Abstract
Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents. However, the underlying mechanisms are incompletely understood. In eukaryotic cells, methionine can be converted to cysteine through the reverse transsulfuration pathway thereby modulating intracellular methionine availability. Whereas previous results obtained in yeast and fruit flies suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging, it is not known whether this function is conserved in evolution. Here we show that depletion of cystathionine beta synthase (CBS), a rate limiting enzyme in the reverse transsulfuration pathway, induces premature senescence in human endothelial cells. We found that CBS depletion induces mild mitochondrial dysfunction and increases the sensitivity of endothelial cells to homocysteine, a known inducer of endothelial cell senescence and an established risk factor for vascular disease. Our finding that CBS deficiency induces endothelial cell senescencein vitro, involving both mitochondrial dysfunction and increased susceptibility of the cells to homocysteine, suggests a new mechanism linking CBS deficiency to vascular aging and disease.
Highlights
Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents [1]
cystathionine beta synthase (CBS) depletion led to decreased cell numbers in human umbilical vein endothelial cells (HUVEC) but not human dermal fibroblasts (HDF) (Fig. 1B); it significantly reduced the rate of cell proliferation, measured by BrdU incorporation studies (Fig. 1C), but had no effect on the rate of apoptotic cell death (Fig. 1D)
Both in HUVEC and human aortic endothelial cells (HAEC), CBS knockdown led to a premature accumulation of cells staining positive for senescence associated ß-galactosidase (SA-ß-gal) (Fig. 2B), whereas the proportion of SA-ß-gal-positive cells was not altered by CBS depletion in HDF (Fig. 2B)
Summary
Availability of methionine is known to modulate the rate of aging in model organisms, best illustrated by the observation that dietary methionine restriction extends the lifespan of rodents [1]. The conversion of homocysteine to cystathionine by CBS depends on pyridoxal 5'-phosphate (PLP), and lifespan extension was observed in a PDX3 deletion strain, deficient for the synthesis of PLP [4] These data suggest that alterations in the transsulfuration pathway affect the aging phenotype in yeast. Overexpression of dCBS was sufficient to increase longevity [5] These findings strongly suggest that alterations in the reverse transsulfuration pathway modulate the rate of aging in lower eukaryotic model organisms. It is not known whether this function is conserved in evolution.
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