Project Summary Persistent low-grade inflammation underlies the development of chronic diseases that are prevalent in the elderly. Adipose tissue displays unique susceptibility to age-related inflammation. Even healthy individuals accumulate visceral adiposity in older age, leading to increased systemic inflammation and reduced metabolic health. A strong candidate source of inflammation in aged adipose tissue is the resident immune compartment. Within every organ is a specialized repertoire of resident immune cells that is essential for tissue homeostasis and stress adaptation. In adipose tissue, resident immune cells coordinate responses to fasting and cold, and our prior work establishes that changes in adipose-resident immune cells impairs responses to both these challenges in old mice. But the mechanisms that drive adipose-resident immune dysfunction throughout the lifespan have remained elusive. This proposal will leverage new technological approaches to address this outstanding question. Peripheral immune cells accumulate intracellular defects during aging, leading to poor immune protection after vaccination or infection. Given that tissue-resident immune cells are seeded early in life and maintained through self-renewal, we expect them to be especially sensitive to age-related regulatory pressures. Importantly, immune cells are also sensitive to environmental cues, and extracellular cytokines and nutrient availability strongly influence the recruitment and function of immune cells. Therefore, we hypothesize that both immune cell-intrinsic and -extrinsic mechanisms cause dysregulation of the aging adipose-resident immune compartment. We will use an inducible fate-mapping strategy, combined with intra-vascular labeling, to study bonafide long-lived adipose-resident immune cells. We will use a viral vector-based proximity ligation approach to discover age-dependent changes in adipose secreted proteins and test how they impact resident immune cells. By comparing old and younger obese mice, we will isolate age-specific mechanisms of inflammation and adipose tissue dysfunction. We will use these results to develop new strategies that protect the aging adipose-resident immune compartment and prevent inflammation. Our methods overcome several longstanding obstacles in aging science: (1) knowing the “age” of an immune cell, and (2) pinpointing known cell sources of age-associated cytokines/secreted factors. With these new capabilities, our work stands to advance aging science and enable discovery of new disease mechanisms affecting any organ system.

Project Narrative Tissue-resident immune cells are responsible for coordinating adaptive stress responses and limiting inflammation. In adipose tissue, age-associated perturbation of the resident immune compartment coincides with the accumulation of inflammation and impaired adaptation to cold and fasting. Here we will leverage new technology to uncover intrinsic and extrinsic mechanisms of adipose-resident immune dysregulation to restore immune function during aging and preserve adipose tissue health.