NIHR Southampton Biomedical Research Centre in nutrition The NIHR Southampton Biomedical Research Centre in nutrition is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton Omega-3 : The science behind the headlines Philip Calder Professor of Nutritional Immunology University of Southampton ([email protected])
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Prof Philip Calder on Omega 3 at Isle Of Wight Cafe Scientifique on 10 Feb 2014
Prof. Philip Calder speaking about Omega 3 at Isle Of Wight Cafe Scientifique on 10 Feb 2014.
His research focuses on understanding the influence of dietary fatty acids on aspects of cell function and human health, in particular in relation to cardiovascular disease, inflammation and immunity.
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NIHR SouthamptonBiomedical Research Centre in nutrition
The NIHR Southampton Biomedical Research Centre in nutrition is funded by the National Institute for Health Research (NIHR) and is a partnership between University Hospital Southampton NHS Foundation Trust and the University of Southampton
About me• PhD in Biochemistry (University of Auckland, NZ)• 1987-1995 in Department of Biochemistry,
University of Oxford• Since 1995 at University of Southampton• Research focus: fatty acid nutrition and
functionality -> implications for public health and for clinical practice
Key points to discuss …
• What are “omega-3”?• Where do you get them from?• Why are they good for you?• How much do you need?• How do you know if you get enough?
Omega-3
w-3
n-3
What are omega-3?• Omega-3 are a type of fat
-> Note: Not all fat is bad!• One of the polyunsaturated fats• Some omega-3 come from plants and some
come from fish• We are interested in fish omega-3 (EPA and
DHA)
More on omega-3
• Much less abundant in the diet than omega-6 fats found in vegetable oils and margarines
• Western diets have too much omega-6 and not enough omega-3
• The most important omega-3 for human health are EPA and DHA from seafood
a-Linolenic acid (18:3w-3)
Stearidonic acid (18:4w-3)
20:4w-3
Eicosapentaenoic acid (20:5w-3)
D6-desaturase
D5-desaturase
Elongase
Docosahexaenoic acid (22:6w-3)
ElongaseElongaseD6-desaturase
b-oxidation
H3C COOH
H3CCOOH
H3CCOOH
H3C COOH
H3CCOOH
Retroconversion
a-Linolenic acid (18:3w-3)
Stearidonic acid (18:4w-3)
20:4w-3
Eicosapentaenoic acid (20:5w-3)
D6-desaturase
D5-desaturase
Elongase
Docosahexaenoic acid (22:6w-3)
ElongaseElongaseD6-desaturase
b-oxidation
H3C COOH
H3CCOOH
H3CCOOH
H3C COOH
H3CCOOH
Retroconversion
Synthesised in plantsFound in green leaves, some seeds, some nuts, some plant oilsIntake of a-linolenic acid is typically 1 to 2 g/day
Found in seafood (especiallyoily fish), in fish oils and lean fish liver oils, in algal oils, in concentrated pharmaceutical preparations
intakes are usually low
EPA & DHA : where do you get them from?
• The only naturally rich source is seafood, especially oily fish (salmon, tuna, sardines, herring, mackerel …)
• Different seafood provides different amounts of EPA+DHA• One meal of salmon or mackerel can provide up to 3 grams of
EPA+DHA• One meal of white fish like cod or one standard fish oil capsule
can provide about one-tenth of this• Supply is limited -> novel sources (algae, plants ..)
11
EPA and DHA content of different foods and supplements
g/serving
Red meat < 0.1Cod & other lean fish 0.3Salmon 1.5Mackerel 3.0
g/capsule (1 gram)
Standard fish oil 0.3Concentrated fish oil 0.45-0.65Pharmaceutical grade 0.9
How much EPA and DHA do people eat?
How much fat do people eat?
75 grams
Total fat from all sources
Variation due to diet
75 grams
Total fat from all sources
Saturated fat
Monounsaturatedfat
Polyunsaturated fat
Trans fat
Saturated fat
Monounsaturatedfat
Polyunsaturated fat
Trans fat
Omega-3
Omega-6
Omega-3
Omega-6
Fish omega-3
Plant omega-3
75 grams
Total fat from all sources
Fish omega-3
How much EPA and DHA do people eat?
75 grams
Total fat from all sources
Fish omega-3: Less than 0.2 g each day Only a quarter of one
percent of dietary fat!
What if people eat fish or take supplements?
Grams per day
1 2 3 4 5 60
0.5
1
1.5
2
2.5
3
3.5
4
Normaldiet
+ one concentrated
fish oil capsule
+ one standard fish oil capsule
+ one Omacorcapsule
One meal of salmon
+ 4 Omacorcapsules
What happens if omega-3 intake is increased?
GUT
Digestion & absorption
BLOOD
Transport
LIVER
Metabolism
ADIPOSE (FAT)
Storage
CELLS ANDTISSUES
Cell membranes
(Important for cell
& tissue function)
DIET (FOOD OR SUPPLEMENTS)
What happens if omega-3 intake is increased?
1 2 3 40
0.5
1
1.5
2
2.5
3
3.5
4EPA in blood plasma
0 1 2 4
Capsules per day
1 2 3 40
1
2
3
4
5
6
7DHA in blood plasma
0 1 2 4
Capsules per day
Time
Incr
ease
in E
PABlood plasma
Red blood cells
Heart tissue
Fat tissue
Increasing EPA+DHA intake increases the EPA and DHA content of blood lipids, blood cells, and tissues – effect is dose, time and tissue
dependent
Functions/roles of EPA and DHA• Energy sources• Cell membrane components (structure -> function)
[Note: DHA especially important in brain and retina]• Signaling molecules• Regulators of gene expression• Precursors of lipid mediators (prostaglandins,
leukotrienes, resolvins etc.)
Altered w-3fatty acid supply
Altered composition of cell membrane
Membrane alterations Lipid mediatorsSignals leading to geneexpression
Altered cell and tissue behaviour
Health vs disease
The cell membrane
EPA and DHA take on different 3D shapes compared with other fatty acids
EPA and DHA: Why are they good for you?
• Vital for good health• Improve blood fats, blood flow, blood clotting, inflammation
-> Heart healthy• Improve immune function• Reduce inflammation – arthritis • Good for bones• Very important for the brain & eye
– Vital in early life for good brain and visual development– May be important for optimal childhood learning– May have a role in preventing psychiatric and psychological
disorders– May slow cognitive decline
Brain growth in humans
Specific need for DHA for brain and visual development
DHA accumulation into humanbrain
0 5 10 15 20 25 30 35 40 45 50
0
50
100
150
200
250
300
N
Brain growth spurt
N = neuritogenesis
Post conceptual age (weeks)
Con
cent
ratio
n (m
g to
tal c
ereb
ellu
m)
Effect of DHA supplementation on visual function in young infants
Series10
0.2
0.4
0.6
0.8
1
Breast-fedControlDHA-suppl
Visu
al a
cuity
(VEP
) (lo
g M
AR)
16 wks 30 wks
**
*
Human milk & DHA formula better than control; ** p<0.001, * p<0.01
Makrides 1995
EPA and DHA take on different 3D shapes compared with other fatty acids
DHA acts like a spring to enable the conformational change required for rhodopsin to signal properly
DHA spring
Light
EPA and DHAand cardiovascular disease
Heart diseaseDisease of the vessels supplying blood to the heart
(coronary artery)
Impeded heart function(heart failure)
Poor blood supply to other tissues
Heart attack
Heart stops functioning
Other tissues stop functioning
Heart disease is one of the cardiovascular diseases
(diseases of the heart or blood vessels)
These diseases are caused by a build-up of fatty material within the blood vessel wall (“atherosclerosis” “plaque”)-> narrowing or hardening of the arteries-> occurs over a prolonged period of time-> can impede blood flow-> pieces of tissue can fall off (“plaque rupture”) blocking the blood vessel or initiating a clot
Coronary arteryNarrowing of the arteries Plaque rupture & clot formation
Time
Athe
rosc
lero
sis
(Pla
que
grow
th)
Threshold where manifestations like chest pain or temporary loss of vision begin to occur
Threshold where more serious manifestations
like heart attacks or strokes begin to occur
The Greenland Inuit (“Eskimo”)
100
80
60
40
20
0Expected Seen
Much lower than expected rate of death from heart attack
How could this be?-> The Inuit diet??
• Ate lots of seal meat, whale meat, whale blubber, fish
• -> Very high intake of omega-3 fats
16
12
8
4
0Greenland Average Inuit UK adult
Marine omega-3 intake (g/day)
100 x difference in intake!
Prospective study
People enter study when they are healthy/disease free
Take information about diet and lifestyle; Take blood etc.
Follow up over many years (10, 20, 30 ….)
Measure disease outcome (e.g. how many have heart attacks or strokes, how many die from heart disease)
Relate the disease outcome back to the earlier diet etc.
100
80
60
40
20
0 Low High
Omega-3 Intake From Diet
100
80
60
40
20
0 Low High
Omega-3 in Blood
Likelihood of fatal heart disease Likelihood of sudden death
Two different prospective studies from the US
EPA and DHA intake and future heart disease : a study from the US
Total CHD (P < 0.001)Fatal CHD (P = 0.01)Non-fatal MI (P = 0.003)
Hu et al. (2002) J. Am. Med. Assoc. 287, 1815-1821
1.0
0.8
0.6
0.4
0.2
0Lowest Highest
Quintile of EPA+DHA intake
EPA+ DHA in blood and future sudden death : a study from the US
10.80.60.40.2
01 2 3 4
Rela
tive
risk
of s
udde
n de
ath
Quartile of blood EPA+DHA
Adjusted for age & smoking
Also adjusted for BMI, diabetes, hypertension, hypercholesterolemia, alcohol, exercise & family history of MI
Albert et al. (2002) New Engl J Med 346, 1113-1118
How can this be?
-> Risk factors
Cardiovascular Disease
Hypertension Hyperlipidaemia Smoking
Maleness
Other genetics
Obesity Diabetes
Lack of exercise
Bad diet
Infections Low birth weight
Secondary Risk Factors
Primary Risk Factors
Family MedicalHistory of CVD
HomocysteinaemiaInflammation
Cardiovascular Disease
Hypertension Hyperlipidaemia Smoking
Maleness
Other genetics
Obesity Diabetes
Lack of exercise
Bad diet
Infections Low birth weight
Secondary Risk Factors
Primary Risk Factors
Family MedicalHistory of CVD
HomocysteinaemiaInflammation
Time
Athe
rosc
lero
sis
(Pla
que
grow
th)
Higher omega-3 intake
What about people who already have heart or cardiovascular disease??
• Can study effect of omega-3 given as supplements just like you would study a drug: randomised, placebo-controlled trial
• Several large studies have been done tracking patients over several years
• Death in patients who survived a previous heart attack
100
80
60
40
20
0 Control group Omega-3 group
Likelihood of death from heart disease over 3.5 years
Time
Illne
ss a
nd d
eath
out
com
es
With oral omega-3
Considered: 97 intervention trials with lipid lowering strategies (incl. EPA+DHA) and with follow-up of at least 6 months
(for EPA+DHA considered 14 studies)
N = 10138 in control group; 10122 in w-3 PUFA group
Findings for w-3 PUFA: Risk of cardiac mortality = 0.68 (P < 0.001)
of mortality = 0.77 (P = 0.01)
Arch. Int. Med. (2005) 165, 725-730
Conclusion “statins and w-3 fatty acids are the most favourable lipid lowering interventions with reduced risks of overall and cardiac mortality”
How can this be?
-> Probably not about the same risk factors as before because they relate to building up the plaque – here we are seeing an effect in
people who already have plaques
Inflammatory activity in the vessel wall
Thinning of protective cap
Rupture and subsequent clot formation
Inflammation causes plaque rupture
Omega-3 are anti-inflammatory
-> Maybe omega-3 reduce deaths in at risk patients by decreasing the
likelihood that plaques will rupture (i.e. increasing plaque stability)
We wished to study the effects of omega-3 on plaque stability in humans
• Needed a source of plaques -> there is a surgical procedure for removal of plaques from the carotid artery
• Needed to be able to give patients omega-3 for a period of time before collecting the plaques -> waiting time for surgery is (was) many weeks-months
• Two randomised controlled trials of omega-3 in these patients
0
-10
-20
-30
-40
-50
-60
Difference from control group in:
Unstable plaques One key marker of plaque inflammation
Our results may explain how omega-3 stop people from having heart attacks and how they stop people from dying
=> A higher EPA+DHA intake and status is protective against CVD risk and against
CVD mortality
Omega-3 Index = EPA + DHA as a % of all fatty acids in red blood cell membranes
Inflammation has two phases: initiation and resolution
Initiationphase
Resolutionphase
TIME
EPA and DHA are precursors ofpro-resolving lipid mediators
To sum up …..
- cell membrane structure & function- brain and visual development- maintenance of cognitive and neurological function (during development & with aging)- regulation of