CR - the wild test
michaelprice
> ... "Steve Austad has been performing caloric restriction on
> mice that were caught in the wild only two generations ago,
> and finds no lifespan extension whatever compared to ad lib.
> This is of course a very significant result, and a lot of people
> will suspend judgement until it's been repeated and looked into
> in a lot more detail than hitherto (the work was only announced
> in November [2000], at the GSA), but the ad lib "real mice"
> already lived a lot longer than typical lab mice.
I couldn't find anything published. Any more news?
Cheers,
Michael C Price
Aubrey de Grey
Michael Price wrote:
Last I heard, the last mouse died in February of this year and they
were writing it up in June. I'd expect publication very soon, but I
don't know where -- but I also doubt it'll be easily overlooked!
Aubrey de Grey
michaelprice
Would it be a breach of etiquette to ask what you've heard,
word-of-mouth prior to publication?
e.g. Was the last survivor an ad-libber or restricted?
With bated breath,
Michael C Price
Aubrey de Grey
Michael Price wrote:
> Would it be a breach of etiquette to ask what you've heard,
> word-of-mouth prior to publication?
Not necessarily :-) In this case I've told you all I know.
Aubrey de Grey
Dean Pomerleau
This appeared to be a related study in the Austad's wild-type mice,
which shows something important - namely that at least one of
wild-type strains has a max LS of 1450 days, *when fed AL*. This is
apparently *longer* than the max LS of Ames' long-lived dwarf mice,
even when the dwarf mice are calorie restricted (1400 day Max LS).
Here is a follow-up post I made to the CR-Society mailing list when
this article appeared, with discusses some outstanding questions
associated with this study, and its possible implications:
Obviously this is important work.
One additional question that I didn't raise in the above post, is
whether or not we (or more specifically Austad) knows how best to care
for wild-type mice in a laboratory setting. In other words, if CR
fails to extend max LS in wild-type mice in the lab, might it be
analogous to the early failure of CR experiments to extend max LS in
rodents, attributed to the fact that early researchers didn't know how
to care for the animals properly? Once proper care was understood,
all the animals lived longer, and the animals subject to CR lived
longer than the rest.
Of course, the fact that they are living to a ripe-old 1450 days
either says Austad knows how to care for them reasonably well, or
these mice really do have great genes.
Comments appreciated.
--Dean
-----------------------------
[1] Exp Biol Med (Maywood) 2002 Jul;227(7):500-8
Longer life spans and delayed maturation in wild-derived mice.
Miller RA, Harper JM, Dysko RC, Durkee SJ, Austad SN.
"Nearly all the experimental mice used in aging research are derived
from
lineages that have been selected for many generations for adaptation
to
laboratory breeding conditions and are subsequently inbred.
To see if inbreeding and laboratory adaptation might have altered the
frequencies of genes that influence life span, we have developed three
lines
of mice (Idaho [Id], Pohnpei [Po], and Majuro [Ma]) from wild-trapped
progenitors, and have compared them with a genetically heterogeneous
mouse
stock (DC) representative of the laboratory-adapted gene pool.
Mean life span of the Id stock exceeded that of the DC stock by 24% (P
<
0.00002), and maximal life span, estimated as mean longevity of the
longest-lived 10% of the mice, was also increased by 16% (P < 0.003).
Mice
of the Ma stock also had a significantly longer maximal longevity than
DC
mice (9%, P = 0.04).
The longest-lived Id mouse died at the age of 1450 days, which appears
to
exceed the previous longevity record for fully fed, non-mutant mice.
The life table of the Po mice resembled that of the DC controls.
Ma and Id mice differ from DC mice in several respects: both are
shorter and
lighter, and females of both stocks, particularly Id, are much slower
to
reach sexual maturity.
As young adults, Id mice have lower levels of insulin-like growth
factor 1
(IGF-I), leptin, and glycosylated hemoglobin compared with DC
controls,
implicating several biochemical pathways as potential longevity
mediators.
The results support the idea that inadvertent selection for rapid
maturation
and large body size during the adaptation of the common stocks of
laboratory
mice may have forced the loss of natural alleles that retard the aging
process.
Genes present in the Id and Ma stocks may be valuable tools for the
analysis
of the physiology and biochemistry of aging in mice."
PMID: 12094015
michaelprice
> 5) Are we humans more like the wild-type mice or the in-bred mice?
> If we're more like the wild-type mice, and CR doesn't work in
> wild-type mice, then perhaps extending life beyond the current human
> max lifespan (~120 years) through CR may be difficult, a point I've made
> repeatedly
Bad news. We more likely to be like wild-type mice than multi-generational,
in-bred 'lab' mice. I admit this is throughly counter-intuitive, but have a
look
at the telomeric evidence. 'Lab' mice have longer telomeres than wild-type
mice[1] and humans have the shortest telomeres of all the primates[2]. So
we are probably more like wild-type mice than the 'lab' mice. Whether CR
will extend our maximal LS may hinge on Austad's results.
[1] Exp Gerontol 2002 May;37(5):615-27
The reserve-capacity hypothesis: evolutionary origins and modern
implications of the trade-off between tumor-suppression and tissue-repair.
Weinstein BS, Ciszek D.
Museum of Zoology, University of Michigan, 1109 Geddes Ave., Ann Arbor, MI
48109-1079, USA. bret.we...@umich.edu
Antagonistic pleiotropy, the evolutionary theory of senescence, posits that
age related somatic decline is the inevitable late-life by-product of
adaptations that increase fitness in early life. That concept, coupled with
recent findings in oncology and gerontology, provides the foundation for an
integrative theory of vertebrate senescence that reconciles aspects of the
'accumulated damage' 'metabolic rate', and 'oxidative stress' models. We
hypothesize that (1) in vertebrates, a telomeric fail-safe inhibits tumor
formation by limiting cellular proliferation. (2) The same system results in
the progressive degradation of tissue function with age. (3) These patterns
are manifestations of an evolved antagonistic pleiotropy in which extrinsic
causes of mortality favor a species-optimal balance between tumor
suppression and tissue repair. (4) With that trade-off as a fundamental
constraint, selection adjusts telomere lengths--longer telomeres increasing
the capacity for repair, shorter telomeres increasing tumor resistance. (5)
In environments where extrinsically induced mortality is frequent, selection
against senescence is comparatively weak as few individuals live long enough
to suffer a substantial phenotypic decline. The weaker the selection against
senescence, the further the optimal balance point moves toward shorter
telomeres and increased tumor suppression. The stronger the selection
against senescence, the farther the optimal balance point moves toward
longer telomeres, increasing the capacity for tissue repair, slowing
senescence and elevating tumor risks. (6) In iteroparous organisms selection
tends to co-ordinate rates of senescence between tissues, such that no one
organ generally limits life-span. A subsidiary hypothesis argues that
senescent decline is the combined effect of (1) uncompensated cellular
attrition and (2) increasing histological entropy. Entropy increases due to
a loss of the intra-tissue positional information that normally regulates
cell fate and function. Informational loss is subject to positive feedback,
producing the ever-accelerating pattern of senescence characteristic of
iteroparous vertebrates. Though telomere erosion begins early in
development, the onset of senescence should, on average, be deferred to the
species-typical age of first reproduction, the balance point at which
selection on this trade-off should allow exhaustion of replicative capacity
to overtake some cell lines. We observe that captive-rodent breeding
protocols, designed to increase reproductive output, simultaneously exert
strong selection against reproductive senescence and virtually eliminate
selection that would otherwise favor tumor suppression. This appears to have
greatly elongated the telomeres of laboratory mice. With their telomeric
failsafe effectively disabled, these animals are unreliable models of normal
senescence and tumor formation. Safety tests employing these animals likely
overestimate cancer risks and underestimate tissue damage and consequent
accelerated senescence.
Publication Types:
Review
Review, Tutorial
PMID: 11909679
[2] Biochem Biophys Res Commun 1999 Sep 24;263(2):308-14
Human is a unique species among primates in terms of telomere length.
Kakuo S, Asaoka K, Ide T.
Department of Cellular and Molecular Biology, Hiroshima University School of
Medicine, Kasumi 1-2-3, Hiroshima, 734-8551, Japan.
TRF (terminal restriction fragments) length in various tissues of non-human
primates such as Macaca mulatta (rhesus monkey), Macaca fuscata (Japanese
monkey), Macaca fascicularis (crab-eating monkey), Pan troglodytes (common
chimpanzee), and Pongo pygmaeus (orangutan) was at least 23 kb without
exception, which was quite different from that of human somatic tissues
(smaller than 10 kb). The distribution pattern of telomerase activity among
tissues was similar between human and non-human primates, while the activity
level showed some differences such as that strong telomerase activity was
observed in gastrointestinal and lymphocytic tissues from non-human
primates. The human appears to be a unique species among primates in terms
of telomere length. Copyright 1999 Academic Press.
PMID: 10491289
Cheers,
Michael C Price
Thomas Carter
Only one of his three strains of wild mice had a longer mean life
span, 24%. And another had a slightly extended max life span, 9%. The
strains with the longer lifespans, Idaho, and Majuro were smaller than
laboratory mice, and had less IGF-1, leptin, and glycated Hb. It seems
they may have already been voluntarilly calorie restricted compared to
lab mice. The three above mentioned pro-aging parameters are well
documented to be lower in CR animals including humans. All in all I
would take these data to be, so far, in support of the CR life
extending paradigm pending the results of the CR studies. If the CR
study is of all three strains, I expect to see positive results in at
least the bigger strain with the shorter lifespan. I will take this
opportunity to introduce an hypothesis I have had for some time. Will
CR be more effective in larger humans than in the smaller "strain"?
Thomas
Austad's abstract:
Exp Biol Med (Maywood) 2002 Jul;227(7):500-8 Longer life spans and
delayed maturation in wild-derived mice. Miller RA, Harper JM, Dysko
RC, Durkee SJ, Austad SN. Department of Pathology and Geriatrics
Center, University of Michigan School of Medicine, 1500 East Medical
Center Drive, Ann Arbor, MI 48109, USA. mil...@umich.edu
michaelprice
Michael Price:
>> Bad news. We more likely to be like wild-type mice
>> than multi-generational, in-bred 'lab' mice. I admit this
>> is throughly counter-intuitive, but have a look at the
>> telomeric evidence. 'Lab' mice have longer telomeres
>> than wild-type mice[1] and humans have the shortest
>> telomeres of all the primates[2]. So we are probably
>> more like wild-type mice than the 'lab' mice.
>
> Interesting thought Michael P. Study [3] certainly supports the idea that
> wild-type mice have shorter telomeres than lab mice. But is also says
that
> telomere length is not correlated with lifespan in different strains of
> mice, despite the fact that mice are notoriously prone to cancer, the main
> mechanism by which you (and [1]) suggest that shorter telomeres may be
> good from a lifespan perspective.
>
> So in general, if telomere length is not closely linked with lifespan, why
> should the fact that we resemble wild-type mice more than in-bred lab
> mice along this dimension be *the* (or even *a*) strong indication that if
> CR fails to extend max lifespan in wild-mice, it will likely fail in
people
> also, as you seem to suggest here:
Because if we resemble wild-type rodents along one dimension (telomeres:
which may or may not have anything directly to do with lifespan) we are
more likely to resemble them along other dimensions (which are more likely,
collectively, to be lifespan limiting) and hence we may resemble Austad's
wild-type rodents who - rumour has it - have failed to show benefit from CR.
So I still think
> Whether CR will extend our maximal LS may hinge on Austad's results.
Cheers,
Michael C Price
michaelprice
> On the topic of whether humans are more like wild-type mice or lab mice:
>
> One obvious objection to the idea we're more like lab mice is the
> claim, that, unlike lab mice which reproduce very rapidly and therefore
> have become reasonable far removed genetically from their wild-type
> ancestors, we humans have a long reproductive cycle, and as a result
> aren't genetically very far removed from our wild heritage.
>
> But it seems to me that one need look no further than the evolution of
> adult tolerance of lactose to see a counterexample. From the evidence
> reviewed in [1], its pretty clear that a few thousands years ago, all
> human adults were lactose intolerant. But with the domestication of
animals,
> milk became a readily available source of food (and lots of important
> nutrients) for adults. The result was a substantial advantage in survival
> (and more importantly reproductive fitness) among those few adults with
> the mutant gene that allowed them to continue to digest milk beyond
> childhood. Through survival of the fittest, this reproductive advantage
has
> translated itself into a pretty high prevalency for gene that allows adult
> production of lactase, particularly among those of us of Northern European
> descent.
>
> Putting aside the whole paleo argument about whether milk is a food we
> should be consuming (even those of us who *can*), the point is that
> significant genetic changes have occurred that differentiate us from our
> ancestors, and such changes have occurred over a relatively short
> timescale, due to relatively modern survival pressures that have resulted
> from changes in our culture/technology/lifestyle.
>
> Interestingly, this particular example has to do with a topic near and
> dear to our hearts (the way our body handles food), and therefore
> would seem particularly relevant to a discussion of the significance to
> humans of CR experiments with lab vs. wild-type mice.
>
> If we've changed from our wild-type ancestors along this one dimension
> (lactose tolerance), whose to say he haven't changed genetically along
> other dimensions as well, to resemble lab mice more than wild-type mice?
> As outlined in my previous message, there are certainly many dimensions
> along which we *appear* to resemble lab mice more than wild mice.
>
> --Dean
I agree, you're quite right, there are many reasons for thinking we should
lab-type rather than wild-type (which was why I started out saying it was
counter-intuitive), with only the telomeres going against this. They may be
irrelevant, I admit, but if (still a big if) Austad's mice don't show CR LE
- as an anti-aging regime then CR obviously becomes much more
problematical for humans, although it wouldn't refute the manifold health
benefits of being slim (or even just non-obese).
> ----------------------------------------------
> [1] Scand J Gastroenterol Suppl 1994;202:7-20
>
> Genetics and epidemiology of adult-type hypolactasia.
>
> Sahi T.
>
> The prevalence of adult-type hypolactasia varies from less than 5% to
almost 100% between different populations of the world. The lowest
prevalence has been found in northwestern Europe, around the North Sea, and
the highest prevalence in the Far East. The reason for the variation is that
selective (primary) hypolactasia is genetically determined by an autosomal
recessive single gene. It is assumed that thousands of years ago all people
had hypolactasia in the same way as most mammals do today. At that time in
cultures where milk consumption was started after childhood, lactase
persistence had a selective advantage. Those people with lactase persistence
were healthier and had more children than people with hypolactasia, and the
frequency of the lactase persistence gene started to increase. The present
prevalence of hypolactasia can be explained fairly well by this culture
historical hypothesis. ...
>
> PMID: 8042019
Cheers,
Michael C Price
Tim
than the length is responsible for replicative senescence in vitro.
However that may apply to organismal aging.
E.G.
J Biol Chem 2002 Aug 9, 277(32)28609-17
Reversible Manipulation of Telomere Expression and Telomere Length.
IMPLICATIONS FOR THE IONIZING RADIATION RESPONSE AND REPLICATIVE
SENESCENCE OF HUMAN CELLS.
Rubin MA,Kim SH,Campisi J
...although telomerase negative cells with short telomeres senesced
after fewer doublings than those with long telomeres, telomere length
per se did not correlate with senescence. Our results support a role
for telomere structure, rather than length, in replicative senecence.
PMID: 12034742
Tim
Ian Goddard
IAN: Just got the scoop on that study: last mouse died
last month. There was no difference in mean lifespan
between CR and adlib wild mice, and if anything, CR
mean LS was slightly shorter!! However, and here's
the good news, longest lived animals were all from
the CR group. This suggests CR had no to a slightly
adverse effect on most wild mice, but for a subset
it did its usual thing, extending maximum lifespan.
Nevertheless, the effect on most mice is "bad news."
What I state above is all I know, which is just the
general information. Obviously these unexpected and
complex findings require a lot of analysis of many
factors involved. Furthermore, given that this is
the only CR longevity study in wild mice I've been
able to find, we're going to need replication before
we can really be sure about what were looking at.
Also this study has not been published yet and thus
has not been subjected to peer review. But Austad is
a respected researcher and my instinct would be to
trust his work, and furthermore, I believe that the
findings also tend to fly in the face of his own CR
hypothesis, so it doesn't look like bias is involved.
A couple things worth considering: CR-induced lifespan
effects differ in different mouse strains, even in lab
mice. See http://users.erols.com/igoddard/cr-adult.gif
which shows a difference between the effect of CR on
the longevity of B6 versus B10 mice. And note that the
B6 mice had the best CR effect yet were started on CR
later in their lives, which would lead one to expect
that they should have had a lesser CR effect. So we
can see that genetics plays a role in what CR does
and whose to say there's not some genetic types
that, like the type of wild mouse tested by Austad,
would display the counter-intuitive results he found?
While I'm very busy these days, after reading the
quotation above I spent hours searching PubMed for CR
studies involving wild mice. There's virtually nothing!
But I found a couple items. PMID 10526115 found the CR
(aka DR) conferred neuroprotection in wild-type mice,
stating: "PS1 mutant knockin mice and wild-type mice
maintained on a DR regimen for 3 months exhibited
reduced excitotoxic damage to hippocampal CA1 and
CA3 neurons compared to mice fed ad libitum."
I also found what may be an important clue that might
explain confounding results in wild-mice studies. PMID
9088903 indicates that the use of wild mice in lifespan
research has been avoided. Here's the reason why: "Wild
populations are not practical to use, despite some
theoretical advantages, as genes retarding aging would
be confounded with those reducing the stress of captivity."
Hypothesis: CR increases hyper alertness while ad lib
feeding increases relaxation. Regarding the counter-
intuitive effect of CR on the mean LS of the wild mice
used by Austad, perhaps by decreasing relaxation CR
maximized the stress of captivity for most wild mice.
That increased stress attenuated the +LS effect of CR.
"To lengthen thy life, lessen thy meals." Ben Franklin
Caloric Restriction: http://users.erols.com/igoddard/cr.htm
michaelprice
Scoop of the century, Ian.
Thanks, I'll split the $200 from Brian Delaney with you :-)
Perhaps CR only works on cold-blooded beasties?
Cheers,
Michael C Price
"Ian Goddard" <igod...@erols.mom> wrote in message
news:7cfdnuotn58mto1id...@4ax.com...
Tim
role in endcapping , so the connections are intriguing. I did misstate
that length didn't matter but the end structure may be more important.
Science 2002;295(5564):2446-9
Senescence induced by altered telomeric state, not telomeric loss.
Karlseder J et al
Primary human cells in culture invariably stop dividing and enter a
state of growth arrest called replicative senescence. This transition
is induced by programmed telomere shortening, but the underlying
mechanisms are unclear. Here, we report that overexpression of TRF2, a
telomeric DNA binding protein, increased the rate of telomeric
shortening in primary cells without accelerating senescence. TRF2
reduced the senescence setpoint defined as telomere length at
senescence from 7 to 4 kilobases. TRF2 protected critically short
telomeres from fusion and repressed chromosome-end fusions in
presenescent cultures which explains the ability of TRF2 to delay
senescence. Thus replicative senescence is induced by a change in
protected states of shortened telomeres rather than by a complete loss
of telomeric DNA.
PMID: 11923537
Proc Natl Acad Sci USA 1999 Dec 21;96(26):14899-904
DNA double strand breaks repair proteins are required to cap the ends
of mammalian chromosomes.
Bailey SM et al
...an essential telomere function, the ability to cap and thereby
protect chromosomes from end-to-end fusions was assessed in
repair-deficient mouse cell lines...telomeric fusions were not
observed in any of the repair proficient controls and occured only
rarely in a p53 null mutant. In striking contrast, chromosomal end
fusions that retained telomeric sequence were observed in
nontransformed DNA-PK(cs)-deficient cells where they were a major
source of chromosomal instability...These studies demonstrate that DNA
double-strand break repair genes play a dual role in maintaining
chromosomal stability in mammalian cells, the known role in repairing
incidental DNA damage, as well as a new protective role.
PMID: 10611310
Tim
Ian Goddard
>Wowww!
>Scoop of the century, Ian.
>
>Thanks, I'll split the $200 from Brian Delaney with you :-)
>
>Perhaps CR only works on cold-blooded beasties?
IAN: Thanks. However, versus 70 years of replicated
lifespan research in all types of lab mice and every
other kind of living thing subjected to CR routinely
finding both mean and max LS extension, I don't see
one unpublished study of wild mice as carrying the
weight to shift our understanding of CR. A review
I quoted explained why wild mice could be expected
to yield confounding results, which is apparently
why wild animals have not been used in CR research.
I'd also put more significance for human-comparison
purposes in the ongoing CR monkey study than any CR
wild-mouse study, since humans are more like monkeys:
Ongoing CR-monkey-study update: "In the monkeys...those on
reduced feeding since the study started are dying at a rate
that is about half that of the monkeys receiving a full food
ration." Associated Press: Eating less may extend human life.
August 1, 2002 : http://www.msnbc.com/news/788746.asp?0si=-
"To lengthen thy life, lessen thy meals." Benjamin Franklin
Caloric Restriction: http://users.erols.com/igoddard/cr.htm