The laboratory of David Sinclair shows an interesting feature of caloric restriction in this paper. Caloric restriction increases the levels of SIRT1, the mammalian counterpart of yeast Sir2, a nicotinamide adenosine dinucleotide-dependent histone deacetylase protein known to be involved in longevity mediated by caloric restriction. This effect can be mimicked in human embryonic kidney 293T cells by treating the cells with serum from calorie-restricted rats. This papers shows that SIRT1 deacetylates Ku70, allowing Ku70 to interact with the pro-apoptotic protein, Bax, and prevent Bax-mediated cell death. It is therefore suggested that calorie restriction extends lifespan through increased SIRT1 expression and promotion of survival of the organism’s irreplaceable cells.

Coupled with a recent paper in Molecular Cell (Cohen et al., 2004), this group shows a very compelling mechanism for the regulation of Bax function through the acetylation and deacetylation of Ku70, a DNA repair protein, originally discovered...  Read more

The laboratory of David Sinclair shows an interesting feature of caloric restriction in this paper. Caloric restriction increases the levels of SIRT1, the mammalian counterpart of yeast Sir2, a nicotinamide adenosine dinucleotide-dependent histone deacetylase protein known to be involved in longevity mediated by caloric restriction. This effect can be mimicked in human embryonic kidney 293T cells by treating the cells with serum from calorie-restricted rats. This papers shows that SIRT1 deacetylates Ku70, allowing Ku70 to interact with the pro-apoptotic protein, Bax, and prevent Bax-mediated cell death. It is therefore suggested that calorie restriction extends lifespan through increased SIRT1 expression and promotion of survival of the organism’s irreplaceable cells.

Coupled with a recent paper in Molecular Cell (Cohen et al., 2004), this group shows a very compelling mechanism for the regulation of Bax function through the acetylation and deacetylation of Ku70, a DNA repair protein, originally discovered by Shigemi Matsuyama, to be a Bax inhibitor (Sawada et al., 2003; Sawada et al., 2003). The suggestion that deacetylated Ku70 sequesters Bax from translocating to the mitochondria to initiate the release of apoptogenic factors such as cytochrome c, apoptosis inducing factor (AIF) or endonuclease G, remains to be shown. However, it is clear that deacetylated Ku70 eliminates Bax pro-apoptotic function.

The suggestion that preventing Bax translocation to the mitochondria explains the extended lifespan of an animal by promoting survival of terminally differentiated cells is intriguing but remains to be proven. Alternatively, cytosolic Bax have a physiological function and retention in the cytosol with Ku70 could promote this function. Furthermore, acetylation and deacetylation of Ku70 could influence DNA repair and allow resistance to age-dependant DNA damage. If Bax and Ku70 are central to longevity, Bax or Ku70 null mice, which are viable, would also be expected to have a longer lifespan.

Alternative possibilities also exist to explain SIRT1-mediated cell survival. SIRT1 deacetylates a number of other proteins including forkhead transcription factors and p53, two other proteins involved in the balance of cellular survival and cell death (Motta et al., 2004). In this paper, it is proposed that downregulation of forkhead factors and p53 increases the threshold for apoptosis and cellular senescence. Furthermore, these authors suggest that the regulation of forkhead-mediated transcription may alter diet-responsive metabolism thereby decreasing the level of oxidative stress and damage to cells. Therefore, it appears that SIRT1 can have multiple beneficial coordinated effects to control cellular survival and longevity.

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