57° CONGRESSO NAZIONALE SIGG
Milano Convention Center
__________________________
21-24 novembre 2012
Nutrition: an essential strategy
to fight Frailty
Pr. Yves Boirie
Human Nutrition Unit, Clinical Nutrition Department
University Hospital of Clermont-Ferrand, France
Role of preventive nutrition
for a healthy aging
Osteoporosis
Nutritional
Prevention?
CVD
Cancer
Age-related disorders:
• Metabolic dysregulations?
• Oxydative Stress?
• Inflammation?
• Physical inactivity?
Physiology
Dysfunction
Sarcopenia
Type 2 Diabetes
Disease
Role of preventive nutrition
for a healthy aging
Osteoporosis
Nutritional
Prevention?
CVD
Cancer
Age-related disorders:
• Metabolic dysregulations?
• Oxydative Stress?
• Inflammation?
• Physical inactivity?
Physiology
Dysfunction
Sarcopenia
Type 2 Diabetes
Disease
Nutrition and Frailty
• Targeting muscle in elderly patients
• Anabolic resistance to nutrients
• Synergistical strategies
Nutrition and Frailty
• Targeting muscle in elderly patients
• Anabolic resistance to nutrients
• Synergistical strategies
Impact of muscle loss in health and disease
AA
Muscle loss
Immunity
Visceral and tissue
Lipid accumulation
Muscle weakness
Reduction of
physical
Activity
Higher risk
of falls
Bone
density
En. Expenditure
Fat oxidation
Insulin resistance
Impact of muscle loss in health and disease
Muscle loss
Cardio-respiratory
Functions
Infections
Mobility
Falls
Fracture
Osteoporosis
Type 2
Diabetes
Impact of muscle loss in health and disease
Muscle loss
Cardio-respiratory
Functions
Infections
Mobility
Falls
Fracture
Osteoporosis
Frailty
Dysautonomia
Type 2
Diabetes
Impact of muscle improvement of global health
Muscle function
improvement
 adiposity
 Immunity
 Bone
Density
 Physical
Activity
 Insulin sensitivity
 Incidence
type 2 diabetes
 Cardiac functions
 Respiratory functions
 Quality of life
 Frailty
Impact of muscle improvement on mortality
• A decline in walking speed of 0.1 m/s within 1 year
increased the subsequent 5-year mortality rate
(Perera S, J Gerontol 2005)
• Improvement in usual walking speed predicts a
substantial reduction in mortality
(Hardy S, JAGS 2007)
 Physical performance (walking speed) is a strong
predictor of morbidity and mortality like other
predictive testing (blood pressure, glycemia,
cholesterol)
– Low muscle mass
+ one of the two components:
– Low muscle strength
– Low physical performance
Cruz-Jentoft AJ, Report of the European Working Group on
Sarcopenia in Older People, Age & Ageing 2010
Nutrition and Frailty
• Targeting muscle in elderly patients
• Anabolic resistance to nutrients
• Synergistical strategies
Impaired anabolic response
to meal intake during aging
(postprandial defect?)
10
FSR %/d
8
Protein synthesis
*
Fasted
Fed
6
Muscle
proteins
4
2
0
10
8
FBR %/d
Anabolic resistance
6
Proteolysis
*
4
2
0
Adult
Old
Anabolic resistance
Defect in the regulation
of mTOR signaling pathway
by amino acids
Defect in the regulation
of mTOR signaling pathway
by insulin
Leucine resistance
Insulin resistance
1.2
p70 S6 kinase activity
P<0.05
0.15
Basal
INSULIN
#
1.0
0.8
Young
Old
*
0.6
FSR %/h
picomoles ATP / 100 mg / 60 min
Impaired anabolic response
to meal intake during aging
#
0.10
0.05
*
0.4
0
100 200 300
400 500 600
Young
Elderly
Leucine mM
Dardevet, J Nutr 2000
Cuthberson, FASEB J 2005
Guillet, FASEB J 2004
Rasmussen, FASEB J 2006
Muscle loss situations
Anabolic
stimulators
Anabolic
resistance
Muscle
Anabolism
Threshold
Meal
time
Physiological situation
Aging or catabolic state
Anabolic
stimulators
Anabolic
response
Anabolic treshold
Meal
Anabolic
stimulators
Anabolic
resistance
Meal
Meal
Increased anabolic
threshold
Anabolic
response
Meal
2 strategies
 to reduce muscle anabolic threshold
 to increase the availability of anabolic stimulators
Anabolic
stimulators
Anabolic
stimulators
Meal
Meal
Nutritional modulation of
muscle anabolic threshold
Improving muscle sensitivity to anabolic factors?
Anabolic
stimulators
Oxidative stress/Inflammation
Meal
Physiological situation
Restore
Muscle
Anabolic
Sensitivity
Anti-inflammatory
nutrients
Aging or catabolic state
Muscle protein
synthesis
Signaling pathways
for the initiation of
Protein synthesis
Smith GI, Am J Clin Nutr 2011
Muscle protein synthesis of old rats fed a control diet,
a high-oleate diet or a high-palmitate diet
+ INS
+ INS
+ INS
Muscle protein
synthesis
Controls
Oleate
Palmitate
+ INS
+ INS
+ INS
Controls
Oleate
Palmitate
Signaling pathways
for the initiation of
Protein synthesis
Tardif N, Clin Nutr 2011
New mechanisms of muscle anabolic resistance?
Anabolic
stimulators
Others?
Oxidative stress/Inflammation
Meal
Physiological situation
Anabolic
resistance
Lipotoxicity
Aging or catabolic state
New mechanism of muscle anabolic
resistance: lipotoxicity
Muscle protein synthesis (%/h)
Muscle Mitochondrial
Protein synthesis (%/h)
0.12
0.10
0.08
0.06
0.04
0.02
R2 = 0,42
0
0
10
20
30
40
50
Fat mass (kg)
Postabsorptive
Insulin clamp
Guillet C, JCEM 2009
Fat mass could be deleterious for
muscle protein synthesis?
Guillet C, Obes Rev 2012 (in press)
Response to high-fat feeding of muscle mixed
and mitochondrial protein synthesis
Mixed muscle protein
Mitochondrial protein
Masgrau A, J Physiol 2012
A double muscle anabolic resistance due to
lipotoxicity
Insulin
Saturated FA
Muscle cell
Ceramides
Akt
EIF2α phosphorylation
Initiation of protein translation
Glucose
entry
Insulin
resistance
&
storage
Proteinsynthesis
anabolic
Protein
resistance
Tardif N, submitted
Modulators of muscle anabolic resistance
Anabolic
stimulators
Others?
Lipotoxicity/Insulin Resistance
Oxidative stress/Inflammation
Anabolic
resistance
Vitamin D deficiency
Meal
Physiological situation
Aging or catabolic state
Nutrition, Metabolisms and Muscle Loss
1,25(OH)2-vitamin D3 combined to anabolic factors
increases protein synthesis and stimulates anabolic
signals in differentiated C2C12 skeletal muscle cells
+Insulin
Muscle cells protein synthesis
2,25
1,75
FSR (%/h)
+Leucin
e
2
a
b
b
0
+
0
10
c
1,5
1,25
1
,75
,5
,25
0
Insulin + leucine
Vitamin D (nM)
+
10
Chanet A, submitted
Muscle loss situations
Other mechanisms?
Anabolic
stimulators
Meal
Immobilization/Chronic Diseases
Lipotoxicity/Insulin Resistance
Oxidative stress/Inflammation
Physiological situation
Anabolic
resistance
Aging or catabolic state
Timmerman KL, Diabetes 2010
Anabolic
substrates
Nutritional
interactions
testosterone
exercise
+
Vitamin D
-
antioxidants
Positive regulators
Permissive effects
n-3 PUFA
Amino
Acids
Negative regulators
Inhibitory effects
Insulin
Anti-anabolic
substrates
saturated FA
Ceramide
cytokines
immobilization
MUSCLE PROTEIN SYNTHESIS
Temporal changes in anabolic threshold?
Anabolic
stimulators
Sedentarity
Lipotoxicity
Insulin-R Oxidative Stress
Inflammation
(Acute disease) (Fat feeding)
Inflammation
(Chronic disease)
Meal
Anabolic response
over baseline
Meal
Boirie Y, J Am Med Dir Ass 2013 (in press)
• Increased availability of anabolic stimulators
Anabolic
stimulators
Anabolic
resistance
Meal
How ?
•
•
Acting on the diet and the determinants of digestion rate
Modulating splanchnic metabolism in physiopathological situations
Acting on the diet and the determinants
of postprandial protein utilization
• Increase protein intake?
• Specific AA supplementation?
• Improve AA bioavailability:
– Change the distribution of protein intake?
– Use proteins of different digestion rate?
• Physical exercise?
Acting on the diet and the determinants
of postprandial protein utilization
• Increase protein intake?
• Specific AA supplementation?
• Improve AA bioavailability:
– Change the distribution of protein intake?
– Use proteins of different digestion rate?
• Physical exercise?
Protein pulse-feeding ingestion pattern (chrononutrition)
Spread-feeding
Dinner
Breakfast
Snack
Lunch
Pulse feeding=
 nitrogen
retention in the
elderly
Pulse-feeding
Breakfast
Dinner
Lunch
(80%)
Arnal et al. AJCN 1999-2002
Protein digestion rate (fast/slow proteins concept)
Fast proteins (Whey)
Slow proteins (Casein)
Meat with healthy dentition
Meat with chewing deficiency
 in plasma leucine, µM
250
200
150
100
50
Time, min
0
0
100
200
300
400
500
Fast proteins=
 postprandial
WB protein
anabolism
in the elderly
Boirie et al., PNAS 1997, Remond et al., Am. J. Clin. Nutr. 2007
Pennings B, Am J Clin Nutr 2011
Temporal changes in postprandial muscle anabolic
response to meal intake: reaching the threshold
Anabolic
stimulators
Sedentarity
Lipotoxicity
Insulin-R Oxidative Stress
Inflammation
(Acute disease) (Fat feeding)
Inflammation
(Chronic disease)
HIGHER
THRESHOLD
Meal
Anabolic
stimulators
Nutrients (AA)
availability
Low androgens
Low GH/IGF1
Macro- and
Micro-nutrients
deficiency
LOWER
STIMULATION
Meal
Postprandial
anabolic response
LOWER
RESPONSE
Meal
Boirie Y, J Am Med Dir Ass 2013 (in press)
Nutrition and Frailty
• Targeting muscle in elderly patients
• Anabolic resistance to nutrients
• Synergistical strategies
Hormones
Exercise
Nutrition
AA
Irving BA, Aging Res Rev 2012
Physical exercise potentiates the
anabolic impact of amino acid
45
c
30
b
15
a
0
-15
-30
Rest
Exercise
Rest
+ AA
Exercise
+ AA
Biolo G, J Clin Invest 1995
40g of protein maximally stimulate protein synthesis
in elderly subjects after resistance exercise
Yang-Y, Phillips-SM et al. BJN 2012
Kim KH, JAGS 2012
Tieland M, JAMDA 2012
Muscle anabolic response according to
protein intake and exercise in older subjects
2
higher
sensitivity
higher
stimulation
1
Protein intake
Physical Activity
Muscle
anabolic
response
Inflammation
Insulin resistance
SENSITIVITY
RESISTANCE
Boirie Y, J Am Med Dir Ass 2013 (in press)
Look for the best synergistical
modulation of muscle protein anabolism
NUTRITION
synthesis
HORMONES
PHYSICAL
ACTIVITY
breakdown
DRUGS
Thank you
Human Nutrition Unit
Metabolism & Health