As the world's population ages, there is an increasingly urgent need to understand the aging process and its role in age-onset disorders. While aging is the greatest risk factor for the development of neurodegenerative disease, the role of aging in these diseases is not well defined. Our recent work suggests that targeting pathways involved in aging may be an effective strategy in the treatment of Parkinson's disease, as well as other neurodegenerative diseases. As the biology of aging is still poorly understood, the goal of the current proposal is to gain insight into the aging process by defining the molecular mechanisms involved in one specific pathway of lifespan extension. We have shown that in C. elegans mild elevation of reactive oxygen species (ROS) levels through deletion of the mitochondrial superoxide dismutase gene sod-2, or directly through treatment with the superoxide-generating compound paraquat, extends lifespan. Importantly, increasing ROS has also been shown to extend lifespan in yeast and mice, indicating conservation across species. However, the mechanism by which ROS increase lifespan is currently unknown. The long-term goal of this work is to advance our understanding of the aging process and to use that knowledge to promote healthy aging and to develop treatments for age-onset neurodegenerative diseases. In the current proposal, the objective is to define the molecular mechanisms by which ROS act to increase lifespan. Our preliminary data demonstrates that the effect of ROS on lifespan is dependent on the precise conditions under which ROS are altered. Increasing mitochondrial superoxide extends longevity, while cytoplasmic superoxide decreases lifespan. Similarly, within the mitochondria, mild increases in superoxide levels increases lifespan, while higher levels of superoxide are toxic. Accordingly, the current proposal will define the conditions required for ROS to increase lifespan, and use this information to elucidate the underlying mechanisms through the completion of three Specific Aims: 1) Determine the mechanism by which elevated mitochondrial superoxide is detected in the cytoplasm; 2). Define the tissues in which mild elevation of mitochondrial superoxide is necessary or sufficient to increase lifespan; and 3) Identify cellular changes induced by elevated mitochondrial superoxide, but not cytoplasmic superoxide, that contribute to longevity. The expected outcome of this project is the elucidation of the mechanism by which mild elevation of mitochondrial superoxide levels extends lifespan. This research is innovative in addressing deficiencies in conventional aging theories by investigating the poorly explored beneficial effect of ROS on lifespan. The work is significant in advancing our molecular understanding of the aging process. This work has the potential to impact public health through the identification of targets for the promotion of healthy aging and treatment of neurodegenerative disease.

Public Health Relevance

As the world's population gets older, it is becoming increasingly urgent to understand the aging process and its role in the development of neurodegenerative disease. This work will define the mechanism by which mild increases in oxidative stress cause increased lifespan. By investigating one specific pathway of lifespan extension, this research will provide novel insights into the aging process, and this information can be used to promote healthy aging and develop new treatments for neurodegenerative disease.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Barski, Oleg
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Harvard Medical School
Schools of Medicine
United States
Zip Code
Cooper, Jason F; Spielbauer, Katie K; Senchuk, Megan M et al. (2018) ?-synuclein expression from a single copy transgene increases sensitivity to stress and accelerates neuronal loss in genetic models of Parkinson's disease. Exp Neurol 310:58-69
Van Raamsdonk, Jeremy M (2018) Mechanisms underlying longevity: A genetic switch model of aging. Exp Gerontol 107:136-139
Senchuk, Megan M; Dues, Dylan J; Schaar, Claire E et al. (2018) Activation of DAF-16/FOXO by reactive oxygen species contributes to longevity in long-lived mitochondrial mutants in Caenorhabditis elegans. PLoS Genet 14:e1007268
Dues, Dylan J; Andrews, Emily K; Senchuk, Megan M et al. (2018) Resistance to stress can be experimentally dissociated from longevity. J Gerontol A Biol Sci Med Sci :
Cooper, Jason F; Machiela, Emily; Dues, Dylan J et al. (2017) Activation of the mitochondrial unfolded protein response promotes longevity and dopamine neuron survival in Parkinson's disease models. Sci Rep 7:16441
Dues, Dylan J; Schaar, Claire E; Johnson, Benjamin K et al. (2017) Uncoupling of oxidative stress resistance and lifespan in long-lived isp-1 mitochondrial mutants in Caenorhabditis elegans. Free Radic Biol Med 108:362-373
Van Raamsdonk, Jeremy M; Vega, Irving E; Brundin, Patrik (2017) Oxidative stress in neurodegenerative disease: causation or association? Oncotarget 8:10777-10778
Senchuk, Megan M; Dues, Dylan J; Van Raamsdonk, Jeremy M (2017) Measuring Oxidative Stress in Caenorhabditis elegans: Paraquat and Juglone Sensitivity Assays. Bio Protoc 7: