Aging is a complex process brought about by a combination of genetic, hormonal and metabolic determinants. Of the factors defined as mechanistically linked to fundamental processes of aging, often referred to as the ?pillars of aging?, inflammation and cellular senescence of adipose tissue take center stage. The focus of this application is the interface between immune cells, adipocytes and cellular senescence with an emphasis on the role(s) that lipids play in orchestrating B-cell biology, adipocyte oxidative stress and senescence. Recently published work from Camell and colleagues describes the age-dependent decrease in catecholamine signaling that occurs in adipose tissue due to the expansion of resident B-cells. Aged adipose B cells (AABs) have a memory-like and inflammatory phenotype, but how they impair catecholamine signaling is unclear. Age-dependent loss of catecholamine signaling decreases adipose lipolysis and release of monounsaturated fatty acids (MUFA) from triacylglycerol droplets. Work carried out collaboratively by the Bernlohr laboratory has shown that MUFAs bind directly to SIRT1 and allosterically activate the enzyme towards some, but not all, deacetylation targets. Of the targets defined, loss of SIRT1 activation leads to attenuated dephosphorylation of PGC1a and decreased transcriptional expression of mitochondrial antioxidant enzymes leading to the production of a,b-unsaturated aldehydes such as 4-hydroxy hexenal (4HHE), 4-oxononenal (4ONE) and 4- hydroxynonenal (4HNE) that diffuse from adipocytes. Unpublished work carried out by the Robbins lab has shown that 4HNE induces senescence in fibroblasts and preadipocytes leading to expression of b- galactosidase, MCP1 and p21. This proposal represents a novel confluence of interest and expertise between the Camell, Bernlohr and Robbins laboratories? to mechanistically define the interplay between inflammation of adipose tissue and lipid metabolism as key factors influencing senescence and aging. The central hypothesis for this application is that diet, age and sex-specific decreases in adipose lipolysis driven by resident B-cells leads to attenuated MUFA-dependent activation of SIRT1 and concomitantly increased oxidative stress. Increased oxidative stress in turn leads to secretion of reactive lipid aldehydes and activation of the senescence program by tissue resident preadipocytes. To test this hypothesis, the following specific aims are proposed:
Aim 1. Define diet, age, sex and depot-specific composition of adipose B cells and their impact on adipocyte lipolysis.
Aim 2. Evaluate the lipid-dependent regulation of SIRT1 and concomitant control of adipocyte oxidative stress.
Aim 3. Assess aldehyde-dependent adipose senescence in murine models and in response to senolytics.

Public Health Relevance

This application is focused on understanding the role that lipids play in regulating adipose senescence. The studies address how immune cells affect adipocytes lipolysis and how fatty acids regulate SIRT1 and oxidative stress. Oxidative stress in turn produces reactive lipids that induce senescence in preadipocytes. The work will establish that intracellular fatty acids, particularly monounsaturated fatty acids, are potential bioregulators of senescence and represent an untapped therapeutic opportunity.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZAG1)
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Fridell, Yih-Woei
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University of Minnesota Twin Cities
Schools of Medicine
United States
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