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.

1. NIHR Southampton
Biomedical Research Centre in nutrition
Omega-3 : The science behind
the headlines
Philip Calder
Professor of Nutritional Immunology
University of Southampton
(pcc@soton.ac.uk)
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

2. 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

4. 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?

5. Omega-3
w-3
n-3

6. 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)

7. 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

8. H3C
COOH
a-Linolenic acid (18:3w-3)
D6-desaturase
H3C
COOH
Stearidonic acid (18:4w-3)
Elongase
H3C
COOH
D5-desaturase
COOH
H3C
Eicosapentaenoic acid (20:5w-3)
Retroconversion
Elongase
Elongase
D6-desaturase
b-oxidation
H3C
COOH
Docosahexaenoic acid (22:6w-3)

9. H3C
COOH
a-Linolenic acid (18:3w-3)
D6-desaturase
H3C
Synthesised in plants
Found in green leaves, some
seeds, some nuts, some plant oils
Intake of a-linolenic acid is typically 1
to 2 g/day
COOH
Stearidonic acid (18:4w-3)
Elongase
H3C
COOH
D5-desaturase
COOH
H3C
Found in seafood (especially
oily fish), in fish oils and lean fish liver
oils, in algal oils, in concentrated
pharmaceutical preparations
Eicosapentaenoic acid (20:5w-3)
Retroconversion
Elongase
Elongase
D6-desaturase
b-oxidation
H3C
 intakes are usually low
COOH
Docosahexaenoic acid (22:6w-3)

10. 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
Cod & other lean fish
Salmon
Mackerel
< 0.1
0.3
1.5
3.0
g/capsule (1 gram)
Standard fish oil
Concentrated fish oil
Pharmaceutical grade
0.3
0.45-0.65
0.9
11

12. How much EPA and DHA do
people eat?

13. How much fat do people eat?
75 grams
Total fat from
all sources
Variation due
to diet

15. 75 grams
Polyunsaturated
fat
Trans fat
Monounsaturated
fat
Total fat from
all sources
Saturated
fat

16. Omega-3
Polyunsaturated
fat
Trans fat
Omega-6
Monounsaturated
fat
Saturated
fat

17. Fish omega-3
Omega-3
Plant omega-3
Omega-6

18. Fish omega-3
75 grams
Total fat from
all sources

19. 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!

20. What if people eat fish or take
supplements?
4
Grams per day
3.5
3
2.5
2
1.5
1
0.5
0
1
Normal
diet
2
+ one
standard
fish oil
capsule
3
+ one
concentrated
fish oil
capsule
4
+ one
Omacor
capsule
5
One meal
of salmon
6
+4
Omacor
capsules

21. What happens if omega-3 intake
is increased?
DIET
(FOOD OR SUPPLEMENTS)
GUT
Digestion & absorption
LIVER
BLOOD
ADIPOSE (FAT)
Metabolism
Transport
Storage
CELLS AND
TISSUES
Cell membranes
(Important for cell
& tissue function)

22. What happens if omega-3 intake
is increased?
EPA in blood plasma
DHA in blood plasma
4
7
3.5
6
3
5
2.5
4
2
3
1.5
1
2
0.5
1
0
0
1
0
2
1
3
2
Capsules per day
4
4
1
0
2
1
3
2
Capsules per day
4
4

23. Increase in EPA
Blood plasma
Red blood cells
Heart tissue
Fat tissue
Time

24. Increasing EPA+DHA intake increases the EPA
and DHA content of blood lipids, blood
cells, and tissues – effect is dose, time and
tissue dependent

25. 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.)

26. Altered w-3
fatty acid supply
Altered composition
of cell membrane
Membrane alterations
Signals leading to gene
expression
Altered cell and tissue behaviour
Health vs disease
Lipid mediators

27. The cell membrane

28. EPA and DHA
take on different
3D shapes
compared with
other fatty acids

29. 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

30. Brain growth in humans

31. Specific need for DHA for brain and
visual development
Concentration (mg total cerebellum)
DHA accumulation into human
brain
Brain growth spurt
300
250
200
150
100
50
N
0
0
5
10 15 20 25 30 35 40 45 50
Post conceptual age (weeks)
N = neuritogenesis

32. Effect of DHA supplementation
on visual function in young infants
Visual acuity (VEP) (log
MAR)
1
0.8
**
0.6
Breast-fed
*
0.4
Control
DHA-suppl
0.2
0
16 wks
30 wks
Human milk & DHA formula better than control;
** p<0.001, * p<0.01
Makrides 1995

35. EPA and DHA
take on different
3D shapes
compared with
other fatty acids

36. DHA acts like a spring to enable the conformational
change required for rhodopsin to signal properly
Light
DHA spring

37. EPA and DHA
and cardiovascular disease

38. Heart disease
Disease of the vessels supplying blood to the heart
(coronary artery)
Impeded heart function
(heart failure)
Poor blood supply to other tissues
Other tissues stop functioning
Heart attack
Heart stops functioning

39. Heart disease is one of the
cardiovascular diseases
(diseases of the heart or blood vessels)

40. 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 artery
Narrowing of the arteries
Plaque rupture
& clot formation

41. Atherosclerosis
(Plaque growth)
Threshold where more
serious manifestations
like heart attacks or
strokes begin to occur
Time
Threshold where
manifestations like chest
pain or temporary loss of
vision begin to occur

42. The Greenland Inuit (“Eskimo”)
Much lower than expected rate
of death from heart attack
100
80
60
40
20
0
Expected
Seen

43. 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
Marine omega-3 intake
(g/day)
12
100 x difference
in intake!
8
4
0
Greenland
Inuit
Average
UK adult

44. 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.

45. Two different prospective studies from the US
Likelihood of fatal heart disease
Likelihood of sudden death
100
100
80
80
60
60
40
40
20
20
0
0
Low
High
Omega-3 Intake From Diet
Low
High
Omega-3 in Blood

46. EPA and DHA intake and future heart disease :
a study from the US
1.0
0.8
0.6
Total CHD (P < 0.001)
Fatal CHD (P = 0.01)
Non-fatal MI (P = 0.003)
0.4
0.2
0
Lowest
Highest
Quintile of EPA+DHA intake
Hu et al. (2002) J. Am. Med. Assoc. 287, 1815-1821

47. Relative risk of sudden death
EPA+ DHA in blood and future sudden death :
a study from the US
Adjusted for age & smoking
1
0.8
Also adjusted for BMI, diabetes,
hypertension,
hypercholesterolemia, alcohol,
exercise & family history of MI
0.6
0.4
0.2
0
1
2
3
Quartile of blood EPA+DHA
4
Albert et al. (2002) New Engl J Med 346, 1113-1118

48. How can this be?
-> Risk factors

49. Primary Risk Factors
Hypertension
Hyperlipidaemia Smoking
Cardiovascular Disease
Family Medical
History of CVD
Lack of exercise
Maleness
Other genetics
Bad diet
Low birth weight
Infections
Obesity Diabetes
Inflammation
Homocysteinaemia
Secondary Risk Factors

50. Primary Risk Factors
Hypertension
Hyperlipidaemia Smoking
Cardiovascular Disease
Family Medical
History of CVD
Lack of exercise
Maleness
Other genetics
Bad diet
Low birth weight
Infections
Obesity Diabetes
Inflammation
Homocysteinaemia
Secondary Risk Factors

51. Higher omega-3 intake
Time
Atherosclerosis
(Plaque growth)

52. What about people who already have heart or
cardiovascular disease??
• Can study effect of omega3 given as supplements just
like you would study a
drug: randomised, placebocontrolled trial
• Several large studies have
been done tracking
patients over several years
• Death in patients who
survived a previous heart
attack
Likelihood of death from heart disease
over 3.5 years
100
80
60
40
20
0
Control group
Omega-3 group

53. Illness and death outcomes
With oral omega-3
Time

54. Arch. Int. Med. (2005) 165, 725-730
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)

55. Conclusion “statins and w-3 fatty acids are the most favourable lipid
lowering interventions with reduced risks of overall and cardiac mortality”

56. 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

57. 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)
Rupture and subsequent clot formation
Inflammatory activity
in the vessel wall
Thinning of protective cap

58. 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 weeksmonths
• Two randomised controlled
trials of omega-3 in these
patients

59. Difference from control group in:
Unstable plaques
0
-10
-20
-30
-40
-50
-60
One key marker
of plaque inflammation

60. Our results may explain how omega-3
stop people from having heart attacks
and how they stop people from dying

61. => A higher EPA+DHA intake and status is
protective against CVD risk and against
CVD mortality

62. Omega-3 Index = EPA + DHA as a % of all fatty acids in red
blood cell membranes

65. Inflammation has two phases:
initiation and resolution
Initiation
phase
Resolution
phase
TIME

66. EPA and DHA are precursors of
pro-resolving lipid mediators

67. To sum up …..

68. EPA and DHA are important in:
- 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

69. EPA and DHA are
vital throughout
the life course

70. 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?

71. 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

72. 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 onetenth of what is recommended!
• Intake can be increased by eating more seafood,
especially oily fish, or by taking fish oil type
supplements

73. 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

74. Thank you!