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Sirtuins Mitigate Chronic Inflammation and Insulin Resistance

Researchers from Berkeley have established that SIRT2 prevents overactivation of the NLRP3 inflammasome through deacetylation. Targeting this pathway can possibly reduce or even reverse age-related chronic inflammation and insulin resistance.

What are sirtuins?

Sirtuins are a family of proteins that have long been a target of longevity research [1]. Sirtuins probably descend from some of the oldest defense mechanisms invented by life billions of years ago. Sirtuin levels have been linked to longevity in yeast, drosophila flies, mice, and, more recently, larger mammals. Last year, we reported on a noteworthy study that tested the hypothesis that species’ longevity can depend on how well their sirtuins work. Indeed, the researchers had found that the longer-lived species of rodents (naked mole rats and beavers with a lifespan of up to 32 years) benefit from an especially robust sirtuin machinery.

How do sirtuins work?

Sirtuins’ main modus operandi is deacetylation: removing acetyl groups from other proteins. For instance, some sirtuins help keep our DNA safe by removing acetyl tags from histones, the bulky proteins that chromatin is wrapped around. When chromatin is in its condensed form, tightly wrapped around a histone, this region of the DNA molecule cannot be transcribed and is better protected from damage. To be “unmuted”, it first must be unwound by adding an acetyl group to the histone. After the transcription is no longer required, sirtuins help to repack the chromatin by removing the acetyl group. They also perform “emergency deacetylation” if a DNA breakage occurs while the chromatin is in its unwound form. Repacking the chromatin prevents further damage and facilitates repair.



NLRP3 inflammasome linked to chronic inflammation

This is by no means the only mechanism by which sirtuins promote cellular health, and a new one has just been discovered: a group of scientists from UC Berkeley found that the SIRT2 protein regulates the activity of the NLRP3 inflammasome [2].

The NLRP3 inflammasome is a multiprotein complex found mostly in immune cells, such as macrophages, that detects various pathogens and other inflammatory triggers. Upon detection, it launches a two-pronged attack, releasing cytokines IL-1β and IL-18 and inducing an especially violent form of cellular demise called pyroptosis (since ‘pyro’ means ‘fire’ in Greek, the term can be loosely translated as ‘fiery death’). This type of cellular self-sacrifice is highly inflammatory. Consequently, overactivation of the NLRP3 inflammasome stimulates chronic inflammation and has been linked to various age-related diseases, including Alzheimer’s disease, atherosclerosis, and type 2 diabetes.

The mechanism of its activation is still not fully known [3]. The UC Berkeley study shows that one of the key factors in this process is acetylation and that the SIRT2 protein inactivates the inflammasome by doing what it does best: removing the acetyl group.

Our studies identify an acetylation switch of the NLRP3 inflammasome in macrophages as a regulatory mechanism to ensure robust yet acute immune responses. Dysregulation of the acetylation switch of the NLRP3 inflammasome underlies chronic low-grade inflammation associated with aging and overnutrition and perpetuates the development of insulin resistance. Importantly, this regulatory mechanism can be targeted to reverse aging-associated inflammation and insulin resistance. Dysregulation of the NLRP3 inflammasome is implicated in numerous pathological conditions. Its activity must be kept in check to prevent untoward physiological consequences.

The authors further note that the NLRP3 inflammasome’s “powerful inflammatory machinery” is subjected to multilayer regulation that can be compromised by conditions such as aging and overnutrition.



The researchers demonstrated that knocking out the SIRT2 gene in macrophages in mice results in higher levels of inflammation and insulin resistance as they age. Insulin resistance is a major factor in developing type 2 diabetes and metabolic syndrome. To determine that the mechanism in play indeed involves acetylation of the NLRP3 inflammasome, the team also studied mice whose reconstituted immune systems produced two different versions of NLRP3 – acetylated and deacetylated. The second group had shown less insulin resistance. Notably, higher levels of SIRT2 seemed to make a difference in young mice only if they had been overfed, as if the NLRP3 circuitry in normally fed young mice worked perfectly and did not require any additional regulation by SIRT2. As the mice aged, though, the advantages of higher levels of SIRT2 became apparent even in normally fed animals. This finding is consistent with what we know about chronic inflammation, namely that it is exacerbated by overnutrition.

Conclusion

Chronic low-grade inflammation has been linked by numerous studies to aging and overeating, but its origins are still not entirely understood. The authors believe that the SIRT2 – NLRP3 pathway that they have discovered can be used to target this elusive enemy. The study also expands our understanding of the ways in which sirtuins can benefit our health and lifespan and underscores the need to find ways to boost sirtuin production in aging bodies.

Literature



[1] Grabowska, W., Sikora, E., & Bielak-Zmijewska, A. (2017). Sirtuins, a promising target in slowing down the ageing process. Biogerontology18(4), 447-476.

[2] He, M., Chiang, H. H., Luo, H., Zheng, Z., Qiao, Q., Wang, L., … & Wu, H. (2020). An Acetylation Switch of the NLRP3 Inflammasome Regulates Aging-Associated Chronic Inflammation and Insulin Resistance. Cell Metabolism.

[3] Swanson, K. V., Deng, M., & Ting, J. P. Y. (2019). The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nature Reviews Immunology19(8), 477-489.

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About the author
Arkadi Mazin

Arkadi Mazin

Arkadi is a seasoned journalist and op-ed author with a passion for learning and exploration. His interests span from politics to science and philosophy. Having studied economics and international relations, he is particularly interested in the social aspects of longevity and life extension. He strongly believes that life extension is an achievable and noble goal that has yet to take its rightful place on the very top of our civilization’s agenda – a situation he is eager to change.
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