cron-web.org

[MR]

(2005-05-04)

Restriction of the amino acid methionine causes an apparent retardation
of aging in rats. This finding has been published several times, but
usually weakly; a study a couple of years back (1) firmed up the case
and reduced the possibility that this is just crypto-CR -- as appears to
be the case for protein restriction. Crypto-CR seemed esp credible
because these animals are significantly smaller than normal; by
pair-feeding some of the MetR animals with animals eating normal chow,
they were able to apparently eliminate this factor -- in rats. However,
it did not do this for mice, leaving open the possiblity that it might
be some kind of strains-specific thing (the typically-used rat strain,
eg, is highly susceptible to renal disease).

However, a new study (2) by Richard Miller and other shows a modest, but
significant, LS extension following MetR, along with considerably
preserved physiological function.

----------
Compared with controls, Meth-R mice have significantly lower levels of
serum IGF-I, insulin, glucose and thyroid hormone. Meth-R mice also have
higher levels of liver mRNA for MIF (macrophage migration inhibition
factor), known to be higher in several other mouse models of extended
longevity.

Meth-R mice are significantly slower to develop lens turbidity and to
show age-related changes in T-cell subsets. They are also dramatically
more resistant to oxidative liver cell injury induced by injection of
toxic doses of acetaminophen. The spectrum of terminal illnesses in the
Meth-R group is similar to that seen in control mice.
--------
Details in the nonspecialist scientific press:

"The team transferred 6-week-old female mice to chow that contained
either a full dose of methionine or 23% of the normal amount and studied
the animals for the rest of their lives. At first, many of them died,
perhaps because the animals weren't getting enough methionine to
subsist. So the team bumped up the methionine content to 28% of normal
when the mice were 4 months of age and 33% at 6 months. These
modifications improved mice survival. The oldest animals in the control
group lasted 1144 days, whereas those on the restricted diet persisted
more than 100 days longer, suggesting that cutting back on methionine
extends the lives of mice as well as rats." (3)

Additionally, a photo in (3) shows old MetR and normal-chow animals at
an unspecified advanced age. The MetR mouse looks a LOT younger than the
decrepit old bastard fed regular chow.

However, crypto-CR STILL hasnt' been totally ruled out. "In a 5-day test
on a small group of animals, the researchers found that mice on the
low-methionine diet ate at least as much as did control animals,
suggesting that the rodents didn't live longer because they consumed
less, says Miller." (3) But "Roger McCarter ... says that assessing
food intake alone isn't a good test ... To really get at whether mice on
low-methionine fare are experiencing CR, researchers need to rigorously
measure how much food animals take in, how much they excrete, and how
active they are, says McCarter. "If they eat the same but weigh less,
where are those extra calories going?" he asks. Miller agrees that the
animals might not be absorbing all of the food they're consuming. The
mice produce more urine than normal, he says, suggesting that they are
excreting some of what they're eating; the animals would need the extra
liquid to dilute breakdown products from the surplus nutrients."

The low growth factor levels are interesting. They certainly COULD be
the result of crypto-CR, but they could also be an anti-aging mechanism
activated by upstream signaling processes activated by low methionine.
It's also worthy of note that Met is in various ways involved in GH
metabolism (eg (4), and that Ames dwarves (who have congenically low GH
and thyroxine) have abnormal metabolism of Met (5,6). Low GH would have
been quite plausible as an anti-aging mechanism until recently; the fact
that GH replacement in Ames dwarves does not shorten their LS (7),
however, throws a very powerful-looking theory much into question, esp
as thyroid hormone replacement DID normalize their LS.

Additionally, MetR is a good anti-cancer treatment in rodents, and has
been the subject of some preliminary human trials; since cancer is the
#1 killer of longevous mice, and a very major killer of rats too, this
alone might explain a LS increase -- but tht won't explain the longer
physiological youth.

Better preservation of GSH might play into it (8) -- but with the
repeated failure of antioxidants to budge lifespan, and the
non-correlation of endogenous AOs with LS, this seems highly unlikely.

I don't recommend trying this -- Met is an essential nutrient, MetR is
even more wildly experimental than CR, the early mortality is scary, and
the effect was much milder than CR -- but this is interesting & could
at least wind up throwing light on the effects of CR, and to further
tweaking of the CR diet. (NB that CR is UNLIKELY to be enhanced by MetR,
as combining it with protein restriction (whic necessarily restricts
Met) has been repeatedly shown not to be beneficial -- but the converse).

I expect, however, that any results we could use will take a long, long
time. With any luck, SENS (9) will give us indefinite youth and
lifespans long before this all gets worked out ...

-MR

1. Zimmerman JA, Malloy V, Krajcik R, Orentreich N.
Nutritional control of aging.
Exp Gerontol. 2003 Jan-Feb;38(1-2):47-52.
PMID: 12543260 [PubMed - indexed for MEDLINE]
http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0208&L=crsociety&P=R11068

2. Richard A. Miller, Gretchen Buehner, Yayi Chang, James M. Harper,
Robert Sigler and Michael Smith-Wheelock
Methionine-deficient diet extends mouse lifespan, slows immune and lens
aging, alters glucose, T4, IGF-I and insulin levels, and increases
hepatocyte MIF levels and stress resistance.
Aging Cell. OnlineEarly.
doi:10.1111/j.1474-9726.2005.00152.x

3: Davenport RJ.
Defining the diet.
Sci Aging Knowledge Environ. 2005 Apr 20;2005(16):nf31. No abstract
available.
PMID: 15843691 [PubMed - in process]

4: Bellone J, Farello G, Bartolotta E, Aimaretti G, Bellone S, Mucci M, De
Matteis F, Ghigo E.
Methionine potentiates both basal and GHRH-induced GH secretion in
children.
Clin Endocrinol (Oxf). 1997 Jul;47(1):61-4.
PMID: 9302373 [PubMed - indexed for MEDLINE]

5. Brown-Borg HM, Rakoczy SG, Uthus EO.
Growth hormone alters methionine and glutathione metabolism in Ames
dwarf mice.
Mech Ageing Dev. 2005 Mar;126(3):389-98.
PMID: 15664625 [PubMed - in process]

6: Uthus EO, Brown-Borg HM.
Altered methionine metabolism in long living Ames dwarf mice.
Exp Gerontol. 2003 May;38(5):491-8.
PMID: 12742526 [PubMed - indexed for MEDLINE]

7. Vergara M, Smith-Wheelock M, Harper JM, Sigler R, Miller RA.
Hormone-treated snell dwarf mice regain fertility but remain long
lived and
disease resistant.
J Gerontol A Biol Sci Med Sci. 2004 Dec;59(12):1244-50.
PMID: 15699523 [PubMed - indexed for MEDLINE]

8. Richie JP Jr, Komninou D, Leutzinger Y, Kleinman W, Orentreich N,
Malloy V,
Zimmerman JA.
Tissue glutathione and cysteine levels in methionine-restricted rats.
Nutrition. 2004 Sep;20(9):800-5.
PMID: 15325691 [PubMed - indexed for MEDLINE]

9. http://www.gen.cam.ac.uk/sens/