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Sirtuins and NAD
Joseph BaurPerelman School of MedicineUniversity of Pennsylvania
DoD State of the Science SymposiumOctober 25, 2019
Caloric Restriction Increases Rodent Lifespan
Barger et al. Exp Gerontol. 38:1343 (2003)
ALCR
Female Mice
Sun et al. Clin. Diagn. Lab. Immunol. 2001, 8(5):1003.
Paraquat Injection
…and Stress Resistance
Will targeting longevity pathways conferstress-resistance like CR?
Carrie Sims, MD, PhD
Associate Professor of Surgery
Hospital of the University of Pennsylvania Presbyterian Medical Center of Philadelphia
Hemorrhagic Shock
Brohi et al. Intensive Care Med, 2019.
Mortality for Trauma Patients Activating a Hemorrhage Protocol and Requiring
Blood Transfusion
How Does CR Work?
Energy Intake
Body Size?
Adiposity?
Metabolic Rate?
Oxidative Stress?
Insulin Signaling?
Chronic Inflammation?
GH/IGF1 Signaling?
Ingestion of AGEs?
Hormesis?
mTOR Signaling?AMPK Activity?
NAD?
…and can we mimic it with drugs?
Sirtuins ?
Mimicking CR-Induced Stress-Resistance
SIRT1
Resveratrol
Resistance to Trauma, Hemorrhagic Shock, Sepsis, Chemotherapy???
?
Rat Hemorrhagic Shock Model
Anesthetized:LinesLaparatomy
30 min stabilizationEmerge from anesthesia
Begin hemorrhageto MAP 40
mmHg
Severe Shock
Resuscitation over 60 min with4X shed volume in LR
- or –4x shed volume in LR + RSV
60 min
60 R 18 hr
18 hours
Decompensation: Incremental Infusion
Req’dto maintain MAP
Physiologic Reserve
Resveratrol Ameliorates Hyperglycemia During Resuscitation from Hemorrhagic Shock
Hyperglycemia Lactate
RSV
Wang et al, J Trauma Acute Care Surg. 2014Wang et al, Shock. 2015
Resveratrol Ameliorates Hyperglycemia During Resuscitation from Hemorrhagic Shock
Wang et al, J Trauma Acute Care Surg. 2014Wang et al, Shock. 2015
RSV RSV
Resveratrol Ameliorates Oxidative Stress Induced by Hemorrhagic Shock
Kidney ROS Liver ROS
RSV RSV RSV RSV
Wang et al, J Trauma Acute Care Surg. 2014Wang et al, Shock. 2015
Resveratrol Ameliorates Mitochondrial Dysfunction Induced by Hemorrhagic Shock
Mitochondrial Respiration
Wang et al, J Trauma Acute Care Surg. 2014Wang et al, Shock. 2015
RSV
Mimicking CR-Induced Stress-Resistance
SIRT1
Resveratrol
Resistance to Trauma, Hemorrhagic Shock, Sepsis, Chemotherapy???
??
Nicotinamidemononucleotide
(NMN)
NAD
?
NMN Ameliorates Hyperglycemia During Resuscitation from Hemorrhagic Shock
Sims et al, JCI Insight. 2018
NMN Ameliorates Mitochondrial Dysfunction Induced by Hemorrhagic Shock
Mitochondrial Respiration
Sims et al, JCI Insight. 2018
Palmitoyl Carntine
Pyruvate/Glutamate
/MalateSubstrate:
pmol
O2/
s/m
g
Summary of Hemorrhagic Shock Data
Both resveratrol and NMN are protective, suggesting a role for SIRT1: Controlled hyperglycemia and reduced lactate Improved mitochondrial function Improved survival (only NMN tested)
Mechanistic studies using genetic tools have been limited by the need to use rats
Hemorrhagic Shock in Mice
base CI M+P CI M+P +G CII CIV
Kidney Mitochondrial Respiration
WH sham
WT HS
* *
*
Qingwei Chu
SIRT1 KO?
Resveratrol Improves Survival Following Septic Shock
Sims et al, unpublished
Cecal Ligation/Puncture
Loss of SIRT1 is Pro-Inflammatory
Sims et al, unpublished
IL6 in Circulation IL6 mRNA in Bone Marrow-Derived Macrophages
Macrophage-Specific Loss of SIRT1 is Pro-Inflammatory
Sims et al, unpublished
IL6 in Circulation Survival
LysM Cre
Deletion of SIRT1 in macrophages onlyX
SIRT1 Flox
Septic Shock
Despite some conflicting pharmacological data in the literature, SIRT1 appears to be beneficial in septic shock
SIRT1 acts at least partially through anti-inflammatory mechanisms in macrophages
Are other sirtuins important? Other cell types?
SIRT3 Does Not Protect Mitochondrial from Septic Shock
Mitochondrial Respiration in Kidneys of Survivors 5 Days After Septic Shock
Sims et al, unpublished
Loss of SIRT3 is Pro-Inflammatory
Sims et al, unpublished
IL6 in Circulation IL6 mRNA in Bone Marrow-Derived Macrophages
Summary
Multiple sirtuins, including SIRT1 and SIRT3, are likely to play roles in critical injuries
A major role of sirtuins is to suppress the inflammatory response in macrophages
Timing and cell-type specificity of interventions will likely be critical…genetic models are extremely useful to tease these details out
Translation
Resveratrol and NMN could be moved into larger animal models after a few additional studies to address timing and optimal dosing.
There is potential to greatly improve the efficacy of these interventions by using genetic tools to understand the mechanisms.
Applying to NIH and DoD opportunities (Congressionally Directed Medical Research Program)
AcknowledgmentsBaur Lab
Karthi ChellappaSarmistha MukherjeeTim LuongoLauren PaolellaJim DavisQingwei ChuXiaoyan YinJames MoYashu BhatCaroline Perry
Past MembersFunding
NIDDKNIAPenn Center for Musculoskeletal Disorders Pilot Award
Will QuinnCarrie SimsDavid FrederickCole PurdyDenice DeFelisePaul BotolinYuxia GuanTony Davila
Hao WangCarrie Sims
Qingwei ChuAnna Garcia-
Whitlock
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