Editors' ChoiceAging

How to reverse acetyl-aging

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Science Translational Medicine  19 Feb 2020:
Vol. 12, Issue 531, eaba9021
DOI: 10.1126/scitranslmed.aba9021

Abstract

SIRT2 deacetylation of NLRP3 reduces inflammation and reverses age-related glucose dysregulation.

With advancing age comes a tide of age-related conditions. Rather than simply advancing lifespan, it has become clear that extending health span is essential in an aging population. Low-grade, chronic inflammation has been associated with the development of a number of age- and obesity-related conditions, including insulin resistance and type 2 diabetes (T2D). He et al. explored the immune and metabolic interactions underlying the development of low-grade inflammation in aging and overnutrition to assess whether age- and obesity-related conditions can potentially be reversed.

Aberrant activation of the NACHT, LRR, and PYD domains–containing protein 3 (NLRP3) inflammasome leads to the production of inflammatory cytokines and contributes to inflammation in obesity and diabetes. He et al. found that in macrophages, the NLRP3 protein is modified by acetylation of lysine residues and deacetylated by the cytosolic deacetylase sirtuin 2 (SIRT2). Acetylation of NLRP3 promoted the assembly of the NLRP3 inflammasome and the production of interleukin-1β. The group performed in vivo hematopoietic stem cell (HSC) transplant studies in mice and found that hematopoietic SIRT2 repressed age-related inflammation and metabolic dysfunction in vivo.

The authors then developed an in vitro coculture system to model the effects of the immune system on metabolic tissues. They cocultured macrophages derived from immortalized myeloid progenitors of old or young mice with white adipose tissue from old or young mice. Macrophages derived from the myeloid progenitors of old mice had higher NLRP3 activity than those from young mice, along with impaired insulin sensitivity in adipose tissue. Overexpressing SIRT2 in macrophages in vitro and mutating the lysine residues of preventing NLRP3 acetylation in HSCs in vivo reversed age-related insulin and glucose intolerance.

Overall, these findings suggest that deacetylating NLRP3 may reduce chronic low-grade inflammation and protect against age-related conditions, such as insulin resistance and T2D. The experiments in this paper were all performed in a single mouse strain, and validation of the effects of aging and overnutrition on NLRP3 acetylation and inflammasome activity will be necessary before this strategy can be adopted to reverse the tide of age-related diseases in humans.

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