2015 List - Association of Zoos and Aquariums

Stress Responsive Signal Transduction
and the Control of Longevity
Dirk Bohmann
University of Rochester
Dept. of Biomedical Genetics
Lifespan is not a “hardwired” property
of organisms and can be tuned by
environmental and genetic parameters*.
What are the critical regulators and
effectors of longevity? Are they
accessible to therapeutic manipulation?
**at
atleast
leastin
insome
someorganisms
organisms
Oxidative Stress and Aging
The rate with which oxidative damage accumulates
throughout life is proportional to lifespan
Fly
Human
Sohal et al. (1993)
PNAS vol. 90
Stadtman (1992)
Science vol. 257
Oxidative Stress and Aging
Conditions that extend lifespan delay accumulation of damage:
• long-lived mutants
• caloric restriction
• low temperature
• decreased Insulin/IGF signaling
What Regulates the Accumulation of Oxidative Damage?
Stress Defense Signaling Pathways
•
•
•
•
JNK
p38
Nrf2
p53
and more
rapid, massive,
and transient
Respond to Acute Stresses, e.g.
Xenobiotics, Radiation, Injury, Hypoxia/Reperfusion
Stress Defense Signaling Pathways
•
•
•
•
JNK
p38
Nrf2
p53
and more
anti
anti oxidant
oxidant genes
genes
repair
repair
proteolysis
proteolysis
Graded
Responses
cell
cell cycle
cycle arrest
arrest
apoptosis
apoptosis
Stress Defense Signaling Pathways
•
•
•
•
JNK
p38
Nrf2
p53
and more
Are acute stress response
mechanisms relevant
for aging?
Stress Defense Signaling Pathways
• JNK
• Nrf2
Are acute stress response
mechanisms relevant
for aging?
JNK
The Drosophila JNK Signal Transduction Pathway
Signal
JNKKK
Slp, Ask, Tak
JNKK
Hep
JNK
Bsk
Foxo
MKP
Puc
Jun/Fos
Transcription Factors
Anti oxidant genes are regulated by JNK
Metallothionein
Hsp 68
Glutathion S Transferase D1
Ferritin
¾
paraquat induction
e.g.:
Inducible by ROS stress in a JNK dependent manner
JNK signaling confers resistance to acute oxidative stress
Paraquat
Hep
Bsk
Puc
stress defense genes
JNK signaling confers resistance to acute oxidative stress
Paraquat
Hep
Bsk
Puc
stress defense genes
JNK signaling confers resistance to acute oxidative stress
Paraquat
Hep
Bsk
Puc
stress defense genes
JNK signaling confers resistance to acute oxidative stress
Paraquat
Hep
Bsk
Puc
stress defense genes
JNK signaling protects against acute oxidative stress
Gain of function JNK genotypes extend longevity Foxo dependently
120%
survival proportion
100%
Hep
80%
60%
Dfoxo21/+
Dfoxo25/+
40%
Bsk
+/+
pucE69/+,Dfoxo21/+
20%
pucE69/+,Dfoxo25/+
pucE69/+
0%
0
10
20
30
40
50
Age (days)
60
70
80
90
100
Foxo
0.5x
Puc
Gain of function JNK genotypes extend longevity Foxo dependently
120%
survival proportion
100%
Hep
80%
60%
Dfoxo21/+
Dfoxo25/+
40%
Bsk
+/+
pucE69/+,Dfoxo21/+
20%
0.5x
Puc
pucE69/+,Dfoxo25/+
pucE69/+
0%
0
10
20
30
40
50
60
70
80
90
100
Foxo
Age (days)
Decrease of the negative regulator Puckered efficiently extends
Lifespan
Puc heterozygosity reduces protein damage,
but does not affect growth, development and fertility
JNK activation reduces protein damage,
but does not affect growth, development and fertility
Conclusions
•
Activation of Foxo by the JNK pathway can confer
a longevity phenotype.
•
JNK signaling can delay the accumulation of
oxidative damage throughout life of the organism.
•
JNK target genes both raise resistance against
acute oxidative stress, and extend lifespan.
•
Lifespan effects require a long term moderate
activation of JNK signaling.
Nrf2
The NRF2/Keap signaling pathway
Xenobiotics (TPA)
Oxidants (H2O2)
Phenolic “anti-oxidants” (tBHQ)
Nrf2
Keap1
Keap1
Keap1 (an actin-binding protein)
is the cytoplasmic inhibitor of
Nrf2.
Maf
ARE:
ROS signaling (mediated by
inducers) dissociates Nrf2 from
Keap1.
Nrf2
Stress response genes
Antioxidant Response Element
Nfr2 can then translocate to the
nucleus and trans activate its
target genes.
The NRF2/Keap signaling pathway
Chemo preventive agents (i.e. Oltipraz)
Chemotherapy Drugs
Nrf2
Keap1
Keap1
NRF2 and Cancer
NRF2 agonists are in clinical
trials as cancer preventive
agents.
Maf
ARE:
Nrf2
Stress response genes
Antioxidant Response Element
Mutations in Keap can boost
resistance to chemotherapy in
non-small cell lung cancer.
Drosophila Nrf2 and Keap1 Homologs
- CncC
Drosophila
CncC/Nrf2
activates an antiOxidative stress
gene expression
program and a
negative
feedback loop.
+ CncC
gstD1
thioredoxin
gstE1
keap1
CncC activity can be measured
with a GFP reporter
CncC reporter responds
to oxidative stress
CncC is inducible by Cancer Chemoprevention agents
CncC activation protects from acute oxidative stress
CncC gain-of-function extends lifespan
CncC
0.5x
Keap1
CncC gain-of-function extends lifespan
CncC
0.5x
Keap1
Decrease of the negative regulator Keap1 extends Lifespan
Conclusions
•
Artificial activation of acute stress response
signaling pathways can extend lifespan.
Speculations
•
The genetic programs that confer acute stress
resistance overlap with those that regulate
longevity.
•
Some components of acute stress response may
also function in lifespan control. These may not be
the highly regulated ones, but factors that set
thresholds or base level activities.
•
Drugs that affect stress signaling, such as Nrf2
activators might be effective to counteract aging or
its manifestations.
Oxidative Stress
Longevity Signals
?
Signaling pathways
Foxo, Nrf2, et al.
“Stress defense genes”
“Longevity genes”
Henri
Henri
Jasper
Jasper
Carla
Carla(Meng)
(Meng
Wang
Wang
Gerasimos
Gerasimos
Sykiotis
Sykiotis
`