Yeast Life Span Extension

Yeast Life Span Extension by Depletion of 60S Ribosomal Subunits Is Mediated by Gcn4

Kristan K. Steffen,Vivian L. MacKay,Emily O. Kerr,Mitsuhiro Tsuchiya,Di Hu,Lindsay A. Fox,Nick Dang,Elijah D. Johnston,Jonathan A. Oakes,Bie N. Tchao,Diana N. Pak,Stanley Fields,Brian K. Kennedy,andMatt Kaeberlein.

Cell, Volume 133, Issue 2, 292-302, 18 April 2008

 

Summary:

It is well known that reduced caloric intake leads to the extension of life span.  For yeast, dietary restriction is mediated by three kinases, that are particularly responsible for mediating various cellular processes such as: stress response, protein turnover, cell growth, and ribosome biogenesis.  This research focused on how the reduction of the level of 60S ribosomal subunits in the cell will slow aging in yeast.  The researchers studied this by using various methods of inhibiting the activity of the 60S subunits with a small molecule inhibitor, or by deleting the gene that codes for the subunit or its processing factors.  These three methods were all sufficient in increasing the life span of the yeast cells.

The life spans were measured by graphing the fraction of viable cells after every generation.  The normal yeast cells typically had relatively good viability until the ~25th generation, whereas when under dietary restriction, a large majority of the cells were still viable until the ~35th generation.

This research showed that the cells that with a long life span due to the decrease in 60S subunit levels, had an increased amount of Gcn4 activation.  Gcn4 is a nutrient-responsive transcription factor.  This factor we required for the cells to have the increased longevity.

It is particularly interesting to note that decreasing the amount of 40S subunits has no major effect on cell longevity.  Also, the basic molecular mechanism discussed in this paper has also been observed to exist in small animals and insects.  Therefore, the authors suggest dietary restriction, protein translation, and longevity are linked and are evolutionary conserved.

 

Significance:

This paper discusses a particular molecular mechanism that contributes to why dietary restriction will increases cell longevity.  The link between caloric intake and life span extension is not fully understood yet, and this was an attempt at identify a possible molecular process that is involved in this process.  However, additional information about the cause of cell death was not thoroughly discussed.  For example, one theory is that cells die because of the accumulation of cellular junk, which when above a particular threshold level, becomes pathological.  With that theory in mind, it would be easy to predict that reducing the level of 60S ribosomal subunit will almost certainly extend life, because less 60S ribosomal subunit means that less translation can occur, which means that there is less stuff that could potentially become cellular junk (i.e. undigestible proteins).  This is also an important factor in regards to the 3 kinases that mediate the dietary restriction, because they are involved with various metabolic cellular processes.  In other words, it is expected that anything that would slow down the rate of metabolism, would also slow down the rate of intracellular junk buildup, which means that it would take longer for the junk buildup to cause pathology.

Further studies into why the 40S subunit have no major effect on cell longevity would be extremely interesting, because this is the only factor that may contradict the theory of cell death.  Also, it would be interesting to know the effects of increasing the intercellular junk collection rate on longevity in cells with and without the decreased 60S subunit level.