Current research on aging has largely focused the molecular mechanisms of age-related diseases, and mitochondrial dysfunction has been associated with several human diseases of aging. However, the cellular mechanisms of mitochondrial dysfunction and how they lead to age-related diseases are not known. Chemical modifications to mitochondrial proteins control several aspects of mitochondrial function, and the long-term goal of this project is to understand how these modifications are regulated by the NAD(+)-dependent sirtuin deacylases and influence the diseases of aging. The objective of this proposal is to define the role of SIRT5 in the molecular mechanisms of aging. The central hypothesis is that SIRT5 regulates mitochondrial function by removing a newly discovered acyl modification from mitochondrial proteins. In the absence of SIRT5, mitochondrial proteins will become hyper-acylated, have reduced mitochondrial function, and exhibit several markers of accelerated aging. The rationale for this hypothesis is based on preliminary data, which suggests an important role for SIRT5 in the cellular mechanisms of aging and disease. To test these hypotheses, three specific aims will be pursued: 1. Determine the changes in protein acylation as a function of age, using a proteomic strategy to quantify hepatic mitochondrial protein acylation from young, middle-aged, and old mice;2. Determine the effect of this novel acyl modification on protein function by using a combination of cell and murine models, in order to to measure the changes in protein activity of specific proteins, as well as the overall function of mitochondria;3. Determine role of SIRT5 on aging by measuring several physiological parameters of aging using both in vitro cellular assays and in vivo assays in mice, to determine how SIRT5 maintains mitochondrial and cellular homeostasis during aging. This study combines a novel protein modification, a comprehensive experimental design, and an innovative conceptual framework. Furthermore, this study will build a foundation for this early-stage investigator and ensure a successful research program focused on the cellular mechanisms of aging and disease. Importantly, the proposed research is significant because it is expected to advance and expand understanding how mitochondrial dysfunction can lead to age-related diseases. Ultimately such knowledge has the potential to inform the development of new therapies against several diseases of aging.

Public Health Relevance

The proposed research is relevant to public health because in the next 50 years, the world's population aged 60 and over will more than triple from 600 million to 2 billion and carries the risk of significant social and economic burden if healthy aging cannot be maintained. Healthy aging can prevent or delay the onset of chronic diseases, and therefore this research proposal addresses an important human health problem aligned with the mission of the NIH.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
1R01AG045351-01A1
Application #
8650231
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
2014-02-01
Project End
2019-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
Wagner, Gregory R; Bhatt, Dhaval P; O'Connell, Thomas M et al. (2017) A Class of Reactive Acyl-CoA Species Reveals the Non-enzymatic Origins of Protein Acylation. Cell Metab 25:823-837.e8
Anderson, Kristin A; Huynh, Frank K; Fisher-Wellman, Kelsey et al. (2017) SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metab 25:838-855.e15
Huynh, Frank K; Hu, Xiaoke; Lin, Zhihong et al. (2017) Loss of sirtuin 4 leads to elevated glucose- and leucine-stimulated insulin levels and accelerated age-induced insulin resistance in multiple murine genetic backgrounds. J Inherit Metab Dis :
Anderson, Kristin A; Madsen, Andreas S; Olsen, Christian A et al. (2017) Metabolic control by sirtuins and other enzymes that sense NAD+, NADH, or their ratio. Biochim Biophys Acta 1858:991-998
Hershberger, Kathleen A; Abraham, Dennis M; Martin, Angelical S et al. (2017) Sirtuin 5 is required for mouse survival in response to cardiac pressure overload. J Biol Chem 292:19767-19781
Wagner, Gregory R; Hirschey, Matthew D (2017) A Prob(e)able Route to Lysine Acylation. Cell Chem Biol 24:126-128
Hershberger, Kathleen A; Martin, Angelical S; Hirschey, Matthew D (2017) Role of NAD+ and mitochondrial sirtuins in cardiac and renal diseases. Nat Rev Nephrol 13:213-225
Weir, Heather J; Yao, Pallas; Huynh, Frank K et al. (2017) Dietary Restriction and AMPK Increase Lifespan via Mitochondrial Network and Peroxisome Remodeling. Cell Metab 26:884-896.e5
Madsen, Andreas S; Andersen, Christian; Daoud, Mohammad et al. (2016) Investigating the Sensitivity of NAD+-dependent Sirtuin Deacylation Activities to NADH. J Biol Chem 291:7128-41
McDonnell, Eoin; Crown, Scott B; Fox, Douglas B et al. (2016) Lipids Reprogram Metabolism to Become a Major Carbon Source for Histone Acetylation. Cell Rep 17:1463-1472

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