Abstract
It is well documented that the rate of aging can be slowed, but it remains unclear to which extent aging-associated conditions can be reversed. How the interface of immunity and metabolism impinges upon the diabetes pandemic is largely unknown. Here, we show that NLRP3, a pattern recognition receptor, is modified by acetylation in macrophages and is deacetylated by SIRT2, an NAD +-dependent deacetylase and a metabolic sensor. We have developed a cell-based system that models aging-associated inflammation, a defined co-culture system that simulates the effects of inflammatory milieu on insulin resistance in metabolic tissues during aging, and aging mouse models; and demonstrate that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated inflammation and insulin resistance. These results establish the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlight the reversibility of aging-associated chronic inflammation and insulin resistance.
Original language | English |
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Pages (from-to) | 580-591.e5 |
Number of pages | 17 |
Journal | Cell Metabolism |
Volume | 31 |
Issue number | 3 |
DOIs | |
State | Published - Mar 3 2020 |
Externally published | Yes |
Keywords
- Acetylation
- Aging/pathology
- Amino Acid Sequence
- Animals
- Chronic Disease
- Disease Models, Animal
- Glucose/metabolism
- Homeostasis
- Inflammasomes/metabolism
- Inflammation/pathology
- Insulin Resistance
- Mice, Inbred C57BL
- Mice, Knockout
- Models, Biological
- NLR Family, Pyrin Domain-Containing 3 Protein/chemistry
- Overnutrition/pathology
- Peptides/chemistry
- Sirtuin 2/metabolism