cron-web.org

[A1CR]

A CRONie noted:

> http://www.freepatentsonline.com/6406853.html
>
> The fasting mRNA and protein levels of nearly every ER
> chaperone studied were found to be significantly and
> consistently reduced in the livers of CR mice
> chronically fed a low calorie diet. In the case of
> GRP78, levels decreased by approximately 66%.
>
> ***This one caught me off guard. I thought CR
> increased the chaperone proteins (AKA heat shock
> proteins). Since these help repair cellular damage I
> don't see how CR is helping us here. Prediction -
> elsewhere the article mentions re-feeding increases
> these proteins. Prediction #1 - I bet intermittent
> fasting allows the benefits of CR without the
> suppression of the proteins.***

Spindler et al and other groups had shown that CR
up-regulated heat shock
proteins. The paper below that is free to all full text and
others like it
reported that heat shock or stress proteins do counter
age-related lower
levels of heat shock proteins.

Colotti C, Cavallini G, Vitale RL, Donati A, Maltinti M, Del
Ry S, Bergamini
E, Giannessi D.

Effects of aging and anti-aging caloric restrictions on
carbonyl and heat
shock protein levels and expression.

Biogerontology. 2005 Dec;6(6):397-406.

PMID: 16518701

http://tinyurl.com/rx3j2

Heat shock proteins (Hsps) are induced by stressful stimuli
and have been shown to protect cells and organs from such
stresses both in vitro and in vivo, and play a positive role
in lifespan determination. An attenuated response to stress
is characteristic of senescence and no Hsp induction is
observed upon exposure to stress and no protective effect of
a mild stress is observed in cells from aged individuals.
The artificial over-expression of Hsps, can produce a
protective effect against a variety of damaging stimuli in
cells from aged rats or aged humans, in whom cardiovascular
disease is a major cause of morbidity in older age. Here, we
show that aging significantly decreases the levels of Hsp27,
Hsp60, Hsp72 and Hsc70 in right atrium and left ventricle of
the rat heart, both at level of protein and of mRNA. Two
different caloric restriction regimens have been found to
counteract in part the decrease in the levels of Hsp
expression in the aged heart tissue as well as the tendency
to an increase of the levels of carbonyl in cardiac
proteins. Our data suggest that cardiac Hsp levels may be a
determinant of longevity in rodents, and that generation of
new regimens of caloric restriction may eventually show how
to improve modulation of cardiac aging.



http://tinyurl.com/qqclu

The ansamycin antibiotic, geldanamycin, targets the hsp 90
protein chaperone and promotes ubiquitin-dependent
proteasomal degradation of its numerous client proteins.
Bortezomib is a specific and potent proteasome inhibitor.
Both bortezomib and the geldanamycin analogue,
17-N-allylamino-17-demethoxy geldanamycin, are in separate
clinical trials as new anticancer drugs. We hypothesized
that destabilization of hsp 90 client proteins with
geldanamycin, while blocking their degradation with
bortezomib, would promote the accumulation of aggregated,
ubiquitinated, and potentially cytotoxic proteins. Indeed,
geldanamycin plus bortezomib inhibited MCF-7 tumor cell
proliferation significantly more than either drug alone.
Importantly, while control cells were unaffected, human
papillomavirus E6 and E7 transformed fibroblasts were
selectively sensitive to geldanamycin plus bortezomib.
Geldanamycin alone slightly increased protein
ubiquitination, but when geldanamycin was combined with
bortezomib, protein ubiquitination was massively increased,
beyond the amount stabilized by bortezomib alone. In
geldanamycin plus bortezomib-treated cells, ubiquitinated
proteins were mostly detergent insoluble, indicating that
they were aggregated. Individually, both geldanamycin and
bortezomib induced hsp 90, hsp 70, and GRP78 stress
proteins, but the drug combination superinduced these
chaperones and caused them to become detergent insoluble.
Geldanamycin plus bortezomib also induced the formation of
abundant, perinuclear vacuoles, which were neither lysosomes
nor autophagosomes and did not contain engulfed cytosolic
ubiquitin or hsp 70. Fluorescence marker experiments
indicated that these vacuoles were endoplasmic reticulum
derived and that their formation was prevented by
cycloheximide, suggesting a role for protein synthesis in
their genesis. These observations support a mechanism
whereby the geldanamycin plus bortezomib combination
simultaneously disrupts hsp 90 and proteasome function,
promotes the accumulation of aggregated, ubiquitinated
proteins, and results in enhanced antitumor activity.