Sarker.Dissertation2015

Curcumin and calorie restriction as
dietary interventions for the
reversal of age-associated
functional decline
Marjana Sarker
Dissertation Seminar
5/21/2015

William Li: Angiogenesis foundation 2010
“Can we eat to starve cancer”
• Growing adipose tissue behave like tumor cells, abnormal angiogenesis
• Require oxygen and nutrients to expand
• Results in hypertrophied adipocytes and increased macrophage accumulation
• Anti-angiogenesis: fat starvation
Sarker.Dissertation20155/21/15

CHS
ADNI
Per unit
BMI
*CHS: Cardiovascular health study
ADNI: Alzheimer’s disease neuroimaging initiative Ho et al., 2010

Chronic obesity
ROS:
oxidative
stress
Systemic
inflammation
Accelerated cognitive
dysfunction
Tissue damage

Inflammatory
cytokines & ROS
Crosses the
BBB
Diminished
cognitive
performance
Hypertrophied adipose tissue
Macrophage accumulation
IL-6
IL-1
TNF-a
GSSG
Liver
inflammation
SYSTEMIC INFLAMMATION
AND OXIDATIVE STRESS
CRP
ANTIANGIOGENIC THERAPY
• ANTIANGIOGENIC AGENT THAT IS SAFE WITH MINIMAL SIDE EFFECTS
• READILY AVAILABLE

• In vivo studies with curcumin- great
potential as an angiogenesis inhibitor
• Limited to adipose tissue and
adipokines
HYPOTHESIS
Curcumin supplementation, by attenuating adiposity -
related inflammation and oxidative stress, would
improve cognitive function in midlife obesity

■ Normal weight or underweight (BMI
under 24.9)
■ Overweight (BMI of 25 to 29.9)
■ Obesity (BMI of 30+)
■ Extreme obesity (BMI of 40+)
Category
Body Mass Index
(kg/m2)
Over Ideal Body
Weight (%)
Underweight <18.5
Normal 18.5-24.9
Overweight 25.0-29.9
Obesity (class 1) 30-34.9 >20% and <100%
Severe obesity
(class 2)
35-39.9 >100%
Severe obesity
(class 3)
40-49.9
Superobesity >50 >250%
Distribution of body mass index
NHANES, 2009-2010, Cleveland clinic

Represented by Sohal and Forster, 2014
Madsen et al., 2010
0 10 20 30 40 50
20
30
40
50
60
70
80
90 C57BL/6
BODYWEIGHT(g)
AGE IN MONTHS
0 10 20 30 40 50
20
30
40
50
60
70
80
90
AL
CR
C57BL/6 ob/ob
~207%
~26%

Metabolic dysfunction with aging
Houtkeeper et al, Nature, 2011

Obesity study-Animal model and diets
• Curcumin is an anti-angiogenic agent –
potential obesity therapeutic
• Calorically restricted mice assigned as the
negative control
• Middle aged ad libitum fed mice as a model
of sedentary mid-life obesity

Obesity study - Results
0 1 2 3 4 5 6 7 8 9 10 11 12 13
0
5
10
15
20
25
30
35
40
BODYWEIGHT(g)
AL
CR
CURAL
a
a,b
WEEKS OF STUDY
0
2
3
4
5
6
FOODINTAKE(g)
Sarker.Dissertation20155/21/15 Sarker et al. Plos One 2015

0.00
0.25
0.50
0.75
1.00
1.25
1.50
a,b
ADIPOSETISSUE(g)
AL
CR
CURAL
VAT SAT
a,b
Sarker et al. Plos One 2015

0
2
4
6
8
10
12
14
CURALCR
a
C-REACTIVEPROTEIN(µg/ml)
a
AL
0
1
2
3
4
5
GSH/GSSG
a,c
AL CR CURAL
Systemic inflammation Oxidative stress

0
2
4
6
8
10
12
14
16
18
20
22
AL
CR
CURAL
a,b
TRIALSTOREACHCRITERION
REVERSALLEARNING
a a
ACQUISITION REVERSAL SESSIONS
Sarker et al. Plos One 2015

Obesity study - Conclusions
• Reduction of body weight was not responsible for
improved cognition following curcumin intake
• Both CR and curcumin intake improved fronto-
cortical function
• There was a significant attenuation of systemic
inflammation and improvement in the redox
state following curcumin intake
• Potential use as an anti-aging therapy for
neurobehavioral dysfunction?
• Combination of CR and curcumin may have
additive or synergistic beneficial effects

• Age: primary risk factor for functional decline
• Sex differences:
– Women are more susceptible to Alzheimer’s disease, whereas men are more
susceptible to Parkinson’s and Lewy bodies.
• Causative factors:
– Oxidative stress and low grade systemic inflammation

Dietary interventions
• 15 dietary supplements recommended to slow
or prevent the onset of cognitive impairment
http://www.alzforum.org/
• CALERIE – 25% calorie restriction for 2 years
• Calorie restriction mimetics – curcumin
• Curcumin (Longvida formulation) – Phase 2
clinical trial for Alzheimer's disease. http://clinicaltrials.gov/

• Antioxidant property– phenol-methoxy moiety
• Anti-inflammatory action via IKKβ – NF-κB
• Minimal side effects reported

Nrf2
Proposed mechanism
Keap1
AREs
P P
Curcumin:
conformational
change of Keap 1
Caloric restriction:
mild nutrition deprivation
causes stress
cytoplasm
nucleus
Antioxidant defense: Up regulation of glutathione synthesis and
glutathione S-transferase
Caloric restriction + Curcumin
Possible robust additive effect?
ROS IKKβ
NF-κB
NF-κB
Transcription of inflammatory
markers and mediators
Nrf2
Magesh S. et al., 2012

Age and cognitive decline
Buckner 2004. Neuron
20-49
Minimal damage
50-69
Reversible damage?
70-
Irreversible damage?

Age groups and translation
Jackson lab
16 months ~ 50 years
Dietary interventions:
• Regular chow (AL)
• Calorie restriction (CR)
• Curcumin w/ regular
chow (CURAL)
• Curcumin+CR (CURCR)
Sex:
Male
Female
20 months ~ 62-65 years

Hypothesis
Dietary curcumin and CR will have additive
beneficial effects on functional impairment
during middle age and senescence

Body weight
0 2 4 6 8 10 12 14 16
0
5
10
15
20
25
30
35
40
0 2 4 6 8 10 12 14 16
0
5
10
15
20
25
30
35
40
0 2 4 6 8 10 12 14 16
0
5
10
15
20
25
30
35
40
0 2 4 6 8 10 12 14 16
0
5
10
15
20
25
30
35
40
AGED MALESMIDDLE AGED MALES
WEEKS
BODYWEIGHT(g)
AL
CR
CURAL
CURCR
MIDDLE AGED FEMALES AGED FEMALES
Sarker.Dissertation20155/21/15 Unpublished data

0
200
400
600
800
1000
1200
CURAL
MIDDLE AGED FEMALES
0
200
400
600
800
1000
1200
AL CR
AGED FEMALES
0
200
400
600
800
1000
1200
CRAL
MIDDLE AGED MALES
AL CURAL CURCR AL CR
0
200
400
600
800
1000
1200
TOTALDISTANCE(cm)
AGED MALES
CURCR
CURAL CURCR CURAL CURCR
Locomotor activity

Locomotor activity
0
50
100
150
200
TIMEINCENTER(s)
AL
AL
MIDDLE AGED MALES
0
50
100
150
200
CURAL CURCR
CURAL CURCRAL CR CURAL CURCR
AGED MALES
0
50
100
150
200
AGED FEMALES
0
50
100
150
200
CR
MIDDLE AGED FEMALES
AL CR CURAL CURCR

Motor learning and performance
0
10
20
30
40
50
60
*
MIDDLE AGED MALES
0
10
20
30
40
50
60
CR CURCR
AGED MALES
0
10
20
30
40
50
60
LATENCYTOFALL(s)
MIDDLE AGED FEMALES
* *
0
10
20
30
40
50
60
AGED FEMALES
AL CR CURAL CURCR AL CURAL
AL CURAL CURCR AL CR CURAL CURCR
**

Motor performance
0
10
20
30
40
CURCRCURALAL CURCR
MIDDLE AGED MALES
0
10
20
30
40
* *AGED MALES
0
10
20
30
40
CURCRCURALCRCURCRCURALCR
LATENCYTOFALL(s)
MIDDLE AGED FEMALES
AL
AL CR CURAL
*
0
10
20
30
40
AGED FEMALES
AL

Motor performance
0
10
20
30
40
50
60
CR CURAL CURCR
MIDDLE AGED MALES
0
10
20
30
40
50
60
CURAL CURCR
AGED MALES
0
10
20
30
40
50
60
LATENCYTOFALL(s)
AL AL CR
MIDDLE AGED FEMALES
0
10
20
30
40
50
60
AGED FEMALES
Unpublished data

Hort et al. PNAS. 2010

Hort et al. 2013
Spatial learning
0
200
400
600
800
1000
1200
LEARNINGINDEX(cm)
MIDDLE AGED FEMALES
0
200
400
600
800
1000
1200
AGED FEMALES
0
200
400
600
800
1000
1200
CURCR
AGED MALES
0
200
400
600
800
1000
1200
CR CURAL CURCR AL CR CURAL
MIDDLE AGED MALES
AL

0
6
12
18
24
30
MIDDLE AGED FEMALES
0
6
12
18
24
30
AGED FEMALES
0
6
12
18
24
30
AL CURAL CURCR
*
MIDDLE AGED MALES
0
6
12
18
24
30
PERCENTTIME
CR
AL CR CURAL CURCR
AL CURAL CURCR
AL CR CURAL CURCR
AGED MALES
Spatial learning

WISCONSIN CARD SORTING TEST

Executive function
0
4
8
12
16
20
24
28
***
*
AL
CR
CURAL
CURCR
MIDDLE AGED FEMALES
*
0
4
8
12
16
20
24
28
*
*
*
AGED FEMALES
*
0
4
8
12
16
20
24
28
TRIALSTOREACHCRITERION
ACQUISITION REVERSAL ACQUISITION REVERSAL
AGED MALES
0
4
8
12
16
20
24
28
†
*
MIDDLE AGED MALES
ACQUISITION REVERSAL SESSIONS

Nrf2Keap1
AREs
P P
Curcumin:
conformational
change of Keap 1
Caloric restriction:
mild nutrition deprivation
causes stress
cytoplasm
nucleus
Antioxidant defense: Up regulation of glutathione
synthesis and glutathione S-transferase
ROS IKKβ
NF-κB
NF-κB
Transcription of inflammatory
markers and mediators
Curcumin + Caloric restriction
gonadal hormones:
Protective/antagonistic?
?
Proposed hypotheses:
Males: more than optimal levels of
testosterone – cognitive dysfunction?
Females: testosterone may improve
memory when estrous cycles are
lacking
Nrf2

Significance of cognitive and motor outcomes
• Sex differences based on results from neurobehavioral
outcomes
• A translatable dose
• Therapeutic window - an intervention period
• Curcumin as a plausible dietary mimetic for caloric
restriction
• However curcumin may not be beneficial for motor
dysfunction
• Curcumin as complementary therapy for normal aging
cognitive decline and fronto-temporal dementia
• Provides valuable insight on combination treatments

ACKNOWLEDGEMENTS
Mentors:
• Dr. Michael Forster
• Dr. Susan Franks
Committee members:
• Dr. Nathalie Sumien
• Dr. Eric Gonzales
• Dr. Derek Schreihofer
• Dr. Joseph Warren
Lab members :
• Dr. Margaret Rutledge
• Dr. Ritu Shetty
• Dr. Nopporn Thangthaeng
• Sean Dolan
• And everyone from the AGE and
NIDA lab
Colleagues:
• Andrew Gdowski
• Avani Mody
• Jessica Wong
• Dr. Kiran Chaudhari
• Akram Sidhu
Funding mechanism:
• NIA P01 AG022550
• Faculty seed grant RI6039
Family and friends
And most importantly my mother
for keeping me well fed the last
couple of weeks, I love you Ammu!

Sarker.Dissertation2015

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