What Do Chronologically Aged Cells Die From

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The chronological life span of a yeast cell begins under conditions highly favorable for growth: low cell density, optimal temperature, high nutrient availability, and the presence of a preferred carbon source (glucose). These conditions allow cells to enter an exponential growth phase, during which cells generate ATP primarily through glycolysis and fermentation of pyruvate to ethanol. As glucose becomes depleted, yeast cells progress through the diauxic shift, a growth phase characterized by large transcriptional changes resulting in enhanced expression of many enzymes involved in the TCA cycle, mito-chondrial function, and respiration. Associated with this transition to a less favorable environment is an up-regulation of many stress responsive and antioxidant genes. Eventually, as nutrients are depleted and cell density increases, a postdiauxic stationary phase is achieved in which cells exit from the cell cycle and enter into a G0-like quiescent state.

Entry of yeast cells into stationary phase is accompanied by a starvation response in which storage carbohydrates, such as glycogen and trehalose, are synthesized and maintained at high levels in the cytoplasm (Gray et al., 2004). Storage carbohydrates serve as the main source of energy production during stationary phase (Fabrizio and Longo, 2003) and adequate production of storage carbohydrates is essential for long-term survival. Interestingly, some chronologically long-lived mutants show dramatically increased glycogen stores, even under logarithmic growth conditions, suggesting that depletion of reserve carbohydrates might be one factor resulting in cell death. This idea is supported by one study in which intracellular glycogen and trehalose levels were reported to decrease dramatically between the second and third week of chronological aging (Samokhvalov et al., 2004). In contrast to this, however, Fabrizio and Longo (Fabrizio and Longo, 2003) have reported that glycogen stores are not significantly depleted even after 70% of cells have senesced during a typical chronological aging experiment. A more comprehensive analysis of reserve carbohydrate levels during chronological aging, particularly in long-lived mutants, will be necessary to definitively address this important question.

A second mechanism by which yeast cells might senesce during chronological aging is apoptosis. Mammalian cells undergo apoptosis in response to specific environmental stimuli, and it has been demonstrated that yeast cells can undergo a similar process (Madeo et al., 2004). Indeed, chronologically aged cells show markers consistent with apoptotic death (Herker et al., 2004). Blocking apoptosis through deletion of the gene coding for yeast caspase, YCA1, failed to substantially increase chronological life span, however, indicating that the apoptosis-like event may be a secondary response to the primary lethal event.

Yeast cells maintained in stationary phase generally do not reenter the cell cycle unless diluted into fresh media. On rare occasions, a yeast cell will escape from the stationary phase-induced cell cycle arrest and begin vegetative growth in the aged culture. It has recently been speculated that this "gasping" effect is an altruistic phenomenon, whereby the majority of cells in an aging population die through a process resembling apoptosis in order to facilitate the outgrowth of a few remaining viable cells (Fabrizio et al., 2004a). The probability that a cell will undergo a "gasping" event was observed to be inversely correlated with resistance to superoxide and chronological life span, but positively correlated with mutation frequency. These findings suggest a plausible mechanism by which an apoptotic pathway might evolve in a single-celled eukaryote.

A third mechanism by which quiescent yeast cells might senesce is due to damage generated by oxidative stress. The free radical theory of aging posits that one cause of aging is the accumulation of macromolecular damage due to oxidative free radicals (Harman, 1956). There are several lines of evidence suggesting that oxidative damage plays a causal role in the chronological aging process of yeast cells. For example, loss of respiratory capacity increases with time spent in stationary phase, suggesting that mitochondrial damage accumulates during chronological aging (Fabrizio and Longo, 2003). Also consistent with the idea that oxidative damage is correlated with chronological longevity, mutation of either mitochondrial superoxide dismutase (Sod2) or cytosolic superoxide dismutase (Sod1) results in a substantial decrease in stationary phase survival (Longo et al., 1996). Finally, overexpression of both Sod2 and Sod1 increases chronological life span by about 30%, suggesting that oxidative stress is one factor limiting the survival of quiescent yeast cells (Fabrizio et al., 2003).

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