Sirtuin 6 in Mammalian Aging

A great deal of time and effort has been spent on investigating the biochemistry of sirtuins in numerous species, with as yet very little to show for it in practical terms. Early attempts to produce viable age-slowing interventions via upregulation of sirtuin 2 were a comprehensive failure, and it is entirely plausible that recent interest in sirtuin 6 will go the same way. This class of metabolic tinkering has a terrible track record, mixed results in mice that then fail to translate to humans, and the reasonable expectation is that this will continue to be the case for the foreseeable future.

The role of sirtuins in senescence was discovered in budding yeast, where overexpression of SIR2 increases replicative lifespan. Subsequently, It was reported that elevated sirtuin levels increase lifespan in the nematode C. elegans and the fruitfly Drosophila, indicating an evolutionarily ancient role of sirtuins in longevity assurance. Mammals contain seven sirtuins, SIRT1-7, which are categorized by their different subcellular localization, unique binding substrates, and diverse enzymatic activities. Recently the direct role of SIR2 in aging and lifespan extension has been disputed, but the overwhelming majority of significant results still support a potential role for SIRT6 in regulating mammalian lifespan.

SIRT6 was shown to extend lifespan in mammals, while deficiency of SIRT6 was associated with progeria, an accelerated aging disorder. Studies have confirmed the important roles for SIRT6 in protecting against aging and disease pathologies: SIRT6-deficient mice are small and have severe metabolic defects, and by 2-3 weeks of age, they develop abnormalities that are usually associated with aging. However, SIRT6 overexpression led to an increase in lifespan in male mice. Mechanistically, SIRT6, being a histone deacetylase, inhibits the transcription of transcription factors related to senescence, maintains the structure of telomere chromatin, prevents genomic instability after DNA damage, and protects cells from senescence.


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