X-Message-Number: 28711
Date: Sun, 3 Dec 2006 12:06:18 -0800 (PST)
Subject: glycotoxin restriction extends rodent lifespan

[Feed restriction has extended lifespan in a wide variety of short lived
animal species. It had been assumed that the toxic effect of ad-libitum
feed consumption was due to excess calories. In the last several years
this assumption has been proven to be false. In nematodes, the benefit of
feed restriction is now ascribed to the restriction of coenzyme Q. In
drosophila, the benefit of feed restriction has been ascribed to protein
restriction. In mice, the benefit of feed restriction has been ascribed
to glycotoxin restriction. Over the years there have been a number of
failures in CR studies, where lifespan was not extended. These can be
explained, in the case of rodents, by a failure to control for glycotoxin

[Glycotoxin content of rodent chow can be increased by roasting it at
high temperatures during sterilization. Rodents are adapted to consuming
only raw food in the wild, and they may be more vulnerable than humans to
the deletarious effects of Advanced Glycation End-products. Below serum
AGE levels closely predicted two year survival. Calorie intake by itself
was without effect. Note that glycotoxins are believed themselves to
affect body weight by influencing water retention.]

Diabetes June 2004 Volume 53 Supplement 2 A343 1426-P
Amelioration of Insulin Resistance, Weight Gain and Markers of Oxidant
Stress in Aging Mice by Dietary Glycotoxin Restriction: A Therapeutic
Alternative to Caloric Restriction?
  Insulin Resistance (IR) and T2D are prevalent in older adults, and
preventable in animals by caloric restriction (CR), which is also known
to extend survival. Dietary AGE restriction prevents diabetic tissue
injury and recent data suggest that it may prevent IR in
db/db(+/+) mice. Herein we asked whether AGE restriction and CR have
similar effects on IR and OS in normal mice. In a 24-mo study, body
weight (BW), fasting glucose:insulin ratio (GIR), serum AGE (sAGE),
glutathone (GSH/GSSG), F8-isoprostanes (8-iso) and 2-ear survival were
assessed in C57BL/6 mice (age: 4 mos, n=20/group) kept on
different diets: Group A) regular ad lib (NIH-31, 323 AGE u/mg
protein); Group B) CR (60% of group A (NIA, 329 AGE u/mg); Group C) Low
in AGE, ad lib (NIH-31, L-AGE; 154 AGE u/mg) and Group D) CR (60% of
A) but high in AGE (H-AGE/CR: 928 AGE u/mg). At 24 mos, the following
data were obtained (Table 1):

Table 1
          Groups BW fasting- sAGE   8-iso   GSH/     2y-
                 (g)  GIR   (u/ml) (pg/ml)  GSSG  survival
H/CR           D  29  11     60     226      90%     0/22
Regular/Ad-Lib A  38  12     42     103     100%     2/22
Regular/CR     B  28  21     23      92     160%     5/22
L/Ad-Lib       C  31  20     20      58     207%     9/22

  Conclusions: 1. Long-term AGE restriction, like CR, prevents
age-related IR, weight gain, systemic OS and extends survival in mice,
but without compromising nutrient or energy content. 2. CR, without
restriction in glycoxidant content reduces BW, but fails to protect
against IR, AGE burden and OS, leading to reduced survival.

[Coenzyme Q10 is nontoxic in nematodes. It is dietary coenzyme Q8 which
reduces their lifespan.]

Science. 2002 Jan 4;295(5552):120-3.
Extension of life-span in Caenorhabditis elegans by a diet lacking
coenzyme Q.
  The isoprenylated benzoquinone coenzyme Q is a redox-active lipid
essential for electron transport in aerobic respiration. Here, we show
that withdrawal of coenzyme Q (Q) from the diet of wild-type nematodes
extends adult life-span by approximately 60%. The longevity of clk-1,
daf-2, daf-12, and daf-16 mutants is also extended by a Q-less diet. These
results establish the importance of Q in life-span determination. The
findings suggest that Q and the daf-2 pathway intersect at the
mitochondria and imply that a concerted production coupled with enhanced
scavenging of reactive oxygen species contributes to the substantial
life-span extension.

Mech Ageing Dev. 2006 Jul;127(7):643-6. Epub 2006 Apr 17.
Restriction of amino acids extends lifespan in Drosophila melanogaster.
  Dietary restriction extends adult Drosophila melanogaster life span
when the concentration of dietary yeast is diluted in a media with
abundant carbohydrates. Here we vary the concentration of casein as a
source of amino acids in adult diet to uncover a quality of nutrient
yeast responsible for longevity control. Longevity is maximized upon diet
with intermediary levels of casein. Differences in survival are not
caused by elevated age-independent mortality; the longevity maximum at
intermediate casein does not arise because casein is non-specifically
harmful at higher concentrations. Furthermore, fecundity increases when
the level of dietary casein is elevated. The demographic phenotypes of
adult Drosophila maintained on intermediate levels of casein resemble
their response to limited dietary yeast. Dietary restriction through
dilution of yeast may extend longevity because this limits the intake of
amino acids.

[Here's are some examples of failures in a CR experiments.]

Aging (Milano). 1995 Apr;7(2):136-9.
Is late-life caloric restriction beneficial?
  Caloric restriction initiated in young mice and rats results in
increases in mean and median life span. When caloric restriction is
implemented in older animals, an increase in life span is still
observed; however, the magnitude of the increase is not as great as that
observed in animals calorie restricted since they were young. Here we
report the results of a pilot study in which caloric restriction was
initiated in mature, older rats. Survival rates and terminal pathology
were characterized and compared between a cohort of 17 continually ad
libitum fed Long Evans rats and a cohort of 18 Long Evans rats, which were
gradually introduced to 33% restriction in diet consumption at 18 months
of age. No difference in the median life span was observed between the
two groups. The data suggest there may be a level of maturity, or a stage
in the aging process, after which caloric restriction no longer increases

Exp Gerontol. 1980;15(4):237-58.
Survival and disease patterns in C57BL/6J mice subjected to undernutrition.
Cheney KE, Liu RK, Smith GS, Leung RE, Mickey MR, Walford RL.

[One can avoid excessive AGEs in food by avoiding food that has been
processed at high temperatures. Example: Boiled oatmeal is low in AGEs,
while "Fiber 1" bran cereal is high in AGEs since "Fiber 1" is extruded
at a higher temperature. In general, steam, or boil instead of fry, or
broil. However it must be added that humans are not rodents, and may not
benefit much from dietary AGE reduction.]

[Can one reduce serum AGEs by means other than diet? Yes, activated
carbon can absorb AGEs, and this has increased lifespan in rodents. In
Japan a prescription activated carbon product has been used for years in
the treatment of kidney failure patients. However the primary dietary
toxin specific for humans which is scavenged by this product may have
another source.]

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