In Aging Cell, researchers have explained how the sirtuin SIRT6 protects against proteostasis-related brain disorders by maintaining the function of nucleoli and limiting protein production.
The nucleus and nucleoli
A cell’s nucleus has one or more nucleoli, where the cell does its critical work of synthesizing ribosomal RNA (rRNA), building the factories that are responsible for translating other DNA into RNA. With aging, nucleoli expand and increase in number [1], and this is found in progeric, premature aging as well [2].
One sirtuin, SIRT6, has been found to recruit the chromatin remodeler SNF2H to sites of DNA double breaks [3]. SNF2H is also part of the nuclear remodeling complex (NoRC), which regulates this transcription of rRNA. Unsurprisingly, SIRT6 has been found to be a necessary part of the brains of mammals; monkeys that do not express it are born with malformed brains and do not live long outside the womb [3], while overexpression extends and improves the lives of mice [4]. Mice that do not express it do not suffer the same immediate fate as monkeys, but they suffer from learning disabilities and their brains resemble those of Alzheimer’s disease patients, who also have decreased levels of SIRT6 [5].
SIRT6 controls protein production
With this evidence in hand, the researchers decided to home in on the proteostasis-related effects of SIRT6. They first took another look at their previous work on SIRT6 and mitochondrial function in neurons [6], and they noticed close relationships between the gene expression of Alzheimer’s patients and that of SIRT6-deficient mice. They also noted that some of the most downregulated genes in the absence of SIRT6 are related to ribosomal function.
Further experiments confirmed this relationship. Neurons taken from SIRT6-deficient mice were found to indeed lack SNF2H at chromatin sites, which also led to a decrease in recruitment of the NoRC component TIP5. The total levels of SNF2H and TIP5 did not decrease in the SIRT6-deficient cells; instead, the cells generated more TIP5 RNA. The lack of SIRT6 led to a similar increase in the number and size of nucleoli, increasing the rate of production of rRNA.
The researchers then created multiple varieties of SIRT6-deficient cells. In every case, unless a transcription inhibitor was introduced to stop it, the deficient cells consistently overproduced proteins. This was found to be accompanied by an overall increase in the amino acids used for building these proteins.
Too much production, not enough quality assurance
However, this increase in protein synthesis was not accompanied by an increase in protein chaperones. The researchers tested a line of immortalized human kidney cells’ ability to refold proteins after a heat shock. Cells that produced SIRT6 normally were able to properly refold roughly three-fifths of the damaged proteins; cells that lacked SIRT6 were only able to refold roughly a fifth. Inhibiting protein translation restored these cells’ maintenance abilities.
The researchers suspected that this overproduction without proper maintenance would lead to the accumulation of protein aggregates. They used a line of cells that are prone to forming aggregates, some of which were made incapable of producing SIRT6. These SIRT6-deficient cells, indeed, produced substantially more aggregates than their unmodified counterparts.
These findings were recapitulated in worms. Without SIRT6, C. elegans nematodes were much more prone to heat shock and had much more rapid declines in motility compared to unmodified worms. The researchers then combined this deficiency with a strain that expresses polyQ in their neurons, which leads to protein aggregates; slowing protein translation with 4PBA restored some of the related motility and lifespan decline in the polyQ worms, even if they expressed SIRT6.
This discovered relationship between SIRT6 deficiency, excessive protein production, and protein aggregation leads to different avenues for potential interventions. The researchers note that 4PBA has already been approved by the FDA and suggest that it might be useful against overproduction-related proteostasis disorders. Previous work has also found that caloric restriction increases SIRT6 [7], although implementing this consistently and safely requires careful monitoring.
Literature
[1] Kriukov, D., Eremenko, E., Smirnov, D., Stein, D., Tsitrina, A., Golova, A., … & Toiber, D. (2024). Nuclear expansion and chromatin structure remodeling in mouse aging neurons. NAR Molecular Medicine, 1(3), ugae011.
[2] Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature communications, 8(1), 1-13.
[3] Zhang, W., Wan, H., Feng, G., Qu, J., Wang, J., Jing, Y., … & Hu, B. (2018). SIRT6 deficiency results in developmental retardation in cynomolgus monkeys. Nature, 560(7720), 661-665.
[4] Roichman, A., Kanfi, Y., Glazz, R., Naiman, S., Amit, U., Landa, N., … & Cohen, H. Y. (2017). SIRT6 overexpression improves various aspects of mouse healthspan. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 72(5), 603-615.
[5] Kaluski, S., Portillo, M., Besnard, A., Stein, D., Einav, M., Zhong, L., … & Toiber, D. (2017). Neuroprotective functions for the histone deacetylase SIRT6. Cell reports, 18(13), 3052-3062.
[6] Smirnov, D., Eremenko, E., Stein, D., Kaluski, S., Jasinska, W., Cosentino, C., … & Toiber, D. (2023). SIRT6 is a key regulator of mitochondrial function in the brain. Cell Death & Disease, 14(1), 35.
[7] Zhang, N., Li, Z., Mu, W., Li, L., Liang, Y., Lu, M., … & Wang, Z. (2016). Calorie restriction-induced SIRT6 activation delays aging by suppressing NF-κB signaling. Cell cycle, 15(7), 1009-1018.
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