X-Message-Number: 25645
Date: Sat, 29 Jan 2005 20:43:09 -0800 (PST)
From: Doug Skrecky <>
Subject: proteasomes may be central to human aging

Biogerontology. 2004;5(1):55-61
Proteasome inhibition induces a senescence-like phenotype in primary human
fibroblasts cultures.
  Senescent human fibroblasts exhibit several genetic and biochemical
differences as compared to their young counterparts including
abnormalities of the main proteolytic mechanism, namely the proteasome.
Specifically, we and others have shown that there is an impaired function
of the proteasome, as senescent cells have reduced proteolytic
activities and less proteasome content. In a complementary work we have
recently shown that inhibition of the proteasome by a specific inhibitor
induces a senescence-like phenotype in young WI38 fibroblasts
[Chondrogianni et al. (2003) J Biol Chem 278: 28026-28037]. In this study
we tested whether the induction of a senescence-like phenotype following
treatment with proteasome inhibitors is a common feature of primary human
fibroblasts. A comparative biochemical analysis, after employing three
different human fibroblasts cell lines (IMR90, MRC5 and WI38 cells), as
well as two proteasome inhibitors (epoxomicin and MG132), has shown that
proteasome inhibition results in the appearance of a senescence-like
phenotype in all cell lines used. Proteasome inhibitors treated cells
were irreversibly stopped dividing, exhibited positive staining to
beta-galactosidase as well as reduced CT-L and PGPH activities. In
summary, these data reveal the fundamental role of the proteasome in the
progression of replicative senescence and open new dimensions towards a
better understanding of protein degradation.

[Benefits of CR may be due to its effect on the proteasome.]

Exp Gerontol. 2002 Dec;37(12):1423-30.
Effect of aging and late onset dietary restriction on antioxidant enzymes
and proteasome activities, and protein carbonylation of rat skeletal
muscle and tendon.
  Many studies have shown that lifelong dietary restriction (DR) can
retard aging processes. Very few reports, however, are found that
examined the effect of late onset DR on biochemical parameters in aging
animals [Goto, S., Takahashi, R., Araki, S., Nakamoto, H., 2002b. Dietary
restriction initiated in late adulthood can reverse age-related alterations
of protein and protein metabolism. Ann. NY Acad. Sci. 959, 50-56]. We
studied the effect of every-other-day feeding, initiated at the age of
26.5 months and continued for 3.5 months, on antioxidant enzymes, protein
carbonyls, and proteasomes of the gastrocnemius muscle and tendon in
rats. Age-related increase in the activity and content of Cu, Zn-SOD and
the content of Mn-SOD was attenuated by the DR in both tissues. The same
was true for glutathione peroxidase and catalase activities. Significant
increase with age in protein reactive carbonyl derivatives (RCD) in the
tendon was noted that was partially reversed by the DR. No significant
change of RCD, however, was observed in the skeletal muscle. The
age-related and DR-induced changes of the RCD in the tendon appeared to
be associated with proteasome activity that decreases with age and
increases by the DR. It is suggested that the late onset DR can have
beneficial effects on the locomotive functions by reducing
age-associated potentially detrimental oxidative protein damage in the
tendon.

[An easier way to upregulate proteasome activity?]

Ann N Y Acad Sci. 2004 Jun;1019:219-22
Algae extract protection effect on oxidized protein level in human
stratum corneum.
  Modification of proteins by reactive oxygen species is implicated in
different disorders. The proteasome is a multicatalytic proteinase in
charge of intracellular protein turnover and of oxidized proteins
degradation. Consequently, proteasome function is very important in
controlling the level of altered proteins in eukaryotic cells. Evidence
for a decline in proteasome activity during skin photo-aging has been
provided in Bulteau et al. in 2002. The ability of a lipid algae extract
(Phaeodactylum tricornutum) to stimulate 20S proteasome peptidase
activities was described by Nizard et al. in 2001. Furthermore,
keratinocytes treated with Phaeodactylum tricornutum extract and then UVA
and UVB irradiated, exhibited a sustained level of proteasome activity
comparable to the one of nonirradiated cells. The level of modified
proteins can be quantified by measurement of protein carbonyl content
(Oxyblot technique), which has been shown to increase with aging and
other disorders. In this paper, it is described that, in the presence of
this lipid algae extract, the level of oxidized proteins is reduced, as
assessed by the Oxyblot technique. These results are obtained both with
culture of human keratinocytes and stratum corneum skin cells (obtained by
stripping) from human volunteers. Altogether, these results argue for the
presence of compounds in this algae extract that have  a stimulating
and/or protective effect on proteasome activity, resulting in a decreased
level of protein oxidation.

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