Large at birth lifespan dearth?

Budding yeast Saccahromyces cerevisiae propagates by asymmetric cell division, during which the partitioning between two resultant cells is unequal in morphological and in molecular aspects. The larger one is designated as mother cell; therefore, it is possible to monitor the budding ability of a specific cell. The total number of daughter cells an actively dividing mother cell can produce is known as the replicative lifespan (RLS), and the process of approaching the limit of cell division is defined as replicative aging. The accumulation of molecular damages and aging factors in mother cells, due to the inherently asymmetrical cell division process, is believed to be the major cause of yeast replicative aging.

One major factor is the accumulation of extrachromosomal ribosomal rDNA circles (ERCs) in mother cells¹. It is suggested that ERCs might cause cell death by titrating away essential transcription and/or replication factors. Yeast Sir2 is a highly conserved NAD⁺-dependent deacetylase which modulates yeast RLS and has been suggested to extend RLS by inhibiting ERC formation² and by increasing genomic stability at the telomere loci³. In addition to increased genomic instability^1,3,4, accumulation of oxidatively damaged proteins is also among the hallmarks of aged yeast cells⁵. It is demonstrated that damaged protein aggregates formed in the daughter cell could be purged and delivered back to the mother cell via an active transport composed by actin filaments, and that the proper folding of actin monomers requires Sir2⁵. Therefore, Sir2 not only protects mother cells by maintaining genomic stability but also improves newborn cell fitness by conferring stress resistance.

Yang et al⁶ propose that cell size control is also a major determinant of yeast replicative aging. Many mammalian cells and yeast cells increase in size as they age⁶. However, a clear correlation between cell size and RLS has not been established. Yang et al analyze the correlation between cell size (both at birth and at death) and RLS of previously identified short-lived and long-lived mutants. Among a total of about 20 mutants analyzed, many long-lived mutants, including 9 ribosomal protein (RP) gene deletion mutants⁷ show reduced cell size whereas the short-lived mutants, including sir2Δ, show large cell size. They also demonstrate that reported large cell size mutants are short-lived, and that small cell size mutants are long-lived. Artificially increasing cell size by employing cell-cycle arresting mutations or nocodazole reduces RLS⁶. Interestingly, yeast cells appear to grow and enter senescence at a relatively constant cell size regardless of their birth size⁶. Therefore, small cell size mutants are predicted to reach the maximum cell size at a slower rate (net cell size increase per generation: total net cell size increase divided by total number of cell divisions). Likewise, large cell size mutants are predicted to reach the maximum cell size at a faster rate. Since a correlation between the expectancy of RLS and cell size is not observed in all lifespan mutants, Yang et al propose that both growth rate and cell size at birth are major determinants of yeast replicative aging (Figure 1).

Figure 1.

Cell size and cell size increase per generation inversely correlate with the expectancy of replicative lifespan. Most yeast cells reach a similar maximum cell size prior to senescence (size at death) regardless of their birth size. In this model, small cells are predicted to reach maximum cell size at a slower rate and are likely to have increased replicative lifespan. Likewise, large cells are predicted to reach maximum cell size at a faster rate and are likely to have decreased replicative lifespan.

This study is the first that demonstrates a genetic link between cell size control and aging. It also illustrates the power of using genetically tractable budding yeast as a model to unravel the major determinants of RLS^1–9. Several questions remain unanswered. Are large cell size mutants short-lived because they are born old? It has been reported that daughter cells produced by old mother cells show reduced RLS⁸. It is possible that these daughter cells are born old because their old mother cells have lost the ability to maintain the segregation asymmetry of certain aging factors^1,5. What factors contribute to the differences in cell size at birth? What are the molecular mechanisms of cell size control? Does the cell size control machinery also play a role in modulating other determinants of replicative aging such as stress response, genome stability, mitochondrial activity and metabolism^1–4,7,9. Does cell size control also play a role in replicative aging in higher eukaryotic cells? It would also be interesting to determine whether the conserved Sir2 family proteins also modulate cell size control in other model system. Further genetic and biochemical studies are necessary to unravel the molecular mechanisms of replicative aging both in yeast and higher eukaryotic cells.