The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 12 No. 6 • October 2009


Advance in Understanding of Autoimmune Disease:
T-Cell Self-Tolerance Requires Sirt1

The famous Sirt1 (sirtuin 1), a gene that plays a role in aging1 in several species including mice (in yeast and nematodes, it is Sirt2, of which Sirt1 is the mammalian ortholog, that is a longevity gene), has been shown to not only be a cancer suppressor,2 but also to be importantly involved in DNA repair.2b Caloric restriction has been found to increase Sirt1 protein levels (but not necessarily in all tissues).3 In a new paper,1 Sirt1 has been found to be essential for the maintenance of T cell tolerance in mice. In the abstract for this paper, the authors suggest that “activators of Sirt1 may be useful as therapeutic agents for the treatment and/or prevention of autoimmune diseases.” As explained in the paper, resveratrol is a Sirt1 activator.4

Self reactive T cells are supposed to be eliminated by the thymus to prevent autoimmunity. Mice with a knockout of Sirt1 have “elevated immune responses and fail to maintain peripheral tolerance to autoantigens, as exemplified by the presence of anti-nuclear antibodies, systemic lymphocyte infiltration, and increased susceptibility to experimental autoimmune encephalomyelitis [a model of the autoimmune disease multiple sclerosis].” Sirt1 regulates a large number of proteins (such as the cancer suppressors p53 and FOXO3)2 as well as histones,1 which control access to DNA (and, thus, whether genes are turned on or off), by removing acetyl groups; Sirt1 is a type III histone deacetylase. Resveratrol, found in red wine, tea, and other foods, is a Sirt1 activator.4 The authors of this paper1 in fact, suggest that, though the mechanisms of action of resveratrol are still under debate (this paper was published in October 2009), resveratrol may provide “a potential avenue for treatment of autoimmune diseases as well as allograft rejections”1 since “its interference with immune function is well established.”1

“The fact that CD4+ T cells of Sirt1–/– [Sirt1 knockouts] mice were unable to be tolerized suggests that Sirt1 could function as an anergic factor in T cells.”1 The researchers found that anergic T cells expressed Sirt1 mRNA (messenger RNA) by 4- to 5-fold as compared to naive (non-activated) T cells but was increased only slightly in already activated T cells. The authors1 report that Sirt1 inhibits T cell activation by suppressing the acetylation of c-Jun, a regulatory molecule.

References

1. Zhang et al. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J Clin Invest 119(10):3048-58 (2009).

2. Kabra et al. SirT1 is an inhibitor of proliferation and tumor formation in colon cancer. J Biol Chem 284(27):18210-17 (2009).

2b. Oberdoerffer et al. SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging. Cell 135:907-18 (2008).

3. Chen et al. Tissue-specific regulation of SIRT1 by calorie restriction. Genes Dev 1;22(13):1753-7 (2008).

4. Borra et al. Mechanism of human SIRT1 activation by resveratrol. J Biol Chem 280(17):17187-95 (2005).

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