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

Omega-3 : The science behind the headlines

Philip CalderProfessor of Nutritional Immunology

University of Southampton(pcc@soton.ac.uk)

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

- blood pressure- platelet function, thrombosis, fibrinolysis - blood triglyceride concentrations- vascular function- cardiac rhythm- inflammation- immune response- bone health- insulin sensitivity

EPA and DHA are important in:

EPA and DHA are vital throughout

the life course

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?

Recommendations for fat and fatty acid intakes for adults in the UK

Total fat intake should not exceed 35% of dietary energy Average contribution of energy from saturated fatty acids

should be < 10% Average contribution of energy from polyunsaturated

fatty acids should be 6 to 10% (linoleic [18:2w-6] at least 1% and a-linolenic [18:3w-3] at least 0.2%)

Trans fatty acids should NOT provide > 2% of energy Trans fatty acid intake should be decreased Marine w-3 fatty acid [EPA+DHA] intake should be at

least 450 mg/day

EPA & DHA : how much do you need?

• The UK Government says all adults need at least 0.45 g EPA+DHA per day to maintain health -> this is probably an underestimate

• Most adults in the UK probably consume less than 0.1 g per day and many will consume less than one-tenth of what is recommended!

• Intake can be increased by eating more seafood,

especially oily fish, or by taking fish oil type supplements

EPA & DHA : how do you know if you get enough

• The amount of EPA and DHA in the blood increases when more is eaten in the diet

• Therefore blood tests can be used to monitor intake and changes in intake and to provide an increased assurance of receiving the health benefit

Thank you!