How physiological responses to alterations in dietary intake affect the process of aging and longevity is a fundamental question to understand the systemic regulation of the complex connection between metabolism and aging. Diet restriction (DR), the single, most reliable regimen known to retard aging and extend lifespan in a variety of organisms, has provided a unique model to address this important question. This research proposal aims to understand molecular mechanisms underlying physiological adaptive responses to DR, particularly the central adaptive response, in mammals. We have been interested in the evolutionarily conserved SIR2 (silent information regulator 2) family of NAD-dependent deacetylases/ADP-ribosyltransferases, also called "sirtuins," as a critical regulator that coordinates physiological responses to DR. Our new study has recently demonstrated a novel function of the mammalian SIR2 ortholog SIRT1 in the hypothalamus, particularly in the dorsomedial and lateral hypothalamic nuclei (DMH and LH, respectively), as a key mediator that controls the orexin type 2 receptor (OX2R)-mediated signaling in response to peripheral signals including ghrelin, an orexigenic hormone secreted from stomach, induced by DR. Therefore, in this proposal, we hypothesize that SIRT1 controls central adaptive responses to DR, including the augmentation of physical activity and the maintenance of body temperature, through the up-regulation of the Ox2r expression and the neural activation in the DHM and LH. To address this hypothesis, we will examine 1) how SIRT1 up-regulates the transcription of the Ox2r gene through a newly identified target homeodomain transcription factor in response to DR, 2) whether stereotactic injection of lentiviruses expressing shRNA against Sirt1 or the SIRT1 target transcription factor into the DMH and/or LH abrogates the central adaptive response to DR, 3) how SIRT1 activity is augmented by DR in the DMH and LH, and 4) whether SIRT1-mediated central adaptive response is also important for the control of longevity in mice. Because very little has been known about the central adaptive mechanism for DR, the proposed study will provide critical insights into the physiological mechanism that orchestrates responses to DR and may assure longevity in mammals.

Public Health Relevance

The proposed study will ultimately enhance our understanding of the regulation of metabolism and aging in mammals and provide critical insights into possible anti-aging interventions in humans for the following reasons: First, this study will elucidate the importance of a novel central regulatory circuit involving SIRT1 and orexin signaling in the hypothalamus. Second, the proposed study will shed a new light on the importance of a specific subset of neurons, namely, OX2R-positive neurons in the DMH and LH, in the regulation of central adaptive responses to DR. Lastly, this study will provide important support for the concept of the NAD World that we have recently proposed and also open a new possibility to develop nutriceutical interventions for age- associated neurological complications, including complications of ingestive behavior in the elderly, called "the anorexia of aging."

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG037457-02
Application #
8254383
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Mackiewicz, Miroslaw
Project Start
2011-05-01
Project End
2016-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$311,600
Indirect Cost
$106,600
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Stromsdorfer, Kelly L; Yamaguchi, Shintaro; Yoon, Myeong Jin et al. (2016) NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice. Cell Rep 16:1851-60
Lin, Jonathan B; Kubota, Shunsuke; Ban, Norimitsu et al. (2016) NAMPT-Mediated NAD(+) Biosynthesis Is Essential for Vision In Mice. Cell Rep 17:69-85
Yoon, Myeong Jin; Yoshida, Mitsukuni; Johnson, Sean et al. (2015) SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice. Cell Metab 21:706-17
Satoh, Akiko; Brace, Cynthia S; Rensing, Nick et al. (2015) Deficiency of Prdm13, a dorsomedial hypothalamus-enriched gene, mimics age-associated changes in sleep quality and adiposity. Aging Cell 14:209-18
Stein, Liana Roberts; Zorumski, Charles F; Imai, Shin-Ichiro et al. (2015) Nampt is required for long-term depression and the function of GluN2B subunit-containing NMDA receptors. Brain Res Bull 119:41-51
Ghisays, Fiorella; Brace, Cynthia S; Yackly, Shawn M et al. (2015) The N-Terminal Domain of SIRT1 Is a Positive Regulator of Endogenous SIRT1-Dependent Deacetylation and Transcriptional Outputs. Cell Rep :
Stein, Liana Roberts; Wozniak, David F; Dearborn, Joshua T et al. (2014) Expression of Nampt in hippocampal and cortical excitatory neurons is critical for cognitive function. J Neurosci 34:5800-15
Imai, Shin-ichiro; Guarente, Leonard (2014) NAD+ and sirtuins in aging and disease. Trends Cell Biol 24:464-71
Satoh, Akiko; Imai, Shin-ichiro (2014) Hypothalamic Sirt1 in aging. Aging (Albany NY) 6:1-2
Satoh, Akiko; Imai, Shin-ichiro (2014) Systemic regulation of mammalian ageing and longevity by brain sirtuins. Nat Commun 5:4211

Showing the most recent 10 out of 16 publications