Inflammation, Lipid Metabolism and Senescence

ABSTRACT
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 Unpublished work carried out by the Robbins lab has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.

Grant Number: 5R01AG069819-05
NIH Institute/Center: NIH
Principal Investigator: Christina Camell