A glutamine a day keeps senescence away

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):

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.