Aging of Budding Yeast

Introduction

I n studying the processes of aging, it is interesting to consider a very primitive organism, the baker's yeast cell Saccharomyces cerevisiae. With micromanipulation techniques, ^1,2 the fate of individual cells can be followed in this organism. When there is a surplus of nutrition, a mother cell propagates parthenogenetically by rapidly budding off small daughter cells, one at a time. The replicative life span of the mother cell is determined by the number of buds (maximum 20–35). When there is limited nutrition, the cells stop dividing, and the life span is determined by the chronological age (metabolic time). At nutrient deprivation, a diploid mother cell, by two meiotic nuclear divisions, becomes tetraploid, leading to four haploid spores. ³

It has been proposed that accumulation of insoluble (i.e., aggregated, cross-linked) protein is a major cause of aging. ^4,5 How this may be reconciled with the aging of yeast cells is shown by studies of the Lansing effect and the chromosomal abnormalities encountered in old yeast cells.

The Lansing Effect

Propagation from old yeast cells leads to daughter cells with reduced life span. ⁶ This effect was originally described by Lansing ⁷ in parthenogenetically propagated rotifers, which are minuscule organisms living in freshwater ponds. It has been speculated that the Lansing effect may depend on the accumulation of some senescence substance, such as damaged macromolecules, ⁶ or of a transmissible factor. ⁷ This is proposed to be insoluble protein that is formed as a side product of protein synthesis. ⁴ At cell division, there is a vigorous synthesis of protein concomitant with DNA replication. A fraction of the protein may become insoluble due to cross-linking and aggregation. Despite elaborate cellular strategies to take care of the aggregated protein, ⁸ some of this protein may escape degradation and accumulate. Old mother cells containing more of the insoluble protein may give rise to a larger share to the daughter cell, thus explaining the Lansing effect.

The Lansing effect is not a universal phenomenon. Sexually propagating organisms, e.g., Drosophila, ⁹ do not exhibit this effect. One explanation may be that DNA at fertilization is doubled without synthesis. In higher organisms, other mechanisms may have been developed to limit insoluble protein accumulation at mitosis.

Chromosomal Abnormalities

Spores from old mother cells have the same replicative life span as spores from young mother cells. ³ This indicates that chromosomal aberration is not a primary cause of aging. Nor is there telomere shortening in yeast mother cells. ¹⁰ Nevertheless, at aging, old mother cells display extrachromosomal ribosomal DNA (rDNA) circles ¹¹ and hyperrecombination of DNA. ¹² McMurray and Gottschling ¹² have postulated that genomic instability is secondary to accumulated damaged protein. Accumulated insoluble protein decreases the volume available to large colloids, which means that the chromosomes come closer to each other, impeding movement and increasing interactions. ⁴ Also the function of the centrosome may become compromised, contributing to chromosomal instability.

Discussion

A unified theory of aging should fulfill some criteria defined by Strehler ¹³ —universality, intrinsicality, progressiveness, and deleteriousness. Most important is that such a theory should be universal, i.e., possible to be applied to all living organisms, from yeast to human. Accumulation of insoluble protein as a cause of aging approaches such a criterion, ⁴ assuming that replicative and chronological aging have the same cause (“…the accumulation of altered structures [inhibitors]” ¹³ ). In yeast aging is displayed as the Lansing effect and genomic instability. In higher organisms, including humans, aging is encountered predominantly in slowly dividing and postmitotic cells and intercellularly. The accumulation of insoluble protein is here assumed to be slow, causing aging, but not compromising propagation. However, if there is a common cause of aging, the study of aging in yeast may also be of value for understanding human aging.

Conclusions

A major cause of aging of the yeast cell may be the accumulation of insoluble (i.e., aggregated, cross-linked) protein. A corollary is that strategies to combat aging should thwart this accumulation.