Krill Oil

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The Clinical and Nutritional Benefits of

Krill Oil
+

A Scientific Summary

December 2010

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Enzymotec ltd. P.O. Box 6 Mi gdal HaEmeq 23106 Israel
Tel : 972 74 7177177 Fax: 972 74 717700 www.enzymotec.com
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Overview
Krill Oil
+
is extracted from the Antarctic krill species Euphausia superba which is found
in the cold Antarctic waters of the Southern Ocean. The total krill biomass is estimated to be
between 125 and 750 million metric tons
1
. Enzymotec Ltd. supports krill sustainability
and an eco-friendly supply chain aimed to maintain the conservation of marine living
resources by sourcing its krill biomass only from CCAMLR members monitored vessels and
facilities. CCAMLR - The Convention on the Conservation of Antarctic Marine Living
Resources, is an international treaty between 25 nations that seeks to manage Antarctic
fisheries with the goal of preserving species diversity and stability of the entire Antarctic
marine ecosystem.
Krill oil is comprised of three major
components: phospholipids attached
to omega-3 fatty acids (FA),
Triglycerides attached to omega-3
FA, and antioxidants, such as:
astaxanthin, vitamin A and vitamin E
12
. Each one of krill oil components
has a proven clinical data suggesting
it has health benefits. Krill oil
efficacy and safety were examined by
a battery of clinical and pre-clinical
trials. These studies revealed that krill
oil is safe and effective for multiple
indications, from chronic
inflammation to hyperlipidemia, cognitive function, fatty liver disease, joint health and
more. Furthermore, in some indications krill oil was found to be more effective than fish oil.
In krill oil, most of the omega-3 fatty acids are conjugated to phospholipids, making these
Eco-Harvesting
CCAMLR - The Convention on the Conservation of
Antarctic Marine Living Resources is an international
treaty between 25 nations that seeks to manage Antarctic
fisheries with the goal of preserving species diversity and
stability of the entire Antarctic marine ecosystem. The
CCAMLR was established in 1982 in response to concerns
that increasing krill fishing activities could have a
deleterious impact on the Southern Ocean ecosystem.
The total krill biomass is estimated to be between 125 and
750 million metric tons, which is estimated to be twice the
weight of all human on earth
1
. Krill for direct human
consumption, in the form of krill oil supplements, amount
to less than 0.1% of the precautionary catch limit set by
CCAMLR, ensuring an eco-friendly supply chain aimed
to maintain the conservation of marine living resources.
Enzymotec Ltd. supports krill sustainability and an eco-
friendly supply chain aimed to maintain the conservation
of marine living resources by sourcing its krill biomass
only from CCAMLR members monitored vessels and
facilities.

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important components bio-available to the body and thus, allowing omega-3 to be absorbed
in the target organs, such as: heart, brain and liver, where they exert their beneficial effects.
Enzymotecs Natural Krill Oil
+
was found to be Generally Recognized As Safe (GRAS)
by the American Food and Drug Administration (FDA), and obtained a Novel Food status
from the European Union.
Krill Oil Bioavailability
Omega-3 bioavailability is the degree and rate at which omega-3 fatty acids are absorbed
into the living system and are made available at the site of physiological activity. Studies
showed that the bioavailability of fatty acids attached to phospholipids is better than fatty
acids attached to triglycerides, and thus the absorbance into target tissues such as the heart,
brain and the liver of the tested animals is greater
21
.
The main difference between krill oil and fish oil is the omega-3 fatty acids carrier. Unlike
fish oil in which the omega-3 FA are attached only to triglycerides, in the krill oil the
majority of the omega-3 FA are attached to phospholipids, while the rest are attached to
triglycerides. Researchers tested krill oil bioavailability in humans, showing that the plasma
level of both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was
significantly elevated after krill oil administration leading to the conclusion that krill oil is
highly bioavailable
1, 22
. These findings are further supported by pre-clinical trials that
showed high bioavailability of EPA and DHA in mice liver and brain after krill
consumption
23, 24
.
Krill Oil Structure
Krill oil is comprised of three major components: triglycerides attached to omega-3 FA,
phospholipids - omega-3 FA, and antioxidants
12
. Each one of krill oil components has a
proven clinical data suggesting health benefits.
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Omega-3 triglycerides exist in krill oil and are the major components of fish oil. Fish oil,
and particularly omega-3 fatty acids, enhance quality of life, lower the risk of premature
death, and has a significant influence on human health in numerous indications, such as:
cardiovascular disease prevention, anti-inflammation, brain development, behavior, mood,
and more
3, 25
.
Besides triglycerides,
krill oil contains a
notable amount of
phospholipids attached
to omega-3, primarily
phosphatidylcholine
(PC). In addition to the
fact that phospholipids
deliver the omega-3 to
the target organ more
efficiently than
triglycerides do, they
were studied
extensively and their
beneficial effect on
human health is well
established.
Phospholipids were
shown to have a
positive effect on cognitive and mental functions
3, 26
, and on chronic liver diseases
27
.
Aside from phospholipids and omega-3 fatty acids, krill oil also contains powerful natural
antioxidants such as astaxanthin, vitamin A and vitamin E. Antioxidants are found
The Structure of Triglycerides and Phospholipids
Phospholipids are distinct from triglycerides in both their structure and
their role in the living organism. Phospholipids are considered the
building blocks of the cell membrane while triglycerides are used by the
human body for storage of fat. Both triglycerides and phospholipids are
comprised of a glycerol backbone attached to fatty acids (Figure 1 a, b).
However, the triglyceride molecule has three fatty acids attached to the
glycerol back bone (Figure 1 a), the phospholipids structure is different. A
phospholipids molecule has the glycerol back bone attached to only two
fatty acids and to a polar head group (Figure 1 b). Different polar head
groups could link to the phosphate, while in krill oil the polar head group
is chiefly phosphocholine and the phospholipids are primarily
phosphatidylcholine. The phosphatidylcholine in krill oil is attached to
different types of fatty acids, among them, a significant amount of the
fatty acids are EPA and DHA (Figure 1b) both of which have long been
recognized as beneficial to human health
2
. Phospholipids are considered
bi-polar molecules since they have fatty acids on one side and to a polar
head group on the other. This unique structure allows them to construct
the bilayer of the biological membrane (Figure 2).

Figure 1 a Figure 1 b

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ubiquitously throughout our body; they can be part of the cell membrane, participate in
enzymatic reactions and are also found in the blood stream. Antioxidants act as protectors of
the human cell, protecting it from oxidation, acting as scavengers that remove free radicals
and inhibiting oxidation of bio-molecules such as fatty acids. As a result, antioxidants
protect the cell from damages that could lead to numerous illnesses.

The Role of Krill Oil Components in the Cell Membrane
To understand the great contribution of krill oil to human health, one should consider the
fact that both phospholipids and antioxidants, two major components of krill oil are present
in the cell membranes of the human body (Figure 2). The cell membrane is one of the most
important cellular structures, acting as a physical barrier that separates the interior of the cell
from the outside environment, allowing selective movement of substances in and out the
cell.
Figure 2: The cell
membrane structure
The cell membrane is a
selectively permeable lipid
bilayer coated by proteins
which comprises the outer
layer of a cell. Phospholipids
with their attached fatty
acids are the molecular
building blocks of the
membrane. Aside from phospholipids and fatty acids, the cell membrane embedded with
antioxidants. Antioxidants protecting the fatty acids from oxidation, by scavenging free radicals and
inhibiting the oxidation chain reaction.

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The structure of the membrane depends on its components. High level of omega-3 fatty
acids, change the membrane fluidity and affect either the structure or functioning of proteins
embedded in the membrane, including enzymes, receptors, and ion channels, leading to
changes in cellular function
28
.
High concentration of omega-3 fatty acids observed in the membranes of heart cells
29
and in
vascular endothelial cells
30
, where it influences the function of the cardiovascular system.
DHA is one of the major fatty acids in the membrane phospholipids of the brain, where it
acts in the maintenance of the membrane fluidity and its function
31
. In addition, DHA level
in the red blood cells found to be associated with mood disorders such as depression
28
.
The Role of Krill Oil in Human Health
Krill oil was shown to have a beneficial effect on human health, from joint health,
cardiovascular health and more. Its effect of various systems and organs can be explained by
the fact that krill oil components are delivered into the cell membrane of different organs
and systems in the human body, including the immune cells, and could therefore influence
wide-scale conditions and illnesses. The possible negative effects of chronic inflammation
include the development of cardiovascular disease (CVD), heart attacks and potentially
stroke. Also, it can lead to degeneration of nerve cells, or even foster cell transformation into
cancer cells. Krill oil modulates the action of the immune system in chronic conditions and
therefore has the potential to prevent the negative influence of the chronic inflammation.
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Krill Oil Benefits - Scientific Evidence
Chronic Inflammation
Inflammation is an immunological self-defense mechanism utilized by the body against
injury, pathogens and diseases. However, when inflammation becomes chronic rather than
transitory, it imposes a serious malfunctioning condition and illnesses.
Today, scientists believe that chronic
inflammation is one of the main
contributing factors to chronic
degenerative diseases and may be the
engine that drives many illnesses of
middle and old age. Such influence
could lead to the development of CVD
by destabilizing cholesterol deposits in
the coronary arteries, leading to heart
attacks and potentially to stroke. Also, it can lead to degeneration of nerve cells in the brain,
or even foster the transformation into cancer cells.
The effect of EPA and DHA on chronic inflammation was studied in a large number of
clinical trials on participants with chronic inflammatory conditions as well as in healthy
subjects. While EPA and DHA do not interfere with the proper immune system function in
healthy subjects, they have the potential to inhibit the incorrect inflammatory responses in
patients with chronic inflammatory conditions
32
.
Krill Oil Is a Potent Anti-Inflammatory Agent
Krill oil mostly contains two potent anti-inflammatory constituents, omega-3 phospholipids
(PC- EPA\DHA) and the carotenoid astaxanthin. The vital lipids found in krill oil can be
considered a next-generation omega-3 dietary supplement, one with benefits that encom-
pass but overreach those of fish oil
3, 33
.
Krill Oil May Have a Beneficial Effects On:
The negative action of chronic inflammation
C-reactive protein (CRP) level
joint health
Blood lipids
blood cholesterol, triglyceride and glucose level
Woman premenstrual syndrome (PMS) symptoms
Emotional swings related to menstrual cycling
Physical discomfort during menstruation
Behavioral function
Stress and mood
Fatty liver conditions

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Figure 3: Krill oil significantly reduces WOMAC Rheumatoid Arthritis parameters in
patients.
The effect of krill oil supplementation on the 3 WOMAC parameters: pain, stiffness and functional
impairment was examined. The patients were supplemented with krill oil (300 mg per day), or
placebo for 30 days. The results represent the mean of 45 patients per group after 14 days of
supplementation. The differences over time within group were assessed by paired Students t-test.
Between-group differences (krill oil to placebo) were assessed with one-way ANOVA ;*p<0.05,
**p<0.005
34
.

Figure 4: Krill oil significantly reduces CRP level in patients with chronic inflammation.
The effect of krill oil supplementation on CRP level in patients with chronic inflammation was
examined. Patients with elevated level of CRP (CRP>1mg/dl) were supplemented with krill oil (300
mg. per day), or placebo for 30 days. The results represent the mean of 45 patients per group. The
differences over time within group were assessed by paired Students t-test. Between-group
differences (krill oil to placebo) were assessed with one-way ANOVA ;*p<0.05, **p<0.005
34
.
*
**
**
** * *
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Human clinical trials and pre clinical trials showed that krill oil inhibits the inflammatory
symptoms in chronic inflammatory patients. Krill oil significantly reduces the arthritis
scores (Figure 3), which mostly relate to the malfunction of the immune system, and
significantly reduce the inflammatory marker C reactive protein (CRP) by 30% after 14
days of administration in human, in addition to reduction in the infiltration of inflammatory
cells into the joint (Figure 4)
34, 35
. Furthermore, krill oil significantly reduces premenstrual
syndrome (PMS) symptoms and pain-relief consumption, even better than fish oil
36
. This is
further supported by two pre clinical trials which showed that krill oil inhibits the
inflammatory response to stimulus in obese rats
37
, and suppresses the development of the
autoimmune disease lupus, in mice model
24
.
Hyperlipidemia and Cardiovascular Disease
Cardiovascular disease (CVD) is the
leading cause of morbidity and mortality
in the world. Several risk factors have
been identified to increase the risk of
coronary heart disease and heart attack.
Among the risk factors are elevated blood
lipids, a condition known as
hyperlipidemia. Hyperlipidemia may be
an elevation in either cholesterol level,
triglyceride level or both.
The beneficial effect of EPA and DHA on
triglyceride-lowering and on reducing the
risk of cardiovascular disease has been
extensively studied and researched over
the years
38
. Based on the existing scientific evidence the American Heart Association
(AHA) has recommended the use of omega-3 fatty acids for secondary prevention of
Bad Cholesterol and Good Cholesterol
Lipids like cholesterol or triglycerides do not move
freely in the blood stream, but rather are transported
via lipoproteins. Cholesterol can be transported in
either a Low Density Lipoprotein (LDL) or a High
Density Lipoprotein (HDL).
High levels of LDL particles were shown to promote
cardiovascular disease and therefore are referred to as
the bad cholesterol particles as opposed to HDL
particles, which are frequently referred to as good
cholesterol or healthy cholesterol particles. When too
much LDL (bad) cholesterol circulates in the blood, it
can slowly build up in the inner walls of the arteries
that feed the heart and brain. Together with other
substances, it can form plaque, a thick, hard deposit
that can narrow the arteries and make them less
flexible. A clot which is formed and blocks a
narrowed artery, can lead to a heart attack or to
stroke.
On the other hand, high levels of HDL seem to
protect against heart attack, therefore providing it
with the name, good cholesterol.
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cardiovascular (CV) events in people with documented coronary artery disease (CAD). In
addition the FDA has approved a prescription drug based on omega-3 fatty acid ethyl ester
formulation, for the treatment of very high triglyceride levels.
However, despite the fact that the benefits of EPA and DHA are well established, fish oil
consumption is known to adversely increase the level of LDL- cholesterol (bad cholesterol).

Figure 5: Krill oil maintains blood lipids and cholesterol in hyperlipidemic patients.
The effect of krill oil supplementation on total cholesterol, LDL-cholesterol, HDL-cholesterol and
triglycerides in hyperlipidemic patients was examined. hyperlipidemic patients were supplemented
with krill oil (1.5 gr per day), or placebo for 12 weeks (90 days). The results represent the mean of
30 patients per group. The differences over time within group (baseline to day 90) were assessed by
paired Students t-test; *P < 0.0001. Between-group differences (krill oil to placebo) were assessed
with one-way ANOVA
39
.

*
* *
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Krill Oil Decreases the Levels of Triglycerides and LDL-Cholesterol
A human clinical trial found that krill oil positively manages blood lipids in hyperlipidemic
patients by significantly reducing triglycerides, total cholesterol and LDL-cholesterol. It also
increases HDL-C cholesterol and reduces glucose blood level (Figure 5). While fish oil may
adversely elevate LDL-C level, krill oil was shown to significantly reduce LDL-C in
hyperlipidemic patients
39
. The data described above is further supported by series of pre-
clinical trials conducted in hyperlipidemic and obese rats showing similar results in
modulating blood lipids as well as hepatic and heart triglycerides reduction
37, 40, 41
.
PMS - Premenstrual Syndrome
Nearly all women of reproductive age experience a variety of physical discomforts and
emotional problems during menstruation. These difficulties adversely impact their quality of
life. A human clinical trial examined healthy women diagnosed with premenstrual syndrome
(PMS), and showed that krill oil reduces the symptoms of PMS and dysmenorea. Among the
physical symptoms is dysmenorrhea, defined as a condition characterized by severe uterine
pain during menstruation, pain that usually limits normal activities or requires medication.
The human clinical trial concluded that krill oil significantly reduces dysmenorrhea, pain
relief consumption and the emotional symptoms of PMS, even compared to fish oil
36
.
Cognitive and Mental Health
Cognitive function in general and memory function in particular are vulnerable to aging and
to a variety of pathologic processes such as neurodegenerative diseases and stroke. The term
cognition holds a vast array of brain functions such as memory, association, concept
formation, language, attention, mood and more.
Extensive scientific research verifies the crucial beneficial role phospholipids and
DHA\EPA have in cognitive and mental functions. Phospholipids were shown to positively
affect mood and stress management, and to improve memory and learning damage caused
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by age or disease
3, 26
. DHA and EPA have been associated with cognitive improvement in a
broad spectrum of psychiatric disorders, as well as several mood parameters, and age-
associated memory impairment
19, 20
.
Krill Oil Improves Cognitive and Mental Health
Krill oil is comprised of a substantial amount of
phospholipids attached to DHA and EPA, therefore
is expected to exert a positive effect of cognitive
functions. A human clinical trial examined women
diagnosed with PMS, concluded that krill oil
significantly reduce the emotional symptoms of
PMS, even compared to fish oil
36
. Another pilot
open-label clinical trial, show that krill oil
significantly improves the scores of executive
function, self control and behavioral inhibition in
Attention deficit hyperactivity disorder (ADHD)
diagnosed young adults
42
.
Fatty Liver
Fatty liver disease (FLD) is a condition caused by
triglyceride fat accumulation in liver cells due to an
abnormal retention of lipids within a cell. One of
the major risks of FLD is liver dysfunction.
Accumulation of fat may also be accompanied by a
progressive inflammation of the liver (hepatitis).
A human clinical trial that was conducted on chronic liver disease patients demonstrated that
administration of PC-omega-3 is beneficial in the treatment of chronic liver diseases
27
.
EPA DHA and Brain Development
DHA is the predominant omega 3 fatty
acid in the cell membranes of the
human brain, in which it is anchored by
phospholipid molecules. Omega 3
seems to have cognitive benefits and to
be vital throughout all human life, from
embryo development through
childhood, middle age and aging.
During the third trimester of pregnancy
and the first two years of childhood, the
brain rapidly grows and consumes high
amount of DHA. DHA and EPA are
important in the development of the
embryos visual and other sensory
functions
3
. The administration of EPA
and DHA has been associated with
cognitive improvement in a broad
spectrum of psychiatric disorders as
shown in many human and animal
studies
4-7
, whereas deficiency of
omega-3 fatty acids is associated with a
wide range of neurological disorders,
such as attention-deficit hyperactivity
disorder (ADHD)
8-11
, dyslexia
13
,
depression and aggression
14
, and
autism
15-18
.
The importance of DHA and EPA
continue throughout adult life. DHA
and EPA supplementation improves
several mood parameters in young,
healthy adults
19
, and improve age-
associated memory impairment
20
.

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These results are supported by 10 years series of pre-clinical trials done by Lieber et. al., in
chronically alcohol-fed baboons. The trials revealed that PC attached to polyunsaturated
fatty acids (PC-PUFA) is effective in preventing alcohol-induced hepatic fibrosis and
cirrhosis, and the polyunsaturated phospholipids themselves might be responsible for the
protective effect, rather than the choline that failed to protect the liver
43-45
.
Fatty liver disease is treated in several European countries with high grade phospholipids
drug called Essentiale.
Krill Oil Benefits in Fatty Liver Diseases
Krill oil contains about 40% phospholipids, mostly PC-LCPUFA, and therefore, has high
potential to protect the liver in fatty liver conditions. Pre-clinical study proves that krill oil
significantly reduces liver weight and total liver fat in mice fed a high-fat diet, and suggests
that krill oil may be of therapeutic value in patients with metabolic syndrome and/or
nonalcoholic fatty liver disease (Figure 6)
40
.

Figure 6: Krill oil significantly reduces liver fat in high fat liver mice model.
The effect of krill oil supplementation on total liver fat, in high-fat-fed mice was examined. Mice
were fed with normal or high fat diets or high fat diets in addition of krill oil supplementation for 8
weeks. The results represent the mean of 6-10 mice per group. Difference between normal and
high fat diets was examined by Students t-test. Difference between high fat and high fat krill oil
diets examined by ANOVA followed by Tukeys test; *P < 0.01
40
.
*

*
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Krill Oil Safety
Krill oil is and has been available on the market and consumed for many years and in
various cultures without any known adverse events. In addition, numerous clinical trials
show that krill oil is safe and well tolerated, with no indication of adverse effects on safety
parameters
1, 22, 34, 36, 39
. Pre-clinical trials support this data and show no toxicity in animal
that consumed krill oil
46
. Furthermore, Krill Oil
+
was found to be Generally Recognized
As Safe (GRAS) by the FDA, and obtained a Novel Food status from the European Union.

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