Inflammation and Aging-associated Diabetes

Project Summary
Epidemiological studies indicate that aging is associated with a chronic increase in circulating levels of
inflammatory molecules. Chronic inflammation has been linked to major aging-related changes and
numerous aging-related chronic diseases, including diabetes. The overarching goal of this proposal is
to elucidate the molecular and cellular mechanisms underlying aging-associated chronic inflammation
and the development of diabetes. Nutritional status affects chronic inflammation, the rate of aging,
and the development of aging related chronic diseases, suggesting a possible crosstalk between
chronic inflammation regulated by physiological aging and nutritional status. We hypothesize that
nutrient sensors regulate the inflammatory response pathways and provide a crosstalk between
chronic inflammation regulated by physiological aging and nutritional status. This hypothesis is
supported by our recent findings that a nutrient sensor regulates a key component of the inflammatory
response pathway and is responsive to both physiological aging and nutritional status. We propose
that the nutrient sensitive inflammatory response pathway forms the molecular interface between
nutrient input and the metabolic network. Through this interface, cells can respond readily to
metabolic and external cues, and dynamically regulate the metabolic status. Perturbation of this
interface contributes to aging-associated chronic inflammation and diseases, such as diabetes.
We have established mouse models to study chronic inflammation and metabolic perturbation during
aging and overnutrition. We have also established a cell-based system to study aging- or
overnutrition-associated inflammatory response in mechanistic details. Using the established system,
we will elucidate the molecular events that result in increased chronic inflammation during aging or
overnutrition. Using a gain-of-function approach, we will test the feasibility of activating these
molecules to dampen aging or overnutrition-associated chronic inflammation and insulin resistance.
Collectively, these studies highlight a novel nutrient sensitive inflammatory response pathway, which
maintains metabolic homeostasis and is perturbed by overnutrition and physiological aging, thus is
highly relevant to human health. The factors identified in our study are likely to play paramount roles
in limiting chronic inflammation and suggest new approaches to combat chronic inflammation-related
deterioration and diseases, such as diabetes.

Grant Number: 5R01AG063389-05
NIH Institute/Center: NIH
Principal Investigator: DANICA CHEN