Oxidative stress contributes substantially to numerous human diseases and aging. Dietary restriction (DR), a dietary regimen that ameliorates various diseases and extends lifespan, reduces the steady state levels of oxidative stress and damage. DR has been postulated to reduce oxidative stress by slowing metabolism, and thereby reducing mitochondrial generation of reactive oxygen species (ROS). Recent findings, however, indicate that mitochondrial activity increases during DR. Thus, the molecular mechanism underlying DR- induced reduction of oxidative stress remains elusive. The central hypothesis of this proposal is that, instead of passively slowing metabolism, DR triggers an active defense program involving a cascade of molecular regulators to reduce oxidative stress. Our recent finding that DR activates a nutrient sensor to reduce oxidative stress supports this hypothesis. We plan to greatly expand this initial finding to delineate the cascade that senses nutrient input to regulate the cellular oxidative stress status. We have established a DR mouse model and a cell culture model to study nutrient sensing and the oxidative stress response. Using the established system, we will elucidate the molecular events that result in either reduced production or improved removal of cellular ROS during DR. Using a gain-of-function approach, we will test the feasibility of activating these molecules to mimic the DR response and reduce oxidative stress. Collectively, these studies challenge the paradigm that DR reduces oxidative stress by passively slowing metabolism and highlight an active defense program provoked by a low calorie diet to reduce oxidative stress. The factors identified in our study are likely to play paramount roles in maintaining the cellular oxidative stress status and suggest new approaches to treat oxidative stress-related diseases and slow aging. The proposed studies will build a solid foundation for a dynamic research program that has a great potential for development: nutrient sensing and the oxidative stress response.

Public Health Relevance

Dietary restriction is the most robust dietary intervention that extends lifespan and prevents many diseases related to aging in mammals. This project details a study of dietary restriction in mice that will lead to the elucidation of the molecular mechanisms regulating this process. This study will have profound implications in drug development for diseases of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG040990-04
Application #
8721823
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Finkelstein, David B
Project Start
2011-09-01
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$307,114
Indirect Cost
$102,114
Name
University of California Berkeley
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Mohrin, Mary; Widjaja, Andrew; Liu, Yufei et al. (2018) The mitochondrial unfolded protein response is activated upon hematopoietic stem cell exit from quiescence. Aging Cell 17:e12756
Budinger, G R Scott; Kohanski, Ronald A; Gan, Weiniu et al. (2017) The Intersection of Aging Biology and the Pathobiology of Lung Diseases: A Joint NHLBI/NIA Workshop. J Gerontol A Biol Sci Med Sci 72:1492-1500
Luo, Hanzhi; Chiang, Hou-Hsien; Louw, Makensie et al. (2017) Nutrient Sensing and the Oxidative Stress Response. Trends Endocrinol Metab 28:449-460
Mohrin, Mary; Chen, Danica (2016) The mitochondrial metabolic checkpoint and aging of hematopoietic stem cells. Curr Opin Hematol 23:318-24
Shin, Jiyung; Mohrin, Mary; Chen, Danica (2015) Reversing stem cell aging. Oncotarget 6:14723-4
Mohrin, Mary; Shin, Jiyung; Liu, Yufei et al. (2015) Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347:1374-7
Xi, Yannan; Chen, Danica (2014) Physiology. Partitioning the circadian clock. Science 345:1122-3
Brown, Katharine; Xie, Stephanie; Qiu, Xiaolei et al. (2013) SIRT3 reverses aging-associated degeneration. Cell Rep 3:319-27
Shin, Jiyung; He, Ming; Liu, Yufei et al. (2013) SIRT7 represses Myc activity to suppress ER stress and prevent fatty liver disease. Cell Rep 5:654-665
Merksamer, Philip I; Liu, Yufei; He, Wenjuan et al. (2013) The sirtuins, oxidative stress and aging: an emerging link. Aging (Albany NY) 5:144-50

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