In modern societies, aging remains the leading risk factor for neurodegenerative disorders, cardiovascular diseases and cancer. Werner Syndrome (WS) is a rare autosomal premature aging syndrome caused by mutations in the WRN gene. The WRN gene encodes for a protein containing a central RecQ helicase domain implicated in DNA repair. WS patients show premature aging hallmarks including hair loss, skin wrinkling, reduced fertility, bilateral cataract, arteriosclerosis, atherosclerosis, typ-2 diabetes, osteoporosis, certain types of cancer and reduced lifespan. Although significant progress has been made over the years to improve our understanding about WS, many questions remain unanswered. Accumulating evidence using patient samples, as well as cellular and animal models of WS, demonstrate that in addition to the genomic instability produced by defects in DNA repair pathways as consequences of mutations in the WRN gene, mitochondrial dysfunction and oxidative stress are among the phenotypes associated with WS. Due to the fundamental role of mitochondria in energy production and reactive oxygen species (ROS) generation, it is tempting to imagine a pathophysiological mechanism, analogous to normal aging, where a progressive decline in mitochondrial function and consequently increase in ROS will lead to genomic instability playing a central role in the course of the disease. However, whil defects in DNA repair as well as mitochondrial dysfunction have been observed in samples from WS patients, the role and importance of mitochondrial dysfunction and the mechanism linking these two hallmarks of aging have not been elucidated. Taking advantage of stem cell technologies, we have generated a novel premature aging model of WS. We believe that this model of premature aging has higher significance and relevance to human aging compared to the currently available models. Taking advantage of this model and its potential to study any of the cell types affected in WS, we propose to investigate the role of mitochondrial function in human aging. For this purpose, we will test manipulations aimed at restoring mitochondrial function and reduce oxidative stress, which we expect will significantly reduce DNA damage and ameliorate the premature aging phenotypes observed in WS patients. Finally, by genetic and pharmacological manipulation of the main pathways linked to aging, we will investigate the mechanism connecting genomic instability and mitochondrial dysfunction and test for the suppression of WS phenotypes with the goal of devising novel therapeutic interventions aimed at palliating the devastating effects of this and other premature aging syndromes, as well as normal aging.

Public Health Relevance

Aging represents the major risk factor for neurodegenerative disorders, cardiovascular diseases and cancer. This project aims to improve our understanding of the role of mitochondria in aging using stem cell models of the premature aging disease known as Werner Syndrome. The results arising from this proposal may potentially lead to discovery of novel therapies aimed at improving mitochondrial function, thereby reducing the impact of age-related diseases and extending a healthy lifespan.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32AG047770-01
Application #
8717445
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Guo, Max
Project Start
2014-08-16
Project End
2016-08-15
Budget Start
2014-08-16
Budget End
2015-08-15
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Reddy, Pradeep; Ocampo, Alejandro; Suzuki, Keiichiro et al. (2015) Selective elimination of mitochondrial mutations in the germline by genome editing. Cell 161:459-469
Ocampo, Alejandro; Izpisua Belmonte, Juan Carlos (2015) Stem cells. Holding your breath for longevity. Science 347:1319-20
Zhang, Weiqi; Li, Jingyi; Suzuki, Keiichiro et al. (2015) Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. Science 348:1160-3