Aging is a major risk factor for acute and chronic diseases of the lung, including emphysema and
idiopathic pulmonary fibrosis. The biology of aging has rapidly advanced in recent years, and several hallmarks
of aging including, dysregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence have
been proposed. However, the precise metabolic underpinnings of how these hallmarks regulate
lifespan/healthspan and accelerated aging have not yet been determined.
Recent studies indicate that aging is associated with loss of cellular plasticity and sustained fibroblast
senescence that leads to persistent/non-resolving fibrosis in response to lung injury. Interestingly, glycosylation
reactions such as the O-linked N-Acetylglucosamine (O-GlcNAc) modification have been integrally linked to
metabolic/nutrient- and stress-responsive signaling, including the regulation of AMPK. We previously reported
that the O-GlcNAc transferase (OGT), through altered glucose utilization and metabolism, regulates smooth
muscle proliferation associated with accelerated progression of idiopathic pulmonary arterial hypertension
(IPAH). OGT is a metabolic stress `sensor' and is responsible for the O-GlcNAc modification of proteins involved
in cell signaling, cell cycle, proliferation/senescence, mitochondrial bioenergetics, and nutrient metabolism. In
addition, OGA (O-GlcNAc hydrolase), the O-GlcNAc removing enzyme, is involved in these cellular processes.
O-GlcNAc/OGT/OGA (hereby, termed the O-GlcNAc axis), thus, may regulate multiple aging-related hallmarks.
The impact of the O-GlcNAc axis as a metabolic sensor and regulator of cellular senescence and aging in IPF,
as well as other diseases of the aging lung, has not been studied.
Our hypothesis to be tested in this proposal is that altered metabolic sensing by the O-GlcNAc signaling
axis predisposes to cellular senescence and accelerated aging in IPF. We will test this hypothesis using the
following specific aims: (1) Investigate the molecular mechanism(s) of the O-GlcNAc axis on accelerated aging
and cellular senescence in IPF; (2) Determine whether the O-GlcNAc axis regulates cellular senescence and
capacity for fibrosis resolution in aged mice.; and (3) Determine the metabolomic and glycomic profiles in normal
human lung aging and in IPF. Completion of these aims will: (a) identify the O-GlcNAc axis as a key hub in
metabolic dysregulation associated with aging; (b) demonstrate the O-GlcNAc axis on specific cell types in the
lung and their susceptibility and contribution to disease and accelerated aging; and (c) demonstrate that one or
more metabolic pathways are regulated by the O-GlcNAc axis in the age-related lung disease, IPF.