April 29 2008 / by mycophage
Category: Health & Medicine Year: 2008 Month: Apr Rating: 9 Hot
(Cross-posted from
Ouroboros: Research in the biology of aging)
Cellular senescence is regarded as a tumor suppressor mechanism:
damaged cells permanently leave the cell cycle (preventing tumor
initiation), and also secrete factors that trigger both tissue
repair and inflammation in the vicinity. This is probably good at
first but bad later on: persistent senescent cells also secrete
growth factors and metalloproteases that degrade the tissue
microenvironment and encourage nearby preneoplastic cells to
progress into full-blown tumors. Thus, senescence has been
implicated in late-life cancer and age-related decline in tissue
function.
The “damage” in question is usually genotoxic in nature:
telomere shortening, indicating that a cell has undergone many
rounds of potentially mutagenic cell division, or high levels of
DNA damage such as that resulting from
ionizing radiation or exposure to chemical clastogens. Oncogene
expression probably also induces senescence via DNA damage, by triggering over-firing of replication
origins and generating broken ends and weird chromatin structures
that are interpreted as damage.
Now it appears that falling cellular ATP levels may also result in cellular senescence.
Unterluggauer et al. report that inhibition of
glutaminolysis (preventing cells from generating ATP from glutamine, an unglamorous and occasionally
overlooked pathway that is nonetheless an important energy source
in many cellular lineages) results in increased senescence in human
vascular endothelial cells (HUVECs): (cont.)
Premature senescence of human endothelial cells induced by
inhibition of glutaminase
Cellular senescence is now recognized as an important mechanism
of tumor suppression, and the accumulation of senescent cells may
contribute to the aging of various human tissues. Alterations of
the cellular energy metabolism are considered key events in
tumorigenesis and are also known to play an important role for
aging processes in lower eukaryotic model systems. In this study,
we addressed senescence-associated changes in the energy metabolism
of human endothelial cells, using the HUVEC model of in vitro senescence. We observed a
drastic reduction in cellular ATP levels
in senescent endothelial cells. Although consumption of glucose and
production of lactate significantly increased in senescent cells,
no correlation was found between both metabolite conversion rates,
neither in young endothelial cells nor in the senescent cells,
which indicates that glycolysis is not the main energy source in
HUVEC. On the other hand, glutamine
consumption was increased in senescent HUVEC and inhibition of glutaminolysis by
DON, a specific inhibitor of glutaminase,
led to a significant reduction in the proliferative capacity of
both early passage and late passage cells. Moreover, inhibition of
glutaminase activity induced a senescent-like phenotype in young
HUVEC within two passages. Together, the
data indicate that glutaminolysis is an important energy source in
endothelial cells and that alterations in this pathway play a role
in endothelial cell senescence.
The authors provide good evidence that endothelial cells rely
heavily on glutaminolysis, and that removal of this energy source
both drastically reduces cellular ATP
levels and results in a “senescent-like” growth arrest. They then
show fairly convincingly that this arrest is very similar to the
arrest induced by telomere shortening, DNA damage or oncogene expression (i.e., cellular
senescence) — in particular, by demonstrating that the arrested
HUVECs express a panoply of senescence-associated gene expression
and cytological markers. No word, as far as I could tell, on the
reversibility of the arrest upon resumption of glutaminolysis
(irreversibility is a hallmark of senescence); I mention this
because growth arrest is a fairly obviously sensible response to an
energy deficit, but it’s not clear why it ought to be
permanent.
The reason I’m interested in this paper is that it might point
toward a unifying principle underlying two major subjects within
the field of biogerontology — cellular senescence and sirtuins — which both receive a great
deal of individual attention but so far have not been demonstrated
to have much to do with one another. Sirtuins such as SIRT1 are regulated by cellular energy state (in
particular, by the NAD+/NADH ratio); if
it turns out that perturbations in the cellular energy budget are
an important means of senescence induction, it might be interesting
to take a closer look and see whether sirtuin signaling might
influence the establishment of cellular senescence.
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