UC Berkeley

Aging was once thought to be an inevitable process of deterioration. However, with significant advance in aging research in recent decades, it is more widely accepted that the aging process is under regulatory control and can be slowed or even reversed, at least to some extent, by different interventions to extend the lifespan or healthspan. Aging is associated with a wide range of human diseases. Understanding how aging-associated conditions are regulated is of great importance and holds promise to help extend the lifespan or healthspan. In addition, it is essential for our body to have the ability to sense and respond to fluctuations in environmental nutrient levels. Dysregulated nutrient sensing plays a role in some known pathological conditions. Aging and overnutrition can both contribute to chronic low-grade inflammation, which has been shown to contribute to many diseases, such as obesity, diabetes, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and cancer. The aim of this dissertation work was to gain molecular insights into the metabolic regulation during aging and overnutrition. Silent information regulator 2 (Sir2) proteins, or sirtuins, are highly conserved nicotinamide adenine dinucleotide (NAD+) dependent protein deacetylases. They have been to play a significant role in cellular metabolic homeostasis regulation. There are seven sirtuins in mammals and located in different subcellular areas. SIRT2, a cytosolic deacetylase, has been reported to suppress inflammation in multiple inflammation-inducing mouse models. Aberrant inflammasome activations are believed to be involved in various inflammatory disorders. However, the molecular mechanisms explaining how inflammasomes activation is regulated under different conditions remain elusive. Thus, we set out to investigate if SIRT2 suppress chronic inflammation through regulating the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome directly or indirectly. We found that SIRT2 can specifically deacetylate NLRP3 to suppress the assembly and activation of NLRP3 inflammasome. Using cell-based systems and aging mouse models, we demonstrated that SIRT2 and NLRP3 deacetylation prevent, and can be targeted to reverse, aging-associated chronic inflammation and insulin resistance. These results suggest the dysregulation of the acetylation switch of the NLRP3 inflammasome as an origin of aging-associated chronic inflammation and highlights the reversibility of aging-associated chronic inflammation and insulin resistance. Our study not only broadens the understanding of the molecular mechanism about how SIRT2-NLRP3 axis is involve in the metabolic regulation during aging and overnutrition, but also provides important insights into the interface of immunity and metabolism. Besides, it may inspire novel therapeutical strategies to deal with aging-associated conditions and diseases.