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1. Cellular & Molecular Mechanisms of Cardiac Aging Aging is a process whereby progressive decline of tissue homeostasis reduces system function and elevates risk of death. Age itself is a major risk factor for a range of human diseases, such as cancer, diabetes, neurodegeneration and heart disease. Specifically, aging is associated with an 8-fold increase of the incidence of sudden cardiac death (SCD), the leading cause of death in western countries. Resolving the contributing mechanisms of heart disease in any of its forms is a pressing goal of basic and translational aging research.
We have recently found that TGF-beta/activin signaling increases with age and negatively regulates autophagic activity. Consistently, suppression of TGF-beta/activin preserves cardiac function and autophagic activity with age. Surprisingly, we show that mTORC2, but not mTORC1, is required for TGF-beta/activin-regulated autophagy. Furthermore, activation of mTORC2 alone promotes autophagic activity, preserves cardiac function with aging, and prolongs lifespan. The mTOR pathway is one of the most important nutrient and longevity regulators, which consists of two distinct multiprotein complexes, mTORC1 and mTORC2. It has been shown that two mTOR complexes play opposite roles in tissue homeostasis and aging, although the underlying mechanisms remain largely unknown. The distinct regulation of autophagy by two mTOR complexes uncovered in our study may explain why mTORC1 and mTORC2 differentially control animal aging. |
Liver-heart communication via inflammatory cytokine upd3, fly homolog of interleukin 6 (IL-6)
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2. Inter-Organ Communication via Systemic Signals
The tissue-specific roles of known longevity pathways in the regulation of lifespan have been reported from several studies. However, it is unclear how genetic manipulation of these pathways within certain tissue can result in a systemic effect on organism’s fitness and survival. Besides cell-autonomous mechanisms (e.g., autophagy), it has become much appreciated that inter-tissue communication is also attributed to age-dependent decline of cardiac function. However, such non-autonomous regulation of cardiac aging has not yet been identified. The liver (oenocytes in flies) is a major endocrine organ, and aging significantly alters liver morphology and function. Patients with liver dysfunction, such as cirrhosis, often show increased cardiac arrhythmias. Thus, there is a clear connection between liver and heart.
Through a genetic screen, we identified oenocyte-derived upd3, an interleukin 6 (IL-6)-like pro-inflammatory cytokine in Drosophila, is a key hormonal factor mediating oenocyte-heart communication and cardiac aging.. Furthermore, we show that age-dependent impairment of peroxisome import is a major cause of oenocyte dysfunction, upd3 induction, and systemic inflammation. Thus, our findings establish peroxisome as a novel regulator of tissue aging and chronic inflammation (inflammaging). Our studies also reveal a new paradigm for cardiac aging, which is that age-related cardiac diseases are rooted from liver inflammation. |
Peroxisomal import declines with age. A) Diagram showing peroxisomal protein import via adaptor protein Pex5. B) Co-localization of Pmp70 (peroxisome marker) and YFP-SKL (import reporter), showing aged peroxisomes (ghosts) contain less matrix proteins. C) Defective peroxisomes cause aging, inflammation, and altered mitochondrial dynamics.
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3. Peroxisome and inter-organelle communication
Peroxisomal import function is often compromised under stress and aging, as demonstrated in recent studies from our group and others. Although it has become more and more appreciated that defective peroxisomal import contributes significantly to the loss of cellular homeostasis and aging, little is known about how cells mount defense mechanisms to maintain cellular and metabolic function during peroxisomal import stress. Recently, we have applied genomic (RNA-Seq) and genetic approaches (CRISPR screening) to comprehensively characterize and uncover cellular stress responses to defective peroxisomal protein import.
In addition, we have begun to explore the role of peroxisome-mitochondrion communication in tisue aging, given that inter-organelle communication plays an essential role in maintaining cellular homeostasis. |
“The lighthouse is always there, but you only see it when it is lit.” ― from Cixin Liu's book, "Ball Lightning"
Or "Just because you cannot see it, doesn't mean it doesn't exist."
Or "Just because you cannot see it, doesn't mean it doesn't exist."