Replicative Life Span

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The asymmetrical division characteristic of S. cerevisiae is an essential for replicative life-span measurements. Daughter cells are normally smaller than mother cells and can be easily distinguished and removed from their progenitors by micromanipulation (Mortimer, 1959). The average replicative life span is 20 divisions. "Replicative aged'' cells divide more slowly, become sterile, and when cell division stops, they are considered dead, although their postreproductive survival time has never been estimated (Bitterman et al., 2003). Whereas few genes are known to regulate both life spans, the relationship between replicative and chronological aging has yet to be established. Notably, yeast replicative life span is analogous to the replicative life span of mammalian fibroblasts and lymphocytes, which undergo a limited number of population doublings in culture. Thus, the "budding life span'' is a model for studying aging of mitotic cells but can also provide insights on fundamental mechanisms of organismal aging.

Replicative aging can be caused by a form of genomic instability that leads to the accumulation of extrachromosomal ribosomal DNA circles (ERCs) (Sinclair and Guarente, 1997) and is delayed by increasing the activity of the silencing regulator Sir2

(Kaeberlein et al., 1999). Sir2 is a NAD-dependent histone-deacetylase whose activity is required to promote chromatin silencing at the telomeres, mating type loci, and rDNA (Braunstein et al., 1993; Tanny et al., 1999). Increased dosage of SIR2 delays replicative aging by inhibiting rDNA recombination and consequently the formation of ERCs (Kaeberlein et al., 1999). Although this aging mechanism has not been observed in any other species, Sir2 was shown to play a conserved antiaging role in higher eukaryotes. In fact, increased dosage of the Sir2 homologs extends the life span of both C. elegans and Drosophila by up to 50%, and Sir2 activity has been associated with the longevity extension caused by calorie restriction—an intervention known to extend the life span of all model organisms (Rogina and Helfand, 2004; Tissenbaum and Guarente, 2001; Wood et al., 2004). However, despite the extensive experimental effort to link the Sir2 family of proteins (sirtuins) to mammalian longevity, a conclusive role for the sirtuins in mediating life-span regulation has not been established.

Other genes implicated in the regulation of replicative aging have been identified. Among these are RAS1/RAS2 and LAG1/LAG2. RAS1 and RAS2, which encode for highly conserved pro-growth signaling G-protein, play opposite roles in replicative aging. The deletion of RAS1 extends replicative life span. By contrast, lack of RAS2 shortens replicative longevity (Sun et al., 1994). Intriguingly, lack of Ras2 promotes chronological survival (see The Genetics of Chronological Aging: Yeast Methuselah Genes). Deletion of Lag1, a protein implicated in ceramides synthesis, extends replicative life span, and so does the overexpression of Lag2, a protein of unknown function (D'Mello N et al., 1994).

The activation of the retrograde response also triggers replicative life-span extension. This response is activated by an intracellular signaling pathway from the mitochondrion to the nucleus and leads to the transcription of several genes encoding for metabolic enzymes (Kirchman et al., 1999).

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