Cells Yeast - Yeast cells are similar to animal cells in their core biochemistry and organelles. We should not be surprised that the 6000 yeast genes include orthologues of insulin-like signaling and other genes in tissue-grade animals (Fig. 1.3A). Fungal genomes diverged from the animals about 1500 million years ago (Cai, 2006). Aging and life span in yeast are studied with two very different experimental models: replicative life span (Piper, 2006; Sinclair et al, 1998) and chronological life span (Fabrizio and Longo, 2003; Fabrizio et al., 2004). The yeast replicative life span is defined by asexual reproduction through the formation of smaller buds on the surface of the mother cell. The intervals between budding lengthen as the replicative life span is approached, at about 20 cell divisions. Oxidatively damaged proteins are retained asymmetrically by the mother cell (Aguilaniu et al, 2003), which may be how the detached buds start the replicative clock at zero, independent of mother cell age.
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The replicativelife span model resembles the Hayflick model in that both show limited cloning. The sterile postreplicative cells may have considerable remaining life span (V. Longo, personal comm). Mechanisms in replicative aging include aunique genomic instability in ribosomal DNA (rDNA) cistrons, through aberrant recombination that causes the accumulation of extra-chromosomal rDNA circles. The rDNA instability is modulated by chromatin condensation under the control of Sir2 (silent information regulator), a NAD-dependent histone deacetylase. Increased Sir2 inhibits the aberrant recombination and extends the replicative life span. Sirtuins and their orthologues have many other metabolic activities in animals (Chapter 3 and 5); e.g., diet restriction activates Sirt1 and modulates lipolysis in mammalian fat (Wolf, 2006).
The chronological life span is defined as the cell viability during prolonged periods with limited external nutrients. Yeast and other autotrophic fungi have evolved adaptive mechanisms in their natural habitats for surviving extended periods of starvation, pending episodes of surfeit. When switched from growth media to water, yeast cells become hypometabolic, extending their life span several fold to 15–20 days. Mutations in the kinase Sch9 increase life span by increasing stress resistance and glycogen reserves. Sch9, a functional homologue of Akt/PBK, which modulates life span in animals (Fig. 1.3A), also synergizes with Sir2 (Longo and Kennedy, 2006).
Ongoing studies point to the convergence of mechanisms in these seemingly different models, by the shared dependence of replicative and chronological life spans on Sch9, Ras/cyr/PKA, and Tor pathways (Longo and Kennedy, 2006). The formation of rDNA circles may be regarded as a ‘yeast disease of aging’ specific to the replicative senescence mode. Besides these single cell models, yeast can also grow as filaments (pseudohyphae) (Gognies et al, 2006), which enable the invasion of ripe fruit. Dense fungal mats can form, possibly including domains with metabolic gradients. These alternate life history modes with complex morphology have not been studied for aging processes.
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