Ying Ann Chiao

Mitochondrial oxidative stress in aging and healthspan

The free radical theory of aging proposes that reactive oxygen species (ROS)-induced accumulation of damage to cellular macromolecules is a primary driving force of aging and a major determinant of lifespan. Although this theory is one of the most popular explanations for the cause of aging, several experimental rodent models of antioxidant manipulation have failed to affect lifespan. Moreover, antioxidant supplementation clinical trials have been largely disappointing. The mitochondrial theory of aging specifies more particularly that mitochondria are both the primary sources of ROS and the primary targets of ROS damage. In addition to effects on lifespan and aging, mitochondrial ROS have been shown to play a central role in healthspan of many vital organ systems. In this article we review the evidence supporting the role of mitochondrial oxidative stress, mitochondrial damage and dysfunction in aging and healthspan, including cardiac aging, age-dependent cardiovascular diseases, skeletal muscle aging, neurodegenerative diseases, insulin resistance and diabetes as well as age-related cancers. The crosstalk of mitochondrial ROS, redox, and other cellular signaling is briefly presented. Potential therapeutic strategies to improve mitochondrial function in aging and healthspan are reviewed, with a focus on mitochondrial protective drugs, such as the mitochondrial antioxidants MitoQ, SkQ1, and the mitochondrial protective peptide SS-31.

Altered proteome turnover and remodeling by short-term caloric restriction or rapamycin rejuvenate the aging heart

Chronic caloric restriction (CR) and rapamycin inhibit the mechanistic target of rapamycin (mTOR) signaling, thereby regulating metabolism and suppressing protein synthesis. Caloric restriction or rapamycin extends murine lifespan and ameliorates many aging‐associated disorders; however, the beneficial effects of shorter treatment on cardiac aging are not as well understood. Using a recently developed deuterated‐leucine labeling method, we investigated the effect of short‐term (10 weeks) CR or rapamycin on the proteomics turnover and remodeling of the aging mouse heart. Functionally, we observed that short‐term CR and rapamycin both reversed the pre‐existing age‐dependent cardiac hypertrophy and diastolic dysfunction. There was no significant change in the cardiac global proteome (823 proteins) turnover with age, with a median half‐life 9.1 days in the 5‐month‐old hearts and 8.8 days in the 27‐month‐old hearts. However, proteome half‐lives of old hearts significantly increased after short‐term CR (30%) or rapamycin (12%). This was accompanied by attenuation of age‐dependent protein oxidative damage and ubiquitination. Quantitative proteomics and pathway analysis revealed an age‐dependent decreased abundance of proteins involved in mitochondrial function, electron transport chain, citric acid cycle, and fatty acid metabolism as well as increased abundance of proteins involved in glycolysis and oxidative stress response. This age‐dependent cardiac proteome remodeling was significantly reversed by short‐term CR or rapamycin, demonstrating a concordance with the beneficial effect on cardiac physiology. The metabolic shift induced by rapamycin was confirmed by metabolomic analysis.

The Aging Heart

Aging results in progressive deteriorations in the structure and function of the heart and is a dominant risk factor for cardiovascular diseases, the leading cause of death in Western populations. Although the phenotypes of cardiac aging have been well characterized, the molecular mechanisms of cardiac aging are just beginning to be revealed. With the continuously growing elderly population, there is a great need for interventions in cardiac aging. This article will provide an overview of the phenotypic changes of cardiac aging, the molecular mechanisms underlying these changes, and will present some of the recent advances in the development of interventions to delay or reverse cardiac aging.

Respiratory chain protein turnover rates in mice are highly heterogeneous but strikingly conserved across tissues, ages, and treatments

The mitochondrial respiratory chain (RC) produces most of the cellular ATP and requires strict quality‐control mechanisms. To examine RC subunit proteostasis in vivo, we measured RC protein half‐lives (HLs) in mice by liquid chromatography‐tandem mass spectrometry with metabolic [2H3]‐leucine heavy isotope labeling under divergent conditions. We studied 7 tissues/fractions of young and old mice on control diet or one of 2 diet regimens (caloric restriction or rapamycin) that altered protein turnover (42 conditions in total). We observed a 6.5‐fold difference in mean HL across tissues and an 11.5‐fold difference across all conditions. Normalization to the mean HL of each condition showed that relative HLs were conserved across conditions (Spearmans ρ = 0.57; P < 10–4), but were highly heterogeneous between subunits, with a 7.3‐fold mean range overall, and a 2.2‐ to 4.6‐fold range within each complex. To identify factors regulating this conserved distribution, we performed statistical analyses to study the correlation of HLs to the properties of the subunits. HLs significantly correlated with localization within the mitochondria, evolutionary origin, location of protein‐encoding, and ubiquitination levels. These findings challenge the notion that all subunits in a complex turnover at comparable rates and suggest that there are common rules governing the differential proteolysis of RC protein subunits under divergent cellular conditions.— Karunadharma, P. P., Basisty, N., Chiao, Y. A., Dai, D.‐F., Drake, R., Levy, N., Koh, W.J., Emond, M.J., Kruse, S., Marcinek, D., Maccoss, M.J., Rabinovitch, P.S.Respiratory chain protein turnover rates in mice are highly heterogeneous but strikingly conserved across tissues, ages, and treatments. FASEB J. 29, 3582‐3592 (2015). www.fasebj.org

Mitochondrial-Targeted Catalase: Extended Longevity and the Roles in Various Disease Models

The free-radical theory of aging was proposed more than 50 years ago. As one of the most popular mechanisms explaining the aging process, it has been extensively studied in several model organisms. However, the results remain controversial. The mitochondrial version of free-radical theory of aging proposes that mitochondria are both the primary sources of reactive oxygen species (ROS) and the primary targets of ROS-induced damage. One critical ROS is hydrogen peroxide, which is naturally degraded by catalase in peroxisomes or glutathione peroxidase within mitochondria. Our laboratory developed mice-overexpressing catalase targeted to mitochondria (mCAT), peroxisomes (pCAT), or the nucleus (nCAT) in order to investigate the role of hydrogen peroxide in different subcellular compartments in aging and age-related diseases. The mCAT mice have demonstrated the largest effects on life span and healthspan extension. This chapter will discuss the mCAT phenotype and review studies using mCAT to investigate the roles of mitochondrial oxidative stresses in various disease models, including metabolic syndrome and atherosclerosis, cardiac aging, heart failure, skeletal muscle pathology, sensory defect, neurodegenerative diseases, and cancer. As ROS has been increasingly recognized as essential signaling molecules that may be beneficial in hormesis, stress response and immunity, the potential pleiotropic, or adverse effects of mCAT are also discussed. Finally, the development of small-molecule mitochondrial-targeted therapeutic approaches is reviewed.

Mitochondrial-Targeted Catalase

The free-radical theory of aging was proposed more than 50 years ago. As one of the most popular mechanisms explaining the aging process, it has been extensively studied in several model organisms. However, the results remain controversial. The mitochondrial version of free-radical theory of aging proposes that mitochondria are both the primary sources of reactive oxygen species (ROS) and the primary targets of ROS-induced damage. One critical ROS is hydrogen peroxide, which is naturally degraded by catalase in peroxisomes or glutathione peroxidase within mitochondria. Our laboratory developed mice-overexpressing catalase targeted to mitochondria (mCAT), peroxisomes (pCAT), or the nucleus (nCAT) in order to investigate the role of hydrogen peroxide in different subcellular compartments in aging and age-related diseases. The mCAT mice have demonstrated the largest effects on life span and healthspan extension. This chapter will discuss the mCAT phenotype and review studies using mCAT to investigate the roles of mitochondrial oxidative stresses in various disease models, including metabolic syndrome and atherosclerosis, cardiac aging, heart failure, skeletal muscle pathology, sensory defect, neurodegenerative diseases, and cancer. As ROS has been increasingly recognized as essential signaling molecules that may be beneficial in hormesis, stress response and immunity, the potential pleiotropic, or adverse effects of mCAT are also discussed. Finally, the development of small-molecule mitochondrial-targeted therapeutic approaches is reviewed.

The Aging Heart: Figure 1.

Aging results in progressive deteriorations in the structure and function of the heart and is a dominant risk factor for cardiovascular diseases, the leading cause of death in Western populations. Although the phenotypes of cardiac aging have been well characterized, the molecular mechanisms of cardiac aging are just beginning to be revealed. With the continuously growing elderly population, there is a great need for interventions in cardiac aging. This article will provide an overview of the phenotypic changes of cardiac aging, the molecular mechanisms underlying these changes, and will present some of the recent advances in the development of interventions to delay or reverse cardiac aging.

The aging heart

Aging results in progressive deteriorations in the structure and function of the heart and is a dominant risk factor for cardiovascular diseases, the leading cause of death in Western populations. Although the phenotypes of cardiac aging have been well characterized, the molecular mechanisms of cardiac aging are just beginning to be revealed. With the continuously growing elderly population, there is a great need for interventions in cardiac aging. This article will provide an overview of the phenotypic changes of cardiac aging, the molecular mechanisms underlying these changes, and will present some of the recent advances in the development of interventions to delay or reverse cardiac aging.