Sir2: The Real McCoy in Yeast?
mik...@my-deja.com
2 news stories based on a report I've not seen, & won't be able to for a
month, in today's _Science_, on sir2, CR, and aging. I'll quote the first
in full off of the CR list, since the NY times threw all kinds of hedges
around my accessing the article -- so piss upon their copyright:
(New York Times)
A Pill to Extend Life? Don't Dismiss the
Notion Too
Quickly
By NICHOLAS WADE
Offering a sharp insight into the
nature of aging,
biologists report today that they
have shown
precisely why a calorically
restricted diet prolongs
life span, at least in a lower organism.
The finding, should
it prove true of people too, would open
the possibility of
developing drugs to mimic the effects
and gain the
remarkable benefits of the draconian
low-calorie diet.
Laboratory rats and mice live up to 40
percent longer than usual when fed a diet that has at
least 30 percent fewer calories than
they would usually eat though otherwise contains all
necessary vitamins and nutrients. The
animals are free of age-related disease and appear
healthy in every respect except that
they are generally less fertile.
Studies with rhesus monkeys, which
usually live around 25 years, have not been in
progress
for long enough to say if caloric
restriction is likely to benefit primates like monkeys
and
people, though initial signs are
positive.
Even if caloric restriction does prove
to prolong human life, very few people could adhere to
such a meager diet. Other means, ideally
a simple pill, might capture the benefits. But drugs
require a target to act on, and the
mechanism by which caloric restriction affects life
span has
long been a mystery.
The issue now seems to have been settled
at least in yeast, a widely studied laboratory
organism whose metabolism is similar to
that of animals in many fundamental ways.
Dr. Leonard Guarente and colleagues at
the Massachusetts Institute of Technology report in
today's issue of Science that caloric
restriction extends life span in yeast because it
interacts
with a gene that controls the activity
of DNA, the genetic material.
The gene is known as SIR2, for silent
information regulator No. 2, and its product, the SIR2
protein, silences genes by making the
material that clads the DNA wrap more tightly, thus
denying a cell access to the underlying
genes.
The SIR2 gene has a direct effect on the
yeast cell's longevity; Dr. Guarente previously
found that yeast cells in which the gene
had been disrupted lived shorter lives than usual,
while those given an extra copy of SIR2
lived longer.
Gene silencing is probably of great
importance to the integrity of a cell because to have
the
wrong genes activated could derange a
cell's function. Dr. Guarente believes that
inefficient
silencing in cells could explain many of
the infirmities of age.
He and colleagues have now found that
caloric restriction appears to work through the SIR2
gene pathway. Yeast cells grown with
very little of their food, sugar in the form of
glucose,
lived longer than normal, but not if
their SIR2 gene was disrupted.
The reason seems to be that both the
cell's glucose metabolism system, and the protein made
by the SIR2 gene, compete for the same
chemical, a substance known as NAD. The SIR2
protein cannot perform its silencing
duties unless it has NAD to help it, but when the cell
is
busily converting glucose to energy,
there is less NAD available for the SIR2 protein.
Dr. Guarente's next project is to see if
his findings in yeast are also true of higher
organisms.
Both mice and people have their own
versions of the SIR2 gene, and the protein requires
NAD to function.
The mechanism makes evolutionary sense,
Dr. Guarente said, because when food is scarce
an organism's best strategy is to
postpone reproduction and wait until conditions
improve.
So a gene like SIR2 that linked greater
longevity to lower calorie intake would be highly
favored by the forces of natural
selection.
Dr. Tomas A. Prolla, a geneticist who
studies aging at the University of Wisconsin, said Dr.
Guarente's report was the first to link
the life extension effects of caloric restriction to a
single gene.
"If the find can be translated to
animals, it will be very important," Dr. Prolla said,
because it
would provide "a starting point in the
design of drugs which would have a broad effect on
human health, including cancer."
The 40 percent life extension seen under
caloric restriction could be just a hint of what would
be possible once the underlying
mechanism is understood. "I don't think a 30-40
percent
range should be considered as some kind
of maximum," Dr. Prolla said.
Dr. George S. Roth of the National
Institute of Aging, who has been conducting a calorie
restriction study on rhesus monkeys
since 1987, said there had been fewer deaths so far
among the dieting monkeys, which receive
30 percent fewer calories, than among a
comparison group that feeds normally.
The mortality difference is not yet
statistically significant, Dr. Roth said, but the
restricted
monkeys have already developed metabolic
patterns suggesting they will prove more
resistant to diabetes and heart disease.
There is an interesting difference of
opinion on the subject of aging between evolutionary
biologists, who believe for strong
theoretical reasons that aging must be influenced by
many
different genes, and molecular
biologists who have found they can extend the life of
laboratory organisms by altering single
genes.
Reflecting this difference, Dr. Michael
Rose, an evolutionary biologist at the University of
California at Irvine, said that the work
with yeast was "really nice and elegant" but that Dr.
Guarente was mistaken in arguing that
gene silencing or any other single mechanism of aging
was likely to be universal.
Dr. Guarente acknowledged that many
genes might be involved in aging. But there is likely
to be a single major genetic pathway, he
said, in the form of a mechanism to slow aging in
response to food scarcity, because any
such mechanism would be heavily favored by the
forces of natural selection.
The second story, which contradicts the above at a crucial point, is at:
... damn!! Now I can't find it... I'm almost sure it was on Yahoo... has
anyone seen this version? More when I find the #$%# thing!!
-Michael
Sent via Deja.com http://www.deja.com/
Before you buy.
Bryan L. Ford
(snipped)
From the latest Science Online: the news header for this article,
followed by the "Perpective" by Judith Campisi on the Sir2 article also
from Science. I hope it is useful.
Eat Less, Live Longer
Severely restricting a rat's daily intake of calories helps
prolong its life. This regimen that works in primates
and even yeast. Now Lin et al. (p. 2126; see the Perspective by
Campisi) have recreated this so-called
caloric restriction in yeast and identified some of the genes
required for its effects on longevity. These include
the chromatin-silencing gene SIR2 and a gene for an enzyme in the
synthesis pathway of the metabolic
intermediate NAD (the oxidized form of nicotinamide adenine
dinucleotide). Because Sir2p is allosterically
regulated by NAD, a decreased metabolic rate included by caloric
restriction could cause altered NAD
levels and thus maintain the ability of Sir2p to silence the
expression of deleterious genes (in this case, the
expression of ribosomal DNA that can be toxic to yeast cells).
This connection between silencing and
prolonged life induced by caloric restriction suggests that
proteins that silence gene expression may prove to
be useful targets for drugs that modulate life-span.
[End of news header from Science]
Here is the Campisi Perspective kindly copied from Science online:
AGING:
Aging, Chromatin, and Food
Restriction--Connecting the Dots
Judith Campisi*
What causes aging? Current hypotheses generally fall into one of two
categories. The first category invokes extrinsic or intrinsic factors
that
damage intracellular or extracellular molecules; the second invokes
changes
in gene expression that are either programmed or that are brought about
by
nonmutational changes in DNA structure. To what extent these hypotheses
overlap or intersect is not known. Regardless of the hypothesis,
however,
caloric restriction (CR) has been an important tool for testing ideas
about causes of aging in animals. Caloric
restriction--reducing the food intake of animals (normally fed ad
libitum) by 50 to 70%--reliably extends the mean and
maximum life-spans of several species, including mammals (1). It
postpones most age-related pathology and alters many,
but not all, age-related processes. It is thought to do this primarily
by reducing oxidative stress and damage caused by
reactive oxygen species (2). Yet, despite more than half a decade of
research, the major pathways through which CR
acts remain enigmatic. Now, on page 2126 of this issue, Lin et al. (3)
describe intriguing results that may link CR to the
control of gene expression and to the suppression of DNA damage (loss
or rearrangement of DNA) caused by mitotic
recombination. These studies were carried out in a model organism, the
yeast Saccharomyces cerevisiae, from which
much basic cellular and molecular information has been gleaned,
including several revelations about the genetics and
physiology of aging (4).
Yeast undergo only a finite number of divisions, after which they die;
thus, their life-span is defined by the number of
divisions each cell completes (4). Lin et al. induced CR in yeast by
limiting glucose availability or by genetically crippling
their ability to sense and respond to glucose. Caloric restriction
extended yeast longevity by 20 to 40%, similar to the
relative life-span extension induced by CR in mammals. Of importance,
this extension required the yeast genes NPT1 and
SIR2. NPT1 encodes one of two enzymes that produce NAD (nicotinamide
adenine dinucleotide), a key intermediate in
energy metabolism. SIR2--one of four silent information regulator
genes--encodes a protein that promotes a compact
chromatin structure, thereby preventing or silencing gene transcription
at selected loci. As noted by Lin et al., the yeast
SIR2 protein, Sir2p, is an NAD-dependent histone deacetylase, an enzyme
that removes acetyl groups from the lysine
residues of histone proteins (which are components of chromatin). This
suggests that, through histone deacetylation, Sir2p
may silence chromatin. In addition, the NAD requirement of Sir2p may
serve to link its activity to the energy status of the
cell. Thus, Sir2p may coordinate energy status with gene expression.
Moreover, because by compressing chromatin
Sir2p regulates the access of many nuclear proteins to the DNA, it
represses homologous recombination at the highly
repetitive ribosomal DNA (rDNA) locus with which it associates. The
formation and accumulation of extrachromosomal
rDNA circles (and possibly other DNA fragments) is a major cause of
yeast aging. These circles are formed by
homologous recombination during the cell cycle. Homologous
recombination is important for repairing damaged DNA,
but can inappropriately excise DNA fragments from regions of extensive
homology, such as the rDNA locus. Sir2p
modulates yeast life-span largely by suppressing rDNA circle formation.
It is gratifying, then, that Lin et al. have
discovered that CR also suppresses rDNA circle formation. Thus, at
least in yeast, CR may extend life-span by
modulating Sir2p activity and hence gene expression and recombination
at silenced loci.
One can now envision a model (see the figure) whereby the inevitable
production of reactive oxygen species
compromises mitochondrial efficiency, and eventually energy output, in
a detrimental feedback loop. NAD levels may
reflect energy status and influence chromatin silencing through the NAD
requirement of Sir2p. Caloric restriction may
ameliorate the impact of reactive oxygen species, including their
indirect effect on the decline in energy production. Thus,
by reducing the impact of reactive oxygen species and the resulting
decrease in Sir2p activity, CR may postpone loss of
chromatin silencing. But how could loss of chromatin silencing lead to
aging? The state of chromatin is essential for
maintaining optimal gene expression and for suppressing homologous
recombination. Loss of chromatin silencing alters
gene expression, which can compromise the cell's ability to function,
and possibly its ability to withstand stressful stimuli.
In addition, increased recombination leads to the lethal accumulation
of rDNA circles, and possibly other detrimental
mutations.
Counting calories. The connection between caloric restriction (CR), the
SIR2 protein, and chromatin silencing. The
maintenance or silencing of chromatin may be at the center of processes
leading to the aging of cells and development of
cancer. Red outlined boxes indicate processes found in mammals but not
in yeast. Dark yellow boxes indicate pathways
in yeast that are connected and that contribute to aging (3). ROS,
reactive oxygen species.
Life-span extension by CR delays but does not prevent aging in both
yeast and mammals. Two processes--DNA
replication and DNA repair--may alter chromatin silencing and
recombination independently of Sir2p and NAD
availability. In both processes, DNA is stripped, albeit transiently,
of regulatory proteins, which must be rapidly
reassembled. Mistakes or transient states in the reassembly process may
leave chromatin susceptible to inappropriate
transcription or recombination events. Because the probability of
undergoing DNA replication and repair increases with
the number of cell divisions, the probability of acquiring imperfectly
silenced (or configured) chromatin will rise with age.
Likewise, the probability that faulty DNA replication or error-prone
repair will generate (or fix) mutations will rise with
age. Thus, CR, or even perfect chromatin silencing, can postpone aging
phenotypes, but cannot delay them indefinitely.
This is consistent with the finding that CR reverses some, but not all,
gene expression changes that accompany aging in
rodents (5).
How pertinent might this model be to mammals? History tells us that we
can learn a great deal about human biology from
model organisms. Therefore, we may expect that chromatin silencing, or
chromatin maintenance in general, will play a role
in the development of aging phenotypes in mammals. Indeed, silenced
genes on human X chromosomes (6) and other loci
become reactivated with age, suggesting that age-related loss of
silencing does occur in some mammalian cells.
Moreover, preliminary studies suggest that CR will be effective in
primates (7). Proteins such as Sir2p may well serve to
link metabolism to chromatin state in mammals, including humans,
although this idea has not yet been rigorously tested,
even in yeast. However, owing to their complexity, mammals may engage
multiple SIR2-like proteins, perhaps some that
are tissue-specific. Finally, WRN, the gene responsible for Werner
syndrome, a disease of premature aging in humans (8),
is a member of a gene family that is likely to participate in
recombination and other DNA repair pathways, suggesting that
recombination and DNA repair may be important determinants of the rate
of aging in mammals.
A fundamental difference between adult mammals and model organisms such
as the yeast, the nematode, and the fruitfly is
the prevalence of cancer in mammals, and essentially the lack of cancer
in yeast, worms, and flies. In mammals,
mutations, very likely coupled to the changes in cellular function that
accompany aging (9), give rise to cancer, which
poses an additional threat to longevity. In addition, most human cells
undergo telomere attrition with successive cell
divisions and aging (that is, the ends of chromosomes become
progressively shorter) (10). The extent to which
telomere-induced cellular senescence contributes to human aging is not
yet clear (9, 10), nor is it known how telomere
length contributes to the senescent phenotype of cells. In yeast,
telomeres increase the compactness of nearby chromatin,
but we do not yet know if this process occurs in human cells. It is
intriguing, however, that telomere shortening occurs
more rapidly on human X chromosomes, which could contribute to the
age-dependent reactivation of X chromosome loci
(6). The state of chromatin is now at the center of several processes
known or suspected to be important in mammalian
aging, suggesting, once again, that model organisms have served us
well.
References
1.E. J. Masoro, Exp. Gerontol. 35, 299 (2000) [Medline].
2.R. S. Sohal and R. Weindruch, Science 273, 59 (1996).
3.S. Lin et al., Science 289, 2126 (2000).
4.S. M. Jazwinski, Science 273, 54 (1996).
5.E. Han et al., Mech. Ageing. Dev. 115, 157 (2000) [Medline].
6.J. Surralles et al., Am. J. Hum. Genet. 65, 1617 (1999) [Medline].
7.G. S. Roth et al., J. Am. Geriatr. Soc. 127, 896 (1999) [Medline].
8.C. E. Yu et al., Science 272, 258 (1996).
9.J. Campisi, In Vivo 14, 183 (2000) [Medline].
10.R. J. Hodes, J. Exp. Med. 190, 153 (2000) [Medline].
The author is at the Life Sciences Division, Lawrence Berkeley National
Laboratory, Berkeley, CA 94720, USA.
Aubrey de Grey
Michael Rae wrote:
> 2 news stories based on a report I've not seen, & won't be able to for a
> month, in today's _Science_, on sir2, CR, and aging.
One of the most irritating aspects of scientific spin these days is the
use of the qualification "at least in xyz" to imply that something that
happens in a lower organism has some relevance to humans. The stories
quoted are bad examples of this. To summarise:
1 CR extends replicative lifespan in yeast. (No great surprise.)
2 Manipulations of the rate of formation of rDNA circles control yeast
replicative lifespan. (The same lab's previous, and very solid, work.)
3 CR extends replicative lifespan in yeast by gene expression changes
that are involved in slowing the formation of rDNA circles. Great,
but that's simply a confirmation of a very firm prediction of results
1 and 2 combined.
In other words, this tells us no more than we knew before about the
similarity or otherwise between replicative lifespan in yeast and aging
in humans. One wouldn't get that impression, however, from the stories
that have been posted.
This is not to say that we know yeast is completely different either,
though. Campisi makes very valid points about the role of chromatin
maintenance in the susceptibility of DNA to mutation or dysregulation.
Aubrey de Grey
mik...@my-deja.com
First, thanks to Brian Ford for repoducing the material from _Science_.
Here's teh Yahoo story I'd seen; evidently, I misrecalled the
"contradictory" detail, so forget about my previous post:
http://dailynews.yahoo.com/h/nm/20000921/hl/aging_1.html
In article <8qi11j$1su$1...@pegasus.csx.cam.ac.uk>,
ag...@mole.bio.cam.ac.uk (Aubrey de Grey) wrote:
> One of the most irritating aspects of scientific spin these days is the
> use of the qualification "at least in xyz" to imply that something that
> happens in a lower organism has some relevance to humans. The stories
> quoted are bad examples of this. To summarise:
>
> 1 CR extends replicative lifespan in yeast. (No great surprise.)
> 2 Manipulations of the rate of formation of rDNA circles control yeast
> replicative lifespan. (The same lab's previous, and very solid, work.)
> 3 CR extends replicative lifespan in yeast by gene expression changes
> that are involved in slowing the formation of rDNA circles. Great,
> but that's simply a confirmation of a very firm prediction of results
> 1 and 2 combined.
>
> In other words, this tells us no more than we knew before about the
> similarity or otherwise between replicative lifespan in yeast and aging
> in humans. One wouldn't get that impression, however, from the stories
> that have been posted.
OK, but the preence of Sir2 homologs in humans -- complete with NAD-
dependent histone deacetylase activity -- was recently confirmed in
Smith JS, Brachmann CB, Celic I, Kenna MA, Muhammad S, Starai VJ, Avalos
JL,
Escalante-Semerena JC, Grubmeyer C, Wolberger C, Boeke JD.
A phylogenetically conserved NAD+-dependent protein deacetylase activity
in the
Sir2 protein family.
Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6658-63.
PMID: 10841563; UI: 20300957
I seem to recall reading that rDNA circle formation does occur in
mammals; is this true?
And this new report confirms the hypothesis they had previously advanced
that reducing energy availability would free up more NAD; maybe this was
self-evident to those in the know, but on the list (& in my mind) there
was some speculation that the organism might just downregulate NAD
production, resulting in no net increase in NAD or of gene silencing.
If both of the above are true, then (while it seems unlikely that
replicative senescence is a big deal in mammalian aging, & thus of CR's
full bennies in same) isn't it now a lot more likely that CR will have
these effects (better maintenance of gene expression with age,
antimutational effects, extension of replicative potential (of possible
relevance in immunological senescence)) in CR mammals?
Also: in vitro, one can quite significantly boost available NAD with
niacinamide, or to al lesser extent niacin; do you think this should
really apply in vivo, long term, in those supplementing this dirt-cheap,
outrageously safe nutrient at high doses, or do you think it's likely
limited by some other factor? If the latter: would it possibly be of
greater benefit in CR practitioners?
rkaufman
<mik...@my-deja.com> wrote in message news:8qi85f$mc4$1...@nnrp1.deja.com...
....
> Also: in vitro, one can quite significantly boost available NAD with
> niacinamide, or to al lesser extent niacin; do you think this should
> really apply in vivo, long term, in those supplementing this dirt-cheap,
> outrageously safe nutrient at high doses, or do you think it's likely
> limited by some other factor? If the latter: would it possibly be of
> greater benefit in CR practitioners?
>
Two points; first nicotinamide (aka niacinamide) does not boost NAD in vivo
according to the
snippet below I snipped off the LEF web site.
Secondly, as you pointed out, one would expect NAD production to be
down-regulated in the
presense of extra NAD. If so, then this isn't the CR life extending
mechanism. Perhaps down-regulation
does not occur if NAD is increased by CR, so increased NAD availability for
the SIR2 gene IS the mechanism
by which CR is effected.
The question is then if increasing NAD levels through a drug or supplement
(or even by taking NAD in pills, if it makes it through the gut into the
blood stream...)
would have the same effect as CR, or would NAD production be downregulated?
I suppose one could try feeding NAD to rats; I'll search MEDLINE when I have
the chance. NAD is sold
in capsules by the supplement industry.
Even if the SIR2/NAD theory is correct, the resulting slowing of DNA
replication would also presumably
apply to mitochondria, and would fit in with mitochondrial theory of aging
by slowing the deterioration
of an organism's mitochondria.
-----------
Enhancement of brain choline levels by nicotinamide: Mechanism of action
Erb C.; Klein J.
J. Klein, Pharmakol. Inst. der Univ. Mainz, Obere Zahlbacher Strasse 67,
D-55101 Mainz Germany
Neuroscience Letters (Ireland), 1998, 249/2-3 (111-114)
Following the subcutaneous (s.c.) administration of nicotinamide (10
mmol/kg), the brain and CSF levels of nicotinamide were increased to
millimolar concentrations, but the concentrations of N-methylnicotinamide
(NMN) in the CSF, and of NMN and NAD+ in brain tissue WERE NOT SIGNIFICANTLY
ALTERED. Concomitantly, nicotinamide caused increases of the choline levels
in the venous brain blood. In hippocampal slices, nicotinamide (1-10 mM)
induced choline release....
rjk3
increased the amount of NAD available for the SIR2 gene to silence
unwanted gene expression, by decreasing the oxidation of glucose which
requires NAD, theus sparing NAD for other uses.
The abstract below though, seems to imply that NAD oxidation is
increased in mitochondria in caloricly restricted rats. Perhaps CR
increases the amount of NAD available overall, or perhaps the
hypothesis is wrong, though it sounds attractive when Dr. Guarante
describes it.
-----
Mech Ageing Dev 1992 Mar 15;63(1):79-89
Decrease of phosphorylating oxidation and increase of heat producing
NADH
oxidation in rat liver mitochondria during life-span prolongation of
rats by
calorie-restricted diet.
Lemeshko VV, Belostotskaya LI
Scientific Research Institute of Biology, Kharkov State University,
USSR.
The influence of calorie-restricted diet, initiated at weaning, on some
of the
oxidative processes in liver homogenates and isolated mitochondria of 2-
, 3-,
4-, 24-, 35- and 45-month-old male Wistar rats was studied in
comparison with
control ad libitum-fed 1-2 day-old rats and 0.5-, 1-, 2-, 3-, 4- and
24-month-old rats. It was shown that a calorie-restricted diet (at 37%
of the ad
libitum calorific level) did not change the rate of succinate oxidation
coupled
with oxidative phosphorylation in homogenates, but resulted in a
decrease of
succinate, glutamate plus malate and beta-hydroxybutyrate oxidation and
cytochrome c-oxidase activity in isolated mitochondria without any
uncoupling of
oxidative phosphorylation or change in cytochrome content in the
mitochondria.
On the other hand, a significant increase in mitochondrial rotenone-
insensitive
NADH oxidation and a higher liver mass/body mass ratio in rats under the
calorie-restricted diet was established. It may be considered that the
activation of a heat-producing mechanism is a very important
physiological
function in such a condition.
PMID: 1602841, UI: 92292673
------
In article <8qi11j$1su$1...@pegasus.csx.cam.ac.uk>,
ag...@mole.bio.cam.ac.uk (Aubrey de Grey) wrote:
>
> Michael Rae wrote:
>
> > 2 news stories based on a report I've not seen, & won't be able to
for a
> > month, in today's _Science_, on sir2, CR, and aging.
>
> One of the most irritating aspects of scientific spin these days is
the
> use of the qualification "at least in xyz" to imply that something
that
> happens in a lower organism has some relevance to humans. The stories
> quoted are bad examples of this. To summarise:
>
> 1 CR extends replicative lifespan in yeast. (No great surprise.)
> 2 Manipulations of the rate of formation of rDNA circles control yeast
> replicative lifespan. (The same lab's previous, and very solid,
work.)
> 3 CR extends replicative lifespan in yeast by gene expression changes
> that are involved in slowing the formation of rDNA circles. Great,
> but that's simply a confirmation of a very firm prediction of
results
> 1 and 2 combined.
>
> In other words, this tells us no more than we knew before about the
> similarity or otherwise between replicative lifespan in yeast and
aging
> in humans. One wouldn't get that impression, however, from the
stories
> that have been posted.
>
> This is not to say that we know yeast is completely different either,
> though. Campisi makes very valid points about the role of chromatin
> maintenance in the susceptibility of DNA to mutation or dysregulation.
>
> Aubrey de Grey
>
Aubrey de Grey
Michael Rae wrote:
> ag...@mole.bio.cam.ac.uk (Aubrey de Grey) wrote:
> > In other words, this tells us no more than we knew before about the
> > similarity or otherwise between replicative lifespan in yeast and aging
> > in humans. One wouldn't get that impression, however, from the stories
> > that have been posted.
> OK, but the preence of Sir2 homologs in humans -- complete with NAD-
> dependent histone deacetylase activity -- was recently confirmed in
> PMID: 10841563; UI: 20300957
Sure. No surprise: we need chromatin silencing for plenty of reasons.
My point is that there's no evidence that we need it to inhibit the
formation of rDNA circles.
> I seem to recall reading that rDNA circle formation does occur in
> mammals; is this true?
I don't think so; rDNA does undergo increased methylation, though. But
I wouldn't be surprised if there is some circle formation; what we don't
have is any reason to suppose that it's at a level that harms cells in
vivo in a normal lifetime.
> And this new report confirms the hypothesis they had previously advanced
> that reducing energy availability would free up more NAD; maybe this was
> self-evident to those in the know, but on the list (& in my mind) there
> was some speculation that the organism might just downregulate NAD
> production, resulting in no net increase in NAD or of gene silencing.
Hm... This report tells us that more NAD is freed up in yeast. That's
not much evidence (to my mind) that there wouldn't be the other reaction
(downregulating NAD production) in mammals.
> If both of the above are true, then (while it seems unlikely that
> replicative senescence is a big deal in mammalian aging, & thus of CR's
> full bennies in same) isn't it now a lot more likely that CR will have
> these effects (better maintenance of gene expression with age,
> antimutational effects, extension of replicative potential (of possible
> relevance in immunological senescence)) in CR mammals?
It's already established that CR has these effecs in rodents; I think
evidence from rodents is definitely more useful than evidence from yeast.
I also think even evidence from rodents is not at all conclusive, though.
> Also: in vitro, one can quite significantly boost available NAD with
> niacinamide, or to al lesser extent niacin; do you think this should
> really apply in vivo, long term, in those supplementing this dirt-cheap,
> outrageously safe nutrient at high doses, or do you think it's likely
> limited by some other factor? If the latter: would it possibly be of
> greater benefit in CR practitioners?
I've no idea, really. However I have concerns about possible deleterious
effects of high-dose NAD, related to the PMOR, which seems (in vitro) to
make extracellular superoxide far faster from extracellular NAD than from
cytosolic NAD (see the O'Donnell and Azzi ref).
Aubrey de Grey
Aubrey de Grey
rjk3 wrote:
> The abstract below though, seems to imply that NAD oxidation is
> increased in mitochondria in caloricly restricted rats. Perhaps CR
> increases the amount of NAD available overall, or perhaps the
> hypothesis is wrong, though it sounds attractive when Dr. Guarante
> describes it.
>
> Mech Ageing Dev 1992 Mar 15;63(1):79-89
...
a significant increase in mitochondrial rotenone-insensitive NADH
oxidation ... was established
Fascinating! In the past few months I've been presenting at meetings
a new model for how CR reduces superoxide production while maintaining
metabolic rate. It was inspired by the discovery of Desai et al 1996,
Arch. Biochem. Biophys. 333:145 that CR also dramatically reduces the
activity of Complex I (the main superoxide generator) -- but does not
at all reduce the activity of Complex II. This change in stoichiometry
is bizarre, given that most of the electrons to both sites come from
the TCA cycle, which (being a cycle) has constant stoichiometry. Also,
we have to explain it in a way that is consistent with CR's established
reduction of superoxide production but maintenance of specific metabolic
rate.
So: I've been saying recently (and will write up soon, unless someone
shoots it down) that maybe some of the TCA's NADH-borne electrons are
diverted to the plasma membrane by the mechanism proposed in RHH, and
are reducing oxygen there rather than at the mitochondrion. Note that
the PMOR is a fine rotenone-insensitive NADH oxidiser.... This would
give less ATP production by mitochondria. **But**, ATP consumption at
the Na/K-ATPase (which uses most of our ATP in highly oxidative cells)
would be reduced, because the PMOR exports 2.3 protons per electron
(Sun et al, J Bioenerg Biomembranes 16:583) and thus does the right
thing to both Na (via the Na/H antiporter) and K (via leak). The big
requirement of this model is that the PMOR should reduce oxygen all the
way to water in CR, whereas in mt-mutant cells it makes superoxide at
least some of the time. There is not much evidence either way on this,
but this proton-pumping character of the PMOR argues that there is a
form of respiratory chain there (more primitive than the mitochondrial
one), so it's quite possible that there is reduction to water most of
the time but electrons are fumbled to make superoxide when the system
is overloaded. This idea can be extended beyond CR to explain why the
PMOR is so suspiciously ubiquitous. Then, RHH is a model in which the
complete absence (rather then just reduced capacity) of mitochondrial
NADH oxidation, due to mtDNA mutations, causes the overloaded state and
consequent superoxide production.
One aspect of the study rjk3 found is ostensibly inconsistent with the
above: the PMOR is (by definition) non-mitochondrial, whereas there is
said to be a rise in mitochondrial rotenone-insensitive NADH oxidation.
But I have now read the full text and there is no analysis of what this
mysterious NADH-oxidiser might be; in particular there is no proposal
for where the electrons go, which is a big problem for any mechanism
that doesn't involve the cell membrane. My interpretation is that the
oxidation seen was due to contamination of the mitochondrial fraction
by plasma membrane.
Lots of the above will be new to many people here -- feel free to ask
questions. However I may be slower than usual to reply, since I'll be
incommunicado most of the time from now till Monday.
Aubrey de Grey
Peter H. Proctor
>From: ag...@mole.bio.cam.ac.uk (Aubrey de Grey)
>Subject: Re: Sir2: The Real McCoy in Yeast?
>Date: 27 Sep 2000 13:03:50 GMT
There is not much evidence either way on this,
>but this proton-pumping character of the PMOR argues that there is a
>form of respiratory chain there (more primitive than the mitochondrial
>one), so it's quite possible that there is reduction to water most of
>the time but electrons are fumbled to make superoxide when the system
>is overloaded. This idea can be extended beyond CR to explain why
the>PMOR is so suspiciously ubiquitous.
We orginally postulated that superoxide is an extracellular
messenger substance because ectopic SODase ( as the antiinflammatory agent
orgotein ) does not get into cells, where it is in pretty high levels anyway.
Interestingly, much of the toxicity of radical-generating anticancer drugs
also seems to be extracellular.
Perhaps making all this superoxide, etc. is an important function of the
plasma membrane oxidoreductase (PMOR), as an alternative to NADH oxidases,
etc.. It sure would explain a lot of things, particularly since it couples
what we know about the role of extracellular superoxide in age-related
degenerative diseases with the apparent role of mitochondria in the same.
Dr P
rjk3
>
> > The abstract below though, seems to imply that NAD oxidation is
> > increased in mitochondria in caloricly restricted rats. Perhaps CR
> > increases the amount of NAD available overall, or perhaps the
> > hypothesis is wrong, though it sounds attractive when Dr. Guarante
> > describes it.
> >
> a significant increase in mitochondrial rotenone-insensitive NADH
> oxidation ... was established
>
> Fascinating! In the past few months I've been presenting at meetings
> a new model for how CR reduces superoxide production while maintaining
> metabolic rate. It was inspired by the discovery of Desai et al 1996,
> Arch. Biochem. Biophys. 333:145 that CR also dramatically reduces the
> activity of Complex I (the main superoxide generator) -- but does not
> at all reduce the activity of Complex II. This change in
stoichiometry
> is bizarre, given that most of the electrons to both sites come from
> the TCA cycle, which (being a cycle) has constant stoichiometry.
Also,
> we have to explain it in a way that is consistent with CR's
established
> reduction of superoxide production but maintenance of specific
metabolic
> rate.
>
> So: I've been saying recently (and will write up soon, unless someone
> shoots it down) that maybe some of the TCA's NADH-borne electrons are
Thank you for the extensive response. It is as if I asked you for the
time, and you explained in detail how to build a watch. ;-)
What still needs to be explained from the original paper of Dr.
Guarante, in light of this, is why does CR not work when the SIR2 gene
is defective?
mik...@my-deja.com
In article <8qsr4m$4n2$1...@pegasus.csx.cam.ac.uk>,
ag...@mole.bio.cam.ac.uk (Aubrey de Grey) wrote:
>
> Michael Rae wrote:
>
> > ag...@mole.bio.cam.ac.uk (Aubrey de Grey) wrote:
>
> > If both of the above are true [CR frees up more NAD, and this does indeed drive greater Sir2 (& mammalian homolog?) activity], then (while it seems unlikely that
> > replicative senescence is a big deal in mammalian aging, & thus of CR's
> > full bennies in same) isn't it now a lot more likely that CR will have
> > these effects (better maintenance of gene expression with age,
> > antimutational effects, extension of replicative potential (of possible
> > relevance in immunological senescence)) in CR mammals?
>
> It's already established that CR has these effecs in rodents; I think
> evidence from rodents is definitely more useful than evidence from yeast.
Ahem. I must start reading things before I post them...
What I MEANT to say: granted that these same effects (better maintenance
of gene expression with age, antimutational effects, extension of
replicative potential (of possible relevance in immunological senescence)
are seen in CR mammals, and granted that this new paper gives a
convincing argument that, IN YEAST, just these effects are generated by
increased NAD availability & consequent Sir2 activity, & the plausibility
of same, THEN is it not more likely now than it was a week ago that these
effects (tho' not necessarily the full spectrum of effects seen in
mammalian CR) are, indeed, caused by this postulated mechanism?
> I also think even evidence from rodents is not at all conclusive, though.
>
The evidence that they better maintain gene silencing, have fewer DNA
mutations, and longer maintenance of replicative potential is not
conclusive? Explain yourself, sir! (Please :) ).
> > Also: in vitro, one can quite significantly boost available NAD with
> > niacinamide, or to al lesser extent niacin; do you think this should
> > really apply in vivo, long term, in those supplementing this dirt-cheap,
> > outrageously safe nutrient at high doses, or do you think it's likely
> > limited by some other factor? If the latter: would it possibly be of
> > greater benefit in CR practitioners?
>
> I've no idea, really. However I have concerns about possible deleterious
> effects of high-dose NAD, related to the PMOR, which seems (in vitro) to
> make extracellular superoxide far faster from extracellular NAD than from
> cytosolic NAD (see the O'Donnell and Azzi ref).
Um, do you mean NADH? Are you reading my "NAD" as "reduced NAD," because
of the absence of the "+"? If not: why would increased NAD+ generate any
extra superoxide unless more electrons were shuttled into it? If caloric
content is content, then elevating NAD+ shouldn't result in significantly
more NADH to be fed into PMOR, ETS, or whatever -- should it? Is NAD+
normally rate-limiting for TCA, etc, outside of ischemia?
Indeed, the article to which I assume you refer (below) asserts just the
OPPOSITE: that the mystery superoxide-generator, while activated by NADH,
is competitively INHIBITED by NAD+ -- suggesting that, if we CAN elevate
NAD+ without concommitant rise in NADH, we'd possibly inhibit RHH!
1: Biochem J 1996 Sep 15;318 ( Pt 3):805-12
High rates of extracellular superoxide generation by cultured human
fibroblasts:
involvement of a lipid-metabolizing enzyme.
O'Donnell VB, Azzi A
PMID: 8836123, UI: 96433095
...these cells also contain an ectoplasmic
enzyme, distinct from NADPH oxidase, which can generate superoxide ... on
exogenous NADH addition. ... Inhibitor studies showed that there was no
involvement of ... mitochondrial respiration ...
----> NAD+ was a competitive inhibitor, whereas NADPH supported 40% of
the rate
seen with NADH.
Now on a tangent:
NADH-stimulated superoxide generation was
enhanced by the addition of (3-30 microM) arachidonic acid, linoleic acid
or
(5S)-hydroxyeicosatetraenoic acid [(5S)-HETE] but not palmitic acid,
(15S)-hydroperoxyeicosatetraenoic acid [(15S)-HPETE], (15S)-HETE or
(12S)-HETE.
Several features suggest involvement of an enzyme related to 15-
lipoxygenase,
and, in support of this, we show superoxide generation and NADH oxidation
by
recombinant rabbit reticulocyte 15-lipoxygenase.
This is interesting! What's the leukotriene-aging-MiFRA connection? Could
tying up lipoxygenase reduce RHH?
Aubrey de Grey
> granted that these same effects (better maintenance
> of gene expression with age, antimutational effects, extension of
> replicative potential (of possible relevance in immunological senescence)
> are seen in CR mammals, and granted that this new paper gives a
> convincing argument that, IN YEAST, just these effects are generated by
> increased NAD availability & consequent Sir2 activity, & the plausibility
> of same, THEN is it not more likely now than it was a week ago that these
> effects (tho' not necessarily the full spectrum of effects seen in
> mammalian CR) are, indeed, caused by this postulated mechanism?
Aha - I understand now. Yes, somewhat, but not much so. The caveat
is that the link you propose depends on the assumption that appropriate
chromatin silencing has a critical role in mammalian aging, and I think
that that is still controversial. It's possible that there could be a role
in lowering mutation rate, but I doubt it's significant.
> > I also think even evidence from rodents is not at all conclusive, though.
> >
> The evidence that they better maintain gene silencing, have fewer DNA
> mutations, and longer maintenance of replicative potential is not
> conclusive? Explain yourself, sir! (Please :) ).
Heh -- I meant "not conclusive re what would occur in humans" !
> > I have concerns about possible deleterious
> > effects of high-dose NAD, related to the PMOR, which seems (in vitro) to
> > make extracellular superoxide far faster from extracellular NAD than from
> > cytosolic NAD (see the O'Donnell and Azzi ref).
>
> Um, do you mean NADH? Are you reading my "NAD" as "reduced NAD," because
> of the absence of the "+"? If not: why would increased NAD+ generate any
> extra superoxide unless more electrons were shuttled into it? If caloric
> content is content, then elevating NAD+ shouldn't result in significantly
> more NADH to be fed into PMOR, ETS, or whatever -- should it?
I was reading your "NAD" as "NADH and/or NAD+", which is what it normally
denotes. Good point, potentially, but in fact the O'Donnell work (yes that
is the right reference) cannot be extrapolated quite so faithfully as you're
doing to the in vivo case: in the circulation, redox-active compounds such as
ascorbate are kept extremely reduced, so any NAD that did get into the blood
stream would (I expect) be mostly NADH very quickly.
> Is NAD+ normally rate-limiting for TCA, etc, outside of ischemia?
"Rate-limiting" is a somewhat outmoded term, but certainly the TCA
cycle will stop very fast if NAD+ is absent.
> What's the leukotriene-aging-MiFRA connection? Could
> tying up lipoxygenase reduce RHH?
I never could make much sense of that aspect of the work, and frankly
I don't think the authors could either. No idea, in short.
Aubrey de Grey
mik...@my-deja.com
In article <8qsr7m$4uu$1...@pegasus.csx.cam.ac.uk>,
ag...@mole.bio.cam.ac.uk (Aubrey de Grey) wrote:
>
> rjk3 wrote:
>
> > The abstract below though, seems to imply that NAD oxidation is
> > increased in mitochondria in caloricly restricted rats. Perhaps CR
> > increases the amount of NAD available overall, or perhaps the
> > hypothesis is wrong, though it sounds attractive when Dr. Guarante
> > describes it.
> >
Mech Ageing Dev 1992 Mar 15;63(1):79-89
Decrease of phosphorylating oxidation and increase of heat producing NADH
oxidation in rat liver mitochondria during life-span prolongation of rats
by
calorie-restricted diet.
Lemeshko VV, Belostotskaya LI
... It was shown that a calorie-restricted diet (at 37% of the ad
libitum calorific level) did not change the rate of succinate oxidation
coupled
with oxidative phosphorylation in homogenates, but resulted in a decrease
of
succinate, glutamate plus malate and beta-hydroxybutyrate oxidation and
cytochrome c-oxidase activity in isolated mitochondria without any
uncoupling of
oxidative phosphorylation or change in cytochrome content in the
mitochondria.
On the other hand, a significant increase in mitochondrial rotenone-
insensitive
NADH oxidation and a higher liver mass/body mass ratio in rats under the
calorie-restricted diet was established.
PMID: 1602841, UI: 92292673
> ...
> a significant increase in mitochondrial rotenone-insensitive NADH
> oxidation ... was established
>
> Fascinating! In the past few months I've been presenting at meetings
> a new model for how CR reduces superoxide production while maintaining
> metabolic rate. It was inspired by the discovery of Desai et al 1996,
> Arch. Biochem. Biophys. 333:145 that CR also dramatically reduces the
> activity of Complex I (the main superoxide generator) -- but does not
> at all reduce the activity of Complex II. This change in stoichiometry
> is bizarre, given that most of the electrons to both sites come from
> the TCA cycle, which (being a cycle) has constant stoichiometry. Also,
> we have to explain it in a way that is consistent with CR's established
> reduction of superoxide production but maintenance of specific metabolic
> rate.
>
> So: I've been saying recently (and will write up soon, unless someone
> shoots it down) that maybe some of the TCA's NADH-borne electrons are
> diverted to the plasma membrane by the mechanism proposed in RHH, and
> are reducing oxygen there rather than at the mitochondrion. ... The big
> requirement of this model is that the PMOR should reduce oxygen all the
> way to water in CR, whereas in mt-mutant cells it makes superoxide at
> least some of the time. There is not much evidence either way on this,
> but this proton-pumping character of the PMOR argues that there is a
> form of respiratory chain there (more primitive than the mitochondrial
> one),
Could this be the mechanism used for ATP synthesis before the (putative)
symbiotic incorporation of the proto-mt bacteria? Or is the mechanism
already known to be something else?
so it's quite possible that there is reduction to water most of
> the time but electrons are fumbled to make superoxide when the system
> is overloaded.
You've lost me, here. Go slowly, please. You appear to be saying that the
PMOR normally takes in some spare NADH as it does big time in RHH, but
that in CR fewer e- are fumbled because the system is not as overloaded
(less e- hanging around at some step on the PMOR's equivalent to the ETS
and consequently being dropped while waiting to be taken up by the next
step in the chain). But the abstract says there's an INCREASE in NADH
oxidation by the non-mt mechanism, which you hypothesize may be the PMOR.
Should this not then lead to MORE e- being crammed into the PMOR, & hence
MORE PMOR e- fumbling? Indeed, that is exactlywhat you seem to be saying
below:
This idea can be extended beyond CR to explain why the
> PMOR is so suspiciously ubiquitous. Then, RHH is a model in which the
> complete absence (rather then just reduced capacity) of mitochondrial
> NADH oxidation, due to mtDNA mutations, causes the overloaded state and
> consequent superoxide production.
>
Also, from the abstract above:
It may be considered that the
activation of a heat-producing mechanism is a very important
physiological
function in such a condition.
But CR animals have LOWER body temperatures!
Still: this would suggest that raising ambient temperature might reverse
this CR effect. Do you think this is plays a role in the curiosity which
follows?
1: Mech Ageing Dev 1996 Nov 29;92(1):67-82
A tumor preventive effect of dietary restriction is antagonized by a high
housing temperature through deprivation of torpor.
Koizumi A, Wada Y, Tuskada M, Kayo T, Naruse M, Horiuchi K, Mogi T,
Yoshioka M,
Sasaki M, Miyamaura Y, Abe T, Ohtomo K, Walford RL
ER induces daily torpor, the induction of which is reduced
by increasing the ambient temperature to 30 degrees C. The effects of
preventing
hypothermia in ER animals were studied in terms of the expected
consequences of
ER on survival, disease pattern and a number of physiological parameters
in
autoimmune prone MRL/lpr mice and lymphoma prone C57BL, 6 mice. The
results
demonstrate that torpor plays a crucial role in the prevention of
lymphoma
development but does not have an affect on other aspects of ER, such as
prevention of autoimmune diseases.
PMID: 9032756, UI: 97184987
The above is explained as being related to reversal of torpor's slowing
of mitosis; but why would torpor reduce mitosis? I don't see any obvious
connection to the above; is there one?
2: J Nutr 1992 Jul;122(7):1446-53
Mitotic activity in mice is suppressed by energy restriction-induced
torpor.
Koizumi A, Tsukada M, Wada Y, Masuda H, Weindruch R
We monitored core body temperature by telemetry in energy-restricted (201
kJ/wk)
and control (397 kJ/wk) C57BL/6 and SHN/C3H F1 mice... Male and
female C57BL/6 mice subjected to energy restriction from 4 wk of age and
tested
at 3 mo of age became torporific (body temperature less than 31 degrees
C) at
ambient air temperatures of 20-22 degrees C, whereas control animals
stayed
euthermic (greater than 35 degrees C).... Energy restriction decreased
mitotic activities to
approximately 30% of control values in both jejunum and epidermis in 3-
mo-old
female C57BL/6 mice maintained at 20-22 degrees C. However, this
suppression of
mitotic activities was antagonized by housing the energy-restricted mice
at 30
degrees C for 2 wk, indicating that torpor plays a substantial role in
suppressing mitotic activities in energy-restricted mice.
PMID: 1619471, UI: 92318012
3: Mech Ageing Dev 1994 Jul;75(1):59-67
Decreased cellular proliferation by energy restriction is recovered by
increasing housing temperature in rats.
Jin YH, Koizumi A
We investigated the effects of life-prolonging energy restriction (ER) on
body
temperature (BT) and cellular proliferation in rats. Animals were fed
either a
control diet (C: 220 kJ/day) or an ER diet (110 kJ/day) from 7 weeks of
age, and
were housed at 20-22 degrees C [or] 30 degrees C (ER + I) at 20
weeks of age. ...Long-term ER reduced the
mean BT by 1 degree C, and reduced cellular proliferation in the jejunum,
epidermis, pituitary, and lung. At 30 degrees C, the inhibitions were
partially
lifted in the examined organs except in the pituitary. Therefore,
decreased
cellular proliferation in the various organs after long-term ER in rats
is
lifted as it is in mice.
PMID: 9128754, UI: 97274669
Any ideas on any of the above?
-Michael
Randall Parker
Is it such a good idea to inhibit mitosis in pituitary cells? Does the
pituitary shrink with age?
Also, are CR and ER different terms for the exact same idea?
On Sat, 07 Oct 2000 01:32:19 GMT esteemed mik...@my-deja.com did'st hold
forth thusly:
Aubrey de Grey
Sorry for my extended absence (abroad). Michael Rae wrote:
> Could this be the mechanism used for ATP synthesis before the (putative)
> symbiotic incorporation of the proto-mt bacteria?
Certainly it could: a few other people have made the same suggestion.
> > so it's quite possible that there is reduction to water most of
> > the time but electrons are fumbled to make superoxide when the system
> > is overloaded.
>
> You've lost me, here. Go slowly, please. You appear to be saying that the
> PMOR normally takes in some spare NADH as it does big time in RHH, but
> that in CR fewer e- are fumbled because the system is not as overloaded
> (less e- hanging around at some step on the PMOR's equivalent to the ETS
> and consequently being dropped while waiting to be taken up by the next
> step in the chain). But the abstract says there's an INCREASE in NADH
> oxidation by the non-mt mechanism, which you hypothesize may be the PMOR.
> Should this not then lead to MORE e- being crammed into the PMOR, & hence
> MORE PMOR e- fumbling?
More than in ad lib mitochondrially wild-type cells, yes, but that's OK.
What I'm proposing is:
- in ad lib mitochondrially wild-type cells, there is no superoxide
production at the cell membrane but a fair amount at the mitochondrion
- in CR mitochondrially wild-type cells, there is still hardly any
superoxide production at the cell membrane but there's a lot less
than normal at the mitochondrion
- in mitochondrially mutant cells (CR or ad lib) there is essentally
no superoxide production at the mitochondrion but plenty at the cell
membrane.
In other words, the CR mito-wt cells are striking a balance that makes
net superoxide production minimal, at the cost of less ATP flux and so
less of certain types of stress-resistance (eg cold) that have to do
with ATP availability but not free radical flux.
> Also, from the abstract above:
> > It may be considered that the activation of a heat-producing mechanism
> > is a very important physiological function in such a condition.
> But CR animals have LOWER body temperatures!
I don't think we can read much into body temperature. CR animals have
lower body temperatures, but they also have higher surface-to-volume
ratio and are insulated by far less fat, both of which would give a low
body temperature even with the same specific metabolic rate. (As I've
mentioned in the past, I essentially follow the McCarter/Masoro line on
this.)
> Still: this would suggest that raising ambient temperature might reverse
> this CR effect. Do you think this is plays a role in the curiosity which
> follows?
>
> 1: Mech Ageing Dev 1996 Nov 29;92(1):67-82
>
> A tumor preventive effect of dietary restriction is antagonized by a high
> housing temperature through deprivation of torpor.
Possibly. It would be interesting to measure the specific metabolic
rate (by oxygen consumption) in such animals.
> The above is explained as being related to reversal of torpor's slowing
> of mitosis; but why would torpor reduce mitosis? I don't see any obvious
> connection to the above; is there one?
>
> 2: J Nutr 1992 Jul;122(7):1446-53
>
> Mitotic activity in mice is suppressed by energy restriction-induced
> torpor.
Hm. The best I can think of is that the cells that showed temperature-
dependent mitosis are ones whose internal temperature is quite sensitive
to ambient temperature, so they work like poikilotherms' cells in which
everything goes faster in the warmth. This would predict no difference
in cells that are relatively impervious to ambient temperature. I'm not
sure this is right though -- just a guess.
Aubrey de Grey
Randall Parker
Has ambient temperature's effect ever been controlled for in studying CR
vs normal diets on rat and mouse life expectancy?
ie would a higher ambient temp in CR rodents allow a longer life by
allowing the body to metabolise less? Or would cooler temp allow the body
to have a lower temp and therefore somehow lengthen life that way?
On 20 Oct 2000 21:28:35 GMT esteemed Aubrey de Grey did'st hold forth
thusly:
Aubrey de Grey
Randall Parker wrote:
> Has ambient temperature's effect ever been controlled for in studying CR
> vs normal diets on rat and mouse life expectancy?
The Koizumi 1996 study Michael mentioned is the only one I know, and its
results are inconclusive -- they found that high ambient temperature
reduced CR lifespan in females of one strain but not in males of another.
Thus the effect is strain- and/or gender-specific and is likely to be
under the control of multiple factors (as you guessed).
Aubrey de Grey