Previous research has demonstrated that overexpressing a protein known as SIRT6 increases lifespan of mice and offers protection against obesity-induced metabolic abnormalities. In contrast mice that lack SIRT6 suffer from various aging-related problems and die before the age of 4 weeks. SIRT6 is part of a class of proteins known as the sirtuins that have been well-studied for their anti-aging effects. Earlier this year we reported on a small molecule drug that could selectively activate SIRT6 (Read the article here).
Now, two papers by the Cohen lab further investigate the effect of SIRT6 on life- and healthspan.
In the first paper the researchers developed a SIRT6 transgenic mouse that has extra copies of the SIRT6 gene (termed MOSES mice). Old MOSES mice had improved insulin sensitivity, reduced fasting glucose levels, increased physical activity, reduced inflammation of their fat tissue, and improved hair growth.
What about SIRT6 knockout?
In the second paper the authors investigate the effect of a complete lack (a so called knockout) of SIRT6. Such work had been done before but all mice died before four weeks of age. The authors wanted to investigate the effect of SIRT6 on health parameters later in the mouse lifespan. By changing the genetic background of the mice that carry the SIRT6 knockout the researchers were able to generate SIRT6 knockout mice that reach adulthood. Average lifespan of males was just 140 days while 80% of female mice were still alive after 200 days. Hence the effect of SIRT6 on lifespan is gender-specific. The authors succeeded in investigating the effect of certain health parameters up to 10 months of age.
By 5-6 months of age SIRT6 knockout mice showed severe corneal injury. The cornea is the transparent outer layer of the eye allowing light to pass into the eye. The age-related thinning of the retina, the eye layer where light is sensed, was accelerated in SIRT6 knockout mice. Furthermore, SIRT6 knockout mice also show degradation of retinal function.
Surprisingly the SIRT6 knockout mice had higher glucose uptake in skeletal muscle compared to normal mice. The authors showed that this glucose uptake was insulin-independent. The interpretation of this observation is unknown at this moment.
A link to neurodegeneration
Finally, in a third paper by another lab the effect of brain-specific SIRT6 knockout was investigated. Mice that lacked SIRT6 in the brain showed learning impairment at 4 months of age. The authors further discovered that such mice had higher levels of phosphorylated tau in their brains, a characteristic of several neurodegenerative diseases including Alzheimer’s disease. Hyperphosphorylated tau is believed to be neurotoxic and indeed mice that lacked SIRT6 had higher levels of cell death and DNA damage in their brains. SIRT6 levels in the brain decrease with age. Finally, the authors showed that Alzheimer’s disease patients had lower levels of SIRT6 protein in their brains.
Roichman A et al. (2017). SIRT6 overexpression improves various aspects of mouse healthspan. J Gerontol A Biol Sci Med Sci 72(5): 603-615.
Peshti V et al. (2017). Characterization of physiological defects in adult SIRT6-/- mice. PLoS One 12(4): e0176371.
Kaluski S et al. (2017). Neuroprotective Functions for the Histone Deacetylase SIRT6. Cell Rep 18(13): 3052-3062.