to
convince myself that fruit flies are the best option, than to
entertain the views of others that would dissent.
I'm waiting for rebuttals from those who oppose the idea, if for no
other reason than to help solidify in my mind, and hopefully in their
minds, that Drosophila Melanogaster is the best way to pursue this
research and help accelerate the discoveries that will eventually lead
to mice that live 8-10 years, and humans that live over 150.
So far, the rebuttals have been found wanting. Ladybugs live far too
long to be of any use. Nothobranchius furzeri have a couple
advantages over flies: genetic relevance (most likely, anyway), and
more relevant mortality rates. However, they are poorly studied,
gestate for as long as they live or longer (they live about 12 weeks
versus about 5 weeks for the flies), and grow to be two inches long or
longer (too large to do "high volume" testing).
Mites were suggested; the lifespan is right; the possibility of very
high volume testing is there; and supposedly diapause would not be an
issue. However, the genome has not been mapped, and they are
currently poorly studied. Creating a prize for fruit flies would be
hard enough; to create a prize for an otherwise ignored species would
be begging failure to come knocking.
I'm not trying to bash the alternatives that have been suggested. But
a stronger case should be made for them.
If at last someone does identify a species better suited to a
prize--and they can back that suggestion with more than just the
"cuteness" factor--then there would be no reason to feel defeated.
After all, that's what we're after: the best short-term alternative to
the mouse.
Jay Fox
Prometheus
intake and I agree with your suggestion that there could well be
widespread understated and undiagnosed nutritional deficiencies which
could be alleviated with strategic megadosing of specific nutrients
(and in some cases the deficiencies are as basic as insufficient daily
water intake).
This does not mean, however, that using these methods will enable
individuals to extend beyond the known envelope of lifespan length and
quality that is achieved by the present statistical outliers.
"Michael C Price" <michaelEXCI...@ntlworld.com> wrote in message news:<Z10Sc.672$FA4...@newsfe4-gui.ntli.net>...
Michael C Price
> I agree that there are definite benefits in optimizing nutritional
> intake and I agree with your suggestion that there could well be
> widespread understated and undiagnosed nutritional deficiencies
> which could be alleviated with strategic megadosing of specific
> nutrients (and in some cases the deficiencies are as basic as
> insufficient daily water intake).
>
> This does not mean, however, that using these methods will
> enable individuals to extend beyond the known envelope of
> lifespan length and quality that is achieved by the present
> statistical outliers.
Nor, since you have not supplied any empirical evidence to
support your belief, does it mean that such an extension
can't be achieved. Which is why we need the experiments to
be conducted.
Michael C Price
> prize--and they can back that suggestion with more than just the
> "cuteness" factor--then there would be no reason to feel defeated.
> After all, that's what we're after: the best short-term alternative to
> the mouse.
Jay,
How about aphids in their asexual reproduction phase?
Prometheus
> > intake and I agree with your suggestion that there could well be
> > widespread understated and undiagnosed nutritional deficiencies
> > which could be alleviated with strategic megadosing of specific
> > nutrients (and in some cases the deficiencies are as basic as
> > insufficient daily water intake).
> >
> > This does not mean, however, that using these methods will
> > enable individuals to extend beyond the known envelope of
> > lifespan length and quality that is achieved by the present
> > statistical outliers.
>
> Nor, since you have not supplied any empirical evidence to
> support your belief, does it mean that such an extension
> can't be achieved. Which is why we need the experiments to
> be conducted.
>
known fact amongst the gerontology community: the only non-genetic
intervention discovered to date that significantly extends lifespan is
caloric restriction. That is not to say that that another non-genetic
intervention will not be discovered in the future, nor am I suggesting
that experiments to investigate the many benefits of strategic
supplementation be discouraged.
I find it unlikely, however, that the genome - whose stability is of
paramount importance - would have evolved in a way that
environmentally common substances (such as nutrients) could
sufficiently exert influence over gene regulation to enable such a
fundamental and complex change as lifespan to be effected.
The belief that a single substance will provide dramatic changes to
lifespan is no more than another manifestation of the timeless myth of
fountain of youth cloaked and promulgated in para-science.
Furthermore, the consideration of strategic supplementation as a means
of dramatically extending lifespan is ultimately a distraction from
the urgent research that needs to be conducted and the message that
needs to be promulgated that only via genetic intervention can we come
closer to achieving real lifespan extension.
Michael C Price
>>> intake and I agree with your suggestion that there could well
>>> be widespread understated and undiagnosed nutritional
>>> deficiencies which could be alleviated with strategic megadosing
>>> of specific nutrients (and in some cases the deficiencies are as
>>> basic as insufficient daily water intake).
>>>
>>> This does not mean, however, that using these methods will
>>> enable individuals to extend beyond the known envelope of
>>> lifespan length and quality that is achieved by the present
>>> statistical outliers.
>>
>> Nor, since you have not supplied any empirical evidence to
>> support your belief, does it mean that such an extension
>> can't be achieved. Which is why we need the experiments to
>> be conducted.
>>
> Rather than cite a litany of references
As Einstein said, one would do. How can I take you
seriously when you can't even cite one?
> I will remind you of a well known fact amongst the
> gerontology community: the only non-genetic
> intervention discovered to date that significantly
> extends lifespan is caloric restriction.
It should have not escaped your attention that this belief
conflicts with the LS studies I've cited. You are correct,
though, that the above belief is wide spread amongst
the gerontology community.
Let's all stop thinking and follow the herd.
> That is not to say that that another non-genetic
> intervention will not be discovered in the future, nor am I
> suggesting that experiments to investigate the many benefits
> of strategic supplementation be discouraged.
Your last paragraph (at end) does sound like you're saying
exactly that.
> I find it unlikely, however, that the genome - whose stability is
> of paramount importance - would have evolved in a way that
> environmentally common substances (such as nutrients) could
> sufficiently exert influence over gene regulation to enable such a
> fundamental and complex change as lifespan to be effected.
I am aware that you find this unlikely (as do most gerontologists),
but can actually explain why you believe this? I have given
a number of reasons why I think the evolutionary arguments are
false, none of which you have rebutted.
> The belief that a single substance will provide dramatic changes
> to lifespan
This has no relevance to my position, since I am not claiming that
a *single* substance will dramatically extend lifespan. I am rather
disappointed that you make such an irrelevant statement, which
looks like an attempt to smear my position by association.
If it isn't, why did you say it?
> is no more than another manifestation of the timeless myth
> of fountain of youth cloaked and promulgated in para-science.
Para-science? You're the one arguing on the basis of purely
theoretical considerations and unable to cite studies or give detailed
explanations of your reasoning. I have cited numerous studies to
support my position and given detailed reasoning. Who's
conducting para-science?
> Furthermore, the consideration of strategic supplementation as a
> means of dramatically extending lifespan is ultimately a distraction
> from the urgent research that needs to be conducted and the
> message that needs to be promulgated that only via genetic
> intervention can we come closer to achieving real lifespan
> extension.
Belief coupled with a lack of evidence = delusion.
Tim Tyler
> Rather than cite a litany of references I will remind you of a well
> known fact amongst the gerontology community: the only non-genetic
> intervention discovered to date that significantly extends lifespan is
> caloric restriction.
A situation which seems unlikely to last for very long -
and is probably already on the verge of being out of date:
``Researchers discover the first compounds that slow aging across species
Three colleagues with a common interest in the biology of aging have
determined that the compound resveratrol, an antioxidant found in red
wine, can slow the aging process in yeast, fruit flies and nematodes.
[...]
This discovery prompted an unusual, three-university experiment that has
netted a true scientific breakthrough: the discovery of the first
compounds that slow aging across species. The results are published in
the July 15, 2004, issue of Nature. [...]''
- http://www.scienceblog.com/community/article3524.html
Doug Brooks
> ``Researchers discover the first compounds that slow aging across species
>
> Three colleagues with a common interest in the biology of aging have
> determined that the compound resveratrol, an antioxidant found in red
> wine, can slow the aging process in yeast, fruit flies and nematodes.
>
> [...]
>
> This discovery prompted an unusual, three-university experiment that has
> netted a true scientific breakthrough: the discovery of the first
> compounds that slow aging across species. The results are published in
> the July 15, 2004, issue of Nature. [...]''
>
> - http://www.scienceblog.com/community/article3524.html
Tatar was described as "cooking" the resveratrol into the flies sweet
corn meal mush. I would think heat would be a bad thing. Then again,
this may be journalistic license.
Also, the article mentions that "sirtuins dissipate quickly in the
blood." So do fruit flies constantly snack?
jayd...@aol.com
> Tim Tyler wrote:
> > ``Researchers discover the first compounds that slow aging across species
> >
> > Three colleagues with a common interest in the biology of aging have
> > determined that the compound resveratrol, an antioxidant found in red
> > wine, can slow the aging process in yeast, fruit flies and nematodes.
> >
> > [...]
> >
> > This discovery prompted an unusual, three-university experiment that has
> > netted a true scientific breakthrough: the discovery of the first
> > compounds that slow aging across species. The results are published in
> > the July 15, 2004, issue of Nature. [...]''
> >
> > - http://www.scienceblog.com/community/article3524.html
>
> Tatar was described as "cooking" the resveratrol into the flies sweet
> corn meal mush. I would think heat would be a bad thing. Then again,
> this may be journalistic license.
Yeah, I remember thinking something similar when I read the article.
> Also, the article mentions that "sirtuins dissipate quickly in the
> blood." So do fruit flies constantly snack?
A pretty consistent trend in the animal kingdom is that smaller
organisms eat a larger percentage of the own mass in food.
Warm-blooded vs. Cold-blooded makes a big difference, but in general,
the rule holds. I would assume that fruit flies eat several times
their own mass in food each day. Doing so probably requires them to
eat pretty constantly, i.e. every hour or two.
Perhaps someone who's worked with them knows for sure?
Jay Fox
Prometheus
Not at all, Michael. You have taken me out of hand.
In a nutshell: the point of contention is how much can be achieved
using nutritional modification before one has to invest resources into
genetic interventions. Your argument is that nutritional augmentation
has a lot to offer - something which I do not dispute.
But let us define what "a lot" is. Is it an average extension of
lifespan of 20%? Is it a reduction of disease incidence by 20%? These
numbers are certainly respectable and desirable.
However if the objective is a more dramatic shift in the aging and
disease process - then nutritional augmentation is not sufficient. A
survey on pubmed will show that in experimental models, the dietary
modification that has resulted in the most significant life extension
is caloric restriction or any therapeutic that will favorably modulate
the associated factors with that pathway (including resveratrol).
The functional motif of most aging related genes converges downstream
to effects related to DNA integrity maintenance. Whether this is due
to reduction of oxidant production, increase of antioxidant
production, increase in mtDNA and nDNA repair function, etc. Of course
there are other apoptotic pathways not related to DNA integrity. Even
so, the message is that "all roads lead to Rome". Hence we can we
examine the various ways by which such pathways may be triggered - at
this stage they all seem to be related to the CR axis.
Yet even with the CR type of effects running at full blast we can only
expect limited gains in life extension based on experimental
observation models (30% -50%). If we were to translate these
experimental interventions to human mid to late life therapeutic
interventions then it is not difficult to appreciate that those
percentages would be reduced.
It is therefore not unreasonable to conclude that genetic level
interventions are required if we are to extend lifespan beyond the
best that has been achieved in the lab using research models.
We can either continue to investigate how exotic compounds may
modulate the CR axis or any other, as yet undiscovered mechanism that
retards aging rate, or we can look at manipulating the known genetic
mechanisms and devise interventions accordingly.
>
> Belief coupled with a lack of evidence = delusion.
>
Not always. There is another word - faith. ;)
Michael C Price
I note the issues of lack of evidence and unexplained
evolutionary beliefs were not addressed. Evidently
"Prometheus" feels his views are so self-evident they
do not require empirical support nor evolutionary analysis.
> In a nutshell: the point of contention is how much can be achieved
> using nutritional modification before one has to invest resources into
> genetic interventions. Your argument is that nutritional augmentation
> has a lot to offer - something which I do not dispute.
>
> But let us define what "a lot" is. Is it an average extension of
> lifespan of 20%? Is it a reduction of disease incidence by 20%?
No, it is a lot more.
> These numbers are certainly respectable and desirable.
>
> However if the objective is a more dramatic shift in the aging and
> disease process - then nutritional augmentation is not sufficient.
Again, a belief not supported by evidence. You are making
claims about the results of experiments (combinations
of megadoses/supra-RDA levels of B-vitamins, minerals etc)
that have not been performed.
> A
> survey on pubmed will show that in experimental models, the dietary
> modification that has resulted in the most significant life extension
> is caloric restriction or any therapeutic that will favorably modulate
> the associated factors with that pathway (including resveratrol).
>
> The functional motif of most aging related genes converges downstream
> to effects related to DNA integrity maintenance. Whether this is due
> to reduction of oxidant production, increase of antioxidant
> production, increase in mtDNA and nDNA repair function, etc. Of
> course there are other apoptotic pathways not related to DNA integrity.
> Even so, the message is that "all roads lead to Rome". Hence we can
> we examine the various ways by which such pathways may be triggered
> - at this stage they all seem to be related to the CR axis.
How they seem depends on your belief system.
> Yet even with the CR type of effects running at full blast we can only
> expect limited gains in life extension based on experimental
> observation models (30% -50%). If we were to translate these
> experimental interventions to human mid to late life therapeutic
> interventions then it is not difficult to appreciate that those
> percentages would be reduced.
>
> It is therefore not unreasonable to conclude that genetic level
> interventions are required if we are to extend lifespan beyond the
> best that has been achieved in the lab using research models.
It is unreasonable to assume that, until the combinatorial
LS experiments with nutritional supplementation have been
performed. A reasonable extrapolation is that the LE from
these will easily exceed the paltry 30% -50% you claim for
CR.
> We can either continue to investigate how exotic compounds may
> modulate the CR axis or any other, as yet undiscovered mechanism
> that retards aging rate, or we can look at manipulating the known
> genetic mechanisms and devise interventions accordingly.
>
>
>>
>> Belief coupled with a lack of evidence = delusion.
>>
> Not always. There is another word - faith. ;)
Another word for delusion.
Prometheus
> "Prometheus" <theo...@gmail.com> wrote in message
>
> I note the issues of lack of evidence and unexplained
> evolutionary beliefs were not addressed. Evidently
> "Prometheus" feels his views are so self-evident they
> do not require empirical support nor evolutionary analysis.
Michael, on what specific assertion I have made would you like
empirical support on?
>
> > In a nutshell: the point of contention is how much can be achieved
> > using nutritional modification before one has to invest resources into
> > genetic interventions. Your argument is that nutritional augmentation
> > has a lot to offer - something which I do not dispute.
> >
> > But let us define what "a lot" is. Is it an average extension of
> > lifespan of 20%? Is it a reduction of disease incidence by 20%?
>
> No, it is a lot more.
What extent of LE, using nutritional modification, do you believe is
possible?
>
> > The functional motif of most aging related genes converges downstream
> > to effects related to DNA integrity maintenance. Whether this is due
> > to reduction of oxidant production, increase of antioxidant
> > production, increase in mtDNA and nDNA repair function, etc. Of
> > course there are other apoptotic pathways not related to DNA integrity.
> > Even so, the message is that "all roads lead to Rome". Hence we can
> > we examine the various ways by which such pathways may be triggered
> > - at this stage they all seem to be related to the CR axis.
>
> How they seem depends on your belief system.
Do you then dispute:
1. That most aging related genes that have been discovered,
specifically Sir-2, Daf-2, Age-1, Akt, Daf-12, Daf-16, Foxo3a, Ku70,
are related to the CR axis?
2. That the above-mentioned genes are related to the DNA structure
maintenance mechanisms?
>
> > Yet even with the CR type of effects running at full blast we can only
> > expect limited gains in life extension based on experimental
> > observation models (30% -50%). If we were to translate these
> > experimental interventions to human mid to late life therapeutic
> > interventions then it is not difficult to appreciate that those
> > percentages would be reduced.
> >
> > It is therefore not unreasonable to conclude that genetic level
> > interventions are required if we are to extend lifespan beyond the
> > best that has been achieved in the lab using research models.
>
> It is unreasonable to assume that, until the combinatorial
> LS experiments with nutritional supplementation have been
> performed. A reasonable extrapolation is that the LE from
> these will easily exceed the paltry 30% -50% you claim for
> CR.
>
How much, in your estimation, do you think LE can be improved by using
combinatorial supplementation?
Michael C Price
>>
>> I note the issues of lack of evidence and unexplained
>> evolutionary beliefs were not addressed. Evidently
>> "Prometheus" feels his views are so self-evident they
>> do not require empirical support nor evolutionary analysis.
>
> Michael, on what specific assertion I have made would
> you like empirical support on?
E.g. from my last post:
P:
> I find it unlikely, however, that the genome - whose stability is
> of paramount importance - would have evolved in a way that
> environmentally common substances (such as nutrients) could
> sufficiently exert influence over gene regulation to enable such a
> fundamental and complex change as lifespan to be effected.
MCP:
I am aware that you find this unlikely (as do most gerontologists),
but can actually explain why you believe this? I have given
a number of reasons why I think the evolutionary arguments are
false, none of which you have rebutted.
>>> In a nutshell: the point of contention is how much can be achieved
>>> using nutritional modification before one has to invest resources into
>>> genetic interventions. Your argument is that nutritional augmentation
>>> has a lot to offer - something which I do not dispute.
>>>
>>> But let us define what "a lot" is. Is it an average extension of
>>> lifespan of 20%? Is it a reduction of disease incidence by 20%?
>>
>> No, it is a lot more.
>
> What extent of LE, using nutritional modification, do you believe
> is possible?
Why are you asking questions answered in the my report
I emailed you? It would save us both some time if you read it
and asked questions based on that, rather than questions already
answered in the report.
>>> The functional motif of most aging related genes converges
>>> downstream to effects related to DNA integrity maintenance.
>>> Whether this is due to reduction of oxidant production, increase
>>> of antioxidant production, increase in mtDNA and nDNA repair
>>> function, etc. Of course there are other apoptotic pathways not
>>> related to DNA integrity. Even so, the message is that "all roads
>>> lead to Rome". Hence we can we examine the various ways by
>>> which such pathways may be triggered - at this stage they all
>>> seem to be related to the CR axis.
>>
>> How they seem depends on your belief system.
>
> Do you then dispute:
>
> 1. That most aging related genes that have been discovered,
> specifically Sir-2, Daf-2, Age-1, Akt, Daf-12, Daf-16, Foxo3a,
> Ku70, are related to the CR axis?
"are related" is rather a vague, unquantified term. All the above genes
are are also "related" to coenzymes and the other enzymic cofactors;
Thence they are related to the B-vitamins and minerals. Which
relationship you judge the more important depends on your belief
system.
> 2. That the above-mentioned genes are related to the DNA
> structure maintenance mechanisms?
Niacin, folate and other enzymic cofactors "are related" to the DNA
structure maintenance mechanisms. PARP requires NAD, for
instance, as a substrate.
>>> Yet even with the CR type of effects running at full blast we can
>>> only expect limited gains in life extension based on experimental
>>> observation models (30% -50%). If we were to translate these
>>> experimental interventions to human mid to late life therapeutic
>>> interventions then it is not difficult to appreciate that those
>>> percentages would be reduced.
>>>
>>> It is therefore not unreasonable to conclude that genetic level
>>> interventions are required if we are to extend lifespan beyond the
>>> best that has been achieved in the lab using research models.
>>
>> It is unreasonable to assume that, until the combinatorial
>> LS experiments with nutritional supplementation have been
>> performed. A reasonable extrapolation is that the LE from
>> these will easily exceed the paltry 30% -50% you claim for
>> CR.
>>
> How much, in your estimation, do you think LE can be improved
> by using combinatorial supplementation?
I think that the LE effects from different enzymic cofactors are
approximately additive in combination. It seems to be so for
drosophila; I expect it to be true for mammals, including humans.