Human aging and a number of age-related diseases are associated with altered protein homeostasis, or proteostasis. Among the critical regulators of proteostasis is autophagy, an evolutionarily conserved membrane trafficking process that degrades a variety of cellular constituents through the lysosome. Autophagy is induced during starvation and calorie restriction, and is essential for maintaining cell and tissue integrity. While autophagy is well-known to degrade cytoplasmic materials, recently I have made the surprising discovery that mammalian autophagy is able to degrade nuclear constituents (Dou et al, Nature, 2015). The autophagy protein LC3 is present in the nucleus and directly interacts with the nuclear lamina protein Lamin B1, and associates with lamin-associated domains (LADs) on chromatin at the genome-wide level. This interaction mediates trafficking and degradation of Lamin B1 and associated heterochromatin, through a nucleus-to- cytoplasm transport process, leading to their digestion in cytoplasmic lysosomes. This lamina and chromatin autodigestion specifically occurs during cellular senescence, a stable form of cell-cycle arrest. Senescence is a specialized cell state in response to oncogene activation, which is beneficial in restraining tumorigenesis; however, senescence is also induced during aging, which contributes to age-related pathologies. I found that inhibiting autophagy or the LC3-Lamin B1 interaction prevents the degradation of Lamin B1 and extends cellular lifespan. These findings provide the first demonstration that mammalian autophagy has functional roles in maintaining homeostasis of the nucleus, suggests a new direction in understanding mammalian aging, and provokes numerous questions to be addressed. In this proposal, I plan to investigate this new perspective of nuclear autophagy, and to study its impact on chromatin and aging. My central hypothesis is that while autophagic degeneration of chromatin is an intrinsic tumor suppressive mechanism, paradoxically it is improperly adapted during aging and contributes to age-related pathologies. I also hypothesize that specific manipulation of this nuclear pathway of autophagy holds promise in treating age-related diseases. For the K99 phase, I propose to study the role of cytoplasmic chromatin shuttled by autophagy in mediating senescence-associated inflammation (Aim 1). I further propose to investigate this pathway in chronic inflammation as seen in human aging, using in vivo aging models (Aim 2). In the R00 phase, I plan to investigate the autophagic degradation of a chromatin modifier that plays an essential role in longevity (Aim 3), and to identify novel nuclear substrates of autophagy that associate with autophagy proteins and regulate senescence and aging (Aim 4). This study will make pioneering contributions to our understanding of mammalian aging from the perspective of nuclear homeostasis, and may help to identify new pharmaceutical targets in ameliorating age-associated disorders. The proposed training and research will greatly facilitate my transition to an independent tenured-track faculty position.

Public Health Relevance

Aging and age-related diseases are the leading causes of morbidity and mortality in the general public. Autophagy as a homeostasis event is closely involved in aging. Manipulation of autophagy to treat human diseases is actively under investigation using pharmaceutical approaches. My proposal aims to uncover a new process of autophagy in shuttling and degrading nuclear and chromatin materials, and suggests that this new direction of autophagy is a suitable pharmaceutical target to intervene in age-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Transition Award (R00)
Project #
5R00AG053406-04
Application #
9791148
Study Section
Special Emphasis Panel (NSS)
Program Officer
Guo, Max
Project Start
2018-09-30
Project End
2021-05-31
Budget Start
2019-07-01
Budget End
2020-05-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
Hospitals
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114