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CRON4healthyfuture posts summaries from several papers being presented at the upcoming American Association of Aging Conference, including an optimistic one by Ingram about the prospects of CRON "working" in primates. Another paper by Merry explores on the impact of CR on free radical production and mitochondria bioenergetics - which also looks very encouraging. Still another covers the powerful evidence that the elder Okinawans own much of their longevity to their CRON lifestyle. A final paper details how important insulin signaling (which is reduced by CRON) contributes to the aging process. Quite a good crop of research findings!

Title of this article:

2005 Am Aging Assoc Gala Event; Ingram confident CR will work
in primates (May 29, 2005 )

I thought there were some interesting updates to their
website....basically, the "headliners" got their "speaking points"
posted.

Ingram summarizes the evidence in primates, and notes that the
reduction in mortality in CR primates has not yet reached statistical
significance......

http://www.americanaging.org/2005/oral/ingram.pdf

"...Results accumulated to date indicate that CR rhesus monkeys are
healthier than controls based on the following observations: (1)
reduced incidence of various diseases; (2) significantly better
indices of predisposition to disease, such as lower insulin levels
and greater insulin sensitivity, reduced blood lipids and pressure,
decreased arterial stiffness, and elevated HDL; and (3) alterations
in candidate biomarkers of aging. Results of recent behavioral
studies also indicate enhanced performance in a motor task that shows
age-related decline, but we have seen no evidence as yet that the
age-related loss in the volume of the neostraitum, which regulates
motor performance, has been attenuated by CR. In a related study we
have observed that short-term CR in adult rhesus monkeys can provide
protection against a neurotoxic insult similar to previous
observations made in rodents. CR rhesus monkeys that were juveniles
at the onset of the study showed delayed skeletal and sexual
maturation, and all CR groups have lower body temperatures than
controls. These latter physiological observations are manifestations
of a fundamental shift in life history strategy, from growth and
reproduction to life maintenance, and appear to reflect adaptations
in metabolic and protective gene expression. Although preliminary
data suggesting that CR animals exhibit reduced mortality have not
yet reached statistical significance, this intervention does appear
to exert beneficial effects in primates that suggest a reduced rate
of aging."

This Dr. Merry over in the UK found some very interesting findings
regarding CR mitochondria that may finally begin to settle the
controversy about "what the heck is going on". Among his findings, I
thought it was interesting that 1) Insulin was equivalent to
refeeding 2) A change in membrane unsaturation "just doesn't cut it"
when trying to explain the changes 3) Proton leak was increased 4)
A decrease of 10-15% in membrane potential was seen under State 4
respiration, or basically, when you push down all the way on the "gas
pedal", these mitochondria spit out all of your energy as exhaust
rather than torque.

http://www.americanaging.org/2005/oral/merry.pdf

"In a study of mitochondria isolated from a range of tissues of BN
male rats maintained on 55% control food intake from 2 months of
age, a significant reduction in ROS generation was observed. This
effect was seen for a range of tissues at all ages studied. However,
no depression in mitochondrial respiration rate during either
non-phosphorylating or phosphorylating respiration was induced by CR
feeding, indeed a significant increase in the rate of respiration was
observed in brown fat mitochondria. Therefore the depression in
mitochondrial ROS generation is not considered to be a simple rate
effect. To identify the functional mechanism underlying the reduced
ROS generation, detailed studies of mitochondrial bioenergetics have
been completed. An increase in the proton leak of the inner
mitochondrial membrane was maintained throughout the life span of
CR rats that was associated with a 10-15% decrease in the membrane
potential maintained under state 4 respiration conditions.
Re-feeding, or an elevation of circulating plasma insulin
concentrations prior to mitochondrial isolation in CR animals
decreased the proton leak rate. The enhanced proton conductance in CR
animals could not be explained by a modification of the lipid
composition of the mitochondrial membrane. It may reflect changes in
the surface area of the inner mitochondria membrane and/or
transporter activity, such as the adenine nucleotide translocator."

Yes, Virginia, the Okinawans are calorically-restricted.......

http://www.americanaging.org/2005/oral/willcox.pdf

"A consistent finding in our study population of older Okinawans,
which includes centenarians and other elderly individuals, has been
that they exhibit several characteristics of the caloric restriction
phenotype. This includes a small body size, low body fat levels, low
risk for chronic disease, high physical and cognitive function, and
long life expectancy. Since long term caloric restriction is a robust
means of reducing age-related diseases and extending lifespan in
multiple species but the effects in humans are uncertain, we analyzed
six decades of population data for evidence that nutrition-related
factors, particularly those related to caloric restriction, may have
played a role in the healthy aging seen in older Okinawans. Data on
caloric intake, energy expenditure, other nutritional variables,
anthropometric measures, age-related hormones and morbidity/mortality
outcomes support a caloric restriction phenotype for elderly
Okinawans that may have contributed to their exceptionally healthy
longevity. These data include low caloric intake, an energy deficit
at younger ages, low body mass index, and relatively high plasma DHEA
levels at older ages with concomitant low risk for
morbidity/mortality. This study is consistent with the well-known
animal literature on caloric restriction-linked phenotypes and
longevity and provides support for the caloric restriction hypothesis
in humans. Further study of the potential role of caloric restriction
and other nutritional interventions for improving human health and
longevity is warranted."

Cheryl Conover over at the Mayo Clinic hit a homerun in a finding
that basically confirms that the IGF-1 axis can modulate aging. A
30-40% increase in lifespan is not too shabby.....they are dwarves,
though.......

http://www.americanaging.org/2005/oral/conover.pdf

THE IGF SYSTEM AND LONGEVITY
C. Conover (P)

Mayo Clinic, 200 First Street SW, Rochester, MN 55905

A reduction in insulin-like growth factor (IGF)-I signaling has been
associated with an increase in longevity and delayed onset of
age-related disorders in diverse species. The IGF system is complex
with ubiquitous ligands and with IGF receptors present on virtually
all cells. However, IGF binding proteins (IGFBPs) and IGFBP proteases
ultimately determine ligand availability and, hence, response. Our
overall hypothesis is that the aging process is regulated, at least
in part, by a specific protease, so-called pregnancy-associated
plasma protein-A (PAPP-A), which degrades inhibitory IGFBP-4 thereby
increasing IGF-I bioavailability without a change in IGF-I
expression. The corollary to this is that PAPP-A deficiency, by
decreasing local IGF availability and receptor signaling, would
result in increased longevity. To test this hypothesis, we generated
PAPP-A knock-out mice mice. These mice are born as proportional
dwarfs due to impaired IGF-II bioavailability during early
embryogenesis. Otherwise, these mice appear healthy and show normal
postnatal growth. We found that this suppression of PAPP-A expression
through genetic manipulation results in the extension of lifetime
survival of these mice by 30-40% in both males and females. This was
not associated with alterations in serum glucose, insulin, IGF-I or
growth hormone levels, and dietary intake was not significantly
different between PAPP-A knock-out mice and wild-type littermates.
These data indicate that the PAPP-A knock-out mouse is a valuable new
model for investigating molecular issues of aging that relate to
IGF-I signaling, and point to PAPP-A as a possible drug target with
potential to regulate longevity and age-related diseases by moderate
restraint of IGF signaling.

And thioredoxin overexpression is looking like it will extend
lifespan in mice.....

http://www.americanaging.org/2005/ikeno%201.pdf

"The survival study, which is ongoing, showed the survival of
Tg(hTrx)+/0 and wild-type mice at 30 months was 67% and 52%,
respectively."