Accepted Manuscript Telomere length and polyunsaturated fatty acids Undurti N. Das, MD, FAMS, FRSC PII:
S0899-9007(14)00187-7
DOI:
10.1016/j.nut.2014.04.001
Reference:
NUT 9273
To appear in:
Nutrition
Received Date: 21 March 2014 Accepted Date: 2 April 2014
Please cite this article as: Das UN, Telomere length and polyunsaturated fatty acids, Nutrition (2014), doi: 10.1016/j.nut.2014.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Commentary Telomere length and polyunsaturated fatty acids Undurti N Das, MD, FAMS, FRSC
E-mail: [email protected]
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UND Life Sciences, 2020 S 360th St, # K-202, Federal Way, WA 98003, USA
SC
Telomeres and telomerase, located at the ends of linear chromosomes, protect ends of the chromosomes from threats to the genome. Without telomeres, genetic material would be lost every time a cell divides. Thus,
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telomere length may serve as a marker of cell’s proliferative history and telomere length can be considered as a “mitotic clock” for a cell’s proliferative history. Telomere attrition leads to cell senescence and telomere loss is linked to DNA damage by reactive oxygen species. Paradoxically, in contrast to mice in the wild, laboratory strains have very long telomeres, yet they do age (1).
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Telomerase has functions other than elongating telomeres. Telomerase overexpression in adult mice mobilizes stem cells and induces stem cell proliferation in the absence of telomere elongation by modulating the wingless in drosophila (Wnt)–β catenin signaling pathway (2, 3). Undoubtedly, telomere
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maintenance and telomerase activation are highly regulated and largely genetically determined. Of several factors that modulate telomere length and
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telomerase activity, reactive oxygen species, hormones, growth factors, smoking status, diet, socioeconomic status, stress level, and lifestyle influence telomere dynamics (4-6). The sex hormones directly increase TERT (Telomerase reverse transcriptase) transcription and telomerase activity in human cells (7, 8). In this context, the report by O’Callaghan et al (9) that telomere shortening can be attenuated by ω-3 fatty acid supplementation is rather interesting. In their 6month intervention study, it was observed that telomere shortening was greatest in the linoleic acid (LA) group (this group received safflower oil, which Page 1 of 15
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typically contains: 7% palmitic 16:0; 3% stearic 18:0; 75% linoleic 18:2 n-6; 14% oleic 18:1 n-9) than in the EPA (that received EPA-rich fish oil containing 1.67 g EPA + 0.16 g DHA per day) and DHA (that received DHA-rich fish oil containing 1.55 g DHA + 0.40 g EPA per day) groups. These results showed
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that changes in telomere length were significantly related to changes in erythrocyte DHA levels suggesting that those in whom the largest increase in erythrocyte DHA levels occurred showed the smallest decline in telomere length. These results are in support of a previous observation that in patients
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with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere
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shortening over 5 years (10). It was noted that adherence to a healthy lifestyle that included non-current smoking, maintaining a healthy body weight (body mass index in 18.5–24.9 kg/m2), engaging in regular moderate or vigorous physical activities (>150 minutes/week), drinking alcohol in moderation (1 drink/week to < 2 drinks/day), and eating a healthy diet was associated with longer telomere length in leukocytes (11). In addition, it was observed that
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stress exposure in intrauterine life (12) and type 2 diabetes mellitus (13) are also associated with decreased length of telomere. This is interesting since, it is known that prenatal stress and maternal undernutrition enhances the risk of development of type 2 diabetes mellitus in adult life (14, 15). Thus, several
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factors influence the length of telomere and telomerase activity.
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In this context, the report by O’Callaghan et al (9) that telomere shortening can be attenuated by ω-3 fatty acid supplementation is not without controversy. For instance, Cassidy et al (16) noted that polyunsaturated fatty acid intake was negatively associated with leukocyte telomere length, though these results have been disputed by others (17) and was opined that ω-6 fatty acids shorten telomere length while ω-3 fatty acids may enhance their length. How can these controversial results be explained especially in the light of the observation that healthy lifestyle that included non-current smoking, exercise, Page 2 of 15
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moderate alcohol intake, and statins are associated with longer telomere length and decreased telomere length is present in subjects with hypertension, type 2 diabetes mellitus, coronary heart disease and free radicals, nitric oxide and
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asymmetrical dimethylarginine shorten telomere length (11, 18-24). Despite the fact that ω-6 fatty acids are considered to be proinflammatory, some of their products do have anti-inflammatory actions. For instance, lipoxins (LXs) formed from arachidonic acid (AA, 20:4 ω-6) is a potent
SC
anti-inflammatory compound. Similarly, resolvins and protectins formed from EPA and DHA respectively are also anti-inflammatory in nature. It has been suggested
that
lipoxins,
resolvins
and
protectins
are
not
only
anti-
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inflammatory molecules but are essential to enhance wound healing and restore homeostasis (25-31, see figures 1 and 2 for metabolism of ω-6 and ω-3 fatty acids). These evidences suggest that formation of anti-inflammatory lipoxins, resolvins and protectins determine the resolution of inflammation and recovery from diseases.
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In this context, it is noteworthy that atherosclerosis, smoking, coronary heart disease, hypertension, metabolic syndrome (including type 2 diabetes mellitus) and ageing in which telomere shortening is known to occur are low-
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grade systemic inflammatory conditions accompanied by low plasma and/or tissue levels of AA, EPA and DHA and their products lipoxins, resolvins and protectins (25-27, 32). Furthermore, regular exercise that prevents telomere
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shortening (11) is anti-inflammatory in nature (33) and enhances LXA4 (lipoxin A4) formation (34), while ageing is characterized by decreased LXA4 formation (35).
Estrogen
that
increases
TERT
(Telomerase
reverse
transcriptase)
transcription and telomerase activity in human cells (7, 8) stimulates LXA4 formation (36). Reactive oxygen species that decrease telomere length are suppressed by lipoxins. In addition, lipoxins, resolvins and protectins enhance endothelial nitric oxide formation (25-27). Thus, endothelial senescence that is due to eNO deficiency that corresponds to the shorter telomere length seen in Page 3 of 15
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aged endothelial cells (23, 24) can be ameliorated by enhanced production of lipoxins, resolvins and protectins that, in turn, augment eNO generation. Exercise induced mitochondrial biogenesis is due to enhanced NO formation (37, 38) implying that lipoxins, resolvins and protectins may have a role in
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mitochondrial biogenesis. It is noteworthy that similar to exercise, statins also enhance LXA4 and eNO formation (39-42) that may explain their ability to prevent telomere shortening (21).
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Based on the preceding discussion, telomere shortening that is attenuated by ω-3 fatty acid supplementation (9, 10) can be attributed to increased formation of lipoxins, resolvins and protectins from AA, EPA and
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DHA and NO. This implies that inability to form adequate amounts of these bioactive lipids and eNO may result in shortening of telomere or negative results
seen
with
supplementation
of
ω-3
PUFAs
(16).
In
addition,
polymorphism of 5-, 12- and 15-lipoxygenases and cyclo-oxygenase-2 (COX-2) enzymes that are necessary for the formation of lipoxins, resolvins and
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protectins (see Figure 2) may account for variable results reported with various PUFAs. Several minerals, trace elements, hormones, drugs and epigenetic factors influence the activities of lipoxygenase and COX-2 (25, 27), one need to take note of these variables while studying the relationship between PUFAs and
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telomere length. The association of shorter telomere with diseases such as type 2 diabetes mellitus, hypertension, coronary heart disease and ageing can also
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be related to the decreased formation of lipoxins, resolvins and protectins and NO in these conditions (13, 15, 19, 27). In the light of this proposal, it will be interesting to study the effect of lipoxins, resolvins and protectins and NO on telomere length and human telomerase reverse transcriptase (hTERT) activity and preliminary evidence is in support of such an association (43, 44).
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Note added in proof: Indirect support to the concept proposed here is derived from the recent work of Kibe et al (45) who showed that oral administration of arginine to mice
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in combination with the probiotic bifidobacteria LKM512 long term suppressed inflammation, improved longevity and protected from age-induced memory impairment. They attributed this beneficial action to increased formation of putrescine in the colon and spermidine and spermin in the blood following
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arginine supplementation. Kibe et al (45) did not measure the length of telomere and NO generation in their study. Since arginine is the precursor of
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NO and NO can maintain the length of telomere, quench superoxide anion that is known to shorten telomere, prevent endothelial senescence and function as a neurotransmitter in the brain, I suggest that the beneficial actions observed by Kibe et al are also due to enhanced formation of NO. It is likely, though needs confirmation, that bifidobacteria may contain a secretable arachidonate 15lipoxygenase-like activity similar to the one seen in other bacteria (46) and/or
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have the ability to enhance formation of lipoxins, resolvins and protectins by the host tissues as was seen in bacteria-induced preterm labor that was associated with substantially increased expression of genes involved in
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References:
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prostaglandin synthesis (47) that modulate host defense and inflammation.
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n-6
n-3
Diet
Cis-LA, 18:2
α-ALA, 18:3 ∆6 Desaturase
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GLA, 18:3 Insulin, Folic Acid, Vitamin B12, B6, Vitamin C,Zn2+ , Se, Mg2+, Ca2+, Alcohol, Viruses, ageing
SC
DGLA, 20:3 ∆5 Desaturase
PGs of 1 series
Exercise
EPA, 20:5
DHA, 22:6
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AA, 20:4
Statins
E
PGs of 2 series, TXs, LTs of 4 series
Resolvins
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Lipoxins
PGs of 3 series, TXs, LTs of 5 series
Pro-inflammatory in Nature
eNO
Protectins (NPDs)
Anti-inflammatory in Nature
ROS
Telomere length maintained
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Telomere shortening
Figure 1. Scheme showing the metabolism of essential fatty acids, co-factors involved in their metabolism, and their role in the shortening or maintenance of telomere. E = Estrogen
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Legend to Figure 1: Dietary essential fatty acids (EFAs): linoleic acid (LA) and α-linolenic acid (ALA) are to form their long-chain metabolites: arachidonic acid (AA) and
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eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) respectively by ∆6 and ∆5 desaturases. 2 series prostaglandins, thromboxanes and 4 series leukotrienes thromboxanes
are
formed
and
5
from
series
AA;
whereas
leukotrienes
3
from
prostaglandins,
EPA.
Prostaglandins,
pro-inflammatory in nature
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thromboxanes and leukotrienes are, in general,
series
except that 3 series prostaglandins, thromboxanes and 5 series leukotrienes are less pro-inflammatory compared to those formed from AA. Lipoxins are
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derived from AA, resolvins from EPA and DHA (resolvins of E series from EPA and resolvins of D series from DHA) and protectins from DHA. DHA also forms precursor to maresins. Lipoxins, resolvins, protectins and maresins are antiinflammatory
compounds
that
antagonize
pro-inflammatory
actions
of
prostaglandins, thromboxanes and leukotrienes. Thus, there is a balance
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maintained between pro- and anti-inflammatory compounds formed form AA, EPA and DHA under normal physiological conditions. Anti-inflammatory cytokines such as IL-4 and IL-12 induce the formation of anti-inflammatory lipoxins, resolvins and protectins whereas pro-inflammatory cytokines IL-6 and
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TNF-α induce formation of pro-inflammatory prostaglandins, thromboxanes and leukotrienes. Thus, there is a close association between anti-inflammatory and pro-inflammatory bioactive lipids and cytokines. Production of adequate
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amounts of pro-inflammatory cytokines such as IL-6 is essential to trigger the induction of formation of anti-inflammatory lipoxins, resolvins and protectins. Exercise, statins and estrogen enhance the formation of anti-inflammatory lipoxins, resolvins and protectins and endothelial nitric oxide to bring about some (if not all) of their beneficial actions. Lipoxins, resolvins and protectins enhance the production of eNO and suppress that of reactive oxygen species (ROS). Telomere length is decreased by ROS and is maintained or increased by Page 13 of 15
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exercise, estrogen, statins and NO. The ability of EPA/DHA, exercise, statins and estrogen to maintain (or increase) the length of telomere could be attributed to their ability to enhance formation of lipoxins resolvins and protectins, eNO and suppress ROS. Controversial results reported with
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EPA/DHA on telomere length could be due to differences in the dose and duration employed in different studies and polymorphisms and differences in the activities of desaturases, COX and LOX enzymes in different subjects. Telomere length is shorter in subjects with type 2 diabetes mellitus,
SC
hypertension and coronary heart disease in whom plasma levels of proinflammatory cytokines IL-6 and TNF-α are increased; AA, EPA and DHA are
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low and consequently levels of lipoxins, resolvins and protectins will be lower; have decreased formation of eNO and enhanced levels of ROS, lipid peroxides and ADMA (asymmetrical dimethylarginine, which interferes with the formation of nitric oxide). The beneficial actions of exercise in type 2 diabetes mellitus, hypertension, coronary heart disease and other diseases could be attributed to enhanced formation of lipoxins, resolvins and protectins, eNO and decreased
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generation of ROS and pro-inflammatory cytokines.
Page 14 of 15
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Figure 2. Scheme showing the formation of LXA4 from AA, resolvin E1 (RvE1) from EPA and protectin D1 (PD1) from DHA that are potent anti-inflammatory compounds and are probably involved in maintaining telomere length
Page 15 of 15
S0899-9007(14)00187-7
DOI:
10.1016/j.nut.2014.04.001
Reference:
NUT 9273
To appear in:
Nutrition
Received Date: 21 March 2014 Accepted Date: 2 April 2014
Please cite this article as: Das UN, Telomere length and polyunsaturated fatty acids, Nutrition (2014), doi: 10.1016/j.nut.2014.04.001. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Commentary Telomere length and polyunsaturated fatty acids Undurti N Das, MD, FAMS, FRSC
E-mail: [email protected]
RI PT
UND Life Sciences, 2020 S 360th St, # K-202, Federal Way, WA 98003, USA
SC
Telomeres and telomerase, located at the ends of linear chromosomes, protect ends of the chromosomes from threats to the genome. Without telomeres, genetic material would be lost every time a cell divides. Thus,
M AN U
telomere length may serve as a marker of cell’s proliferative history and telomere length can be considered as a “mitotic clock” for a cell’s proliferative history. Telomere attrition leads to cell senescence and telomere loss is linked to DNA damage by reactive oxygen species. Paradoxically, in contrast to mice in the wild, laboratory strains have very long telomeres, yet they do age (1).
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Telomerase has functions other than elongating telomeres. Telomerase overexpression in adult mice mobilizes stem cells and induces stem cell proliferation in the absence of telomere elongation by modulating the wingless in drosophila (Wnt)–β catenin signaling pathway (2, 3). Undoubtedly, telomere
EP
maintenance and telomerase activation are highly regulated and largely genetically determined. Of several factors that modulate telomere length and
AC C
telomerase activity, reactive oxygen species, hormones, growth factors, smoking status, diet, socioeconomic status, stress level, and lifestyle influence telomere dynamics (4-6). The sex hormones directly increase TERT (Telomerase reverse transcriptase) transcription and telomerase activity in human cells (7, 8). In this context, the report by O’Callaghan et al (9) that telomere shortening can be attenuated by ω-3 fatty acid supplementation is rather interesting. In their 6month intervention study, it was observed that telomere shortening was greatest in the linoleic acid (LA) group (this group received safflower oil, which Page 1 of 15
ACCEPTED MANUSCRIPT
typically contains: 7% palmitic 16:0; 3% stearic 18:0; 75% linoleic 18:2 n-6; 14% oleic 18:1 n-9) than in the EPA (that received EPA-rich fish oil containing 1.67 g EPA + 0.16 g DHA per day) and DHA (that received DHA-rich fish oil containing 1.55 g DHA + 0.40 g EPA per day) groups. These results showed
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that changes in telomere length were significantly related to changes in erythrocyte DHA levels suggesting that those in whom the largest increase in erythrocyte DHA levels occurred showed the smallest decline in telomere length. These results are in support of a previous observation that in patients
SC
with coronary artery disease, there was an inverse relationship between baseline blood levels of marine omega-3 fatty acids and the rate of telomere
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shortening over 5 years (10). It was noted that adherence to a healthy lifestyle that included non-current smoking, maintaining a healthy body weight (body mass index in 18.5–24.9 kg/m2), engaging in regular moderate or vigorous physical activities (>150 minutes/week), drinking alcohol in moderation (1 drink/week to < 2 drinks/day), and eating a healthy diet was associated with longer telomere length in leukocytes (11). In addition, it was observed that
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stress exposure in intrauterine life (12) and type 2 diabetes mellitus (13) are also associated with decreased length of telomere. This is interesting since, it is known that prenatal stress and maternal undernutrition enhances the risk of development of type 2 diabetes mellitus in adult life (14, 15). Thus, several
EP
factors influence the length of telomere and telomerase activity.
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In this context, the report by O’Callaghan et al (9) that telomere shortening can be attenuated by ω-3 fatty acid supplementation is not without controversy. For instance, Cassidy et al (16) noted that polyunsaturated fatty acid intake was negatively associated with leukocyte telomere length, though these results have been disputed by others (17) and was opined that ω-6 fatty acids shorten telomere length while ω-3 fatty acids may enhance their length. How can these controversial results be explained especially in the light of the observation that healthy lifestyle that included non-current smoking, exercise, Page 2 of 15
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moderate alcohol intake, and statins are associated with longer telomere length and decreased telomere length is present in subjects with hypertension, type 2 diabetes mellitus, coronary heart disease and free radicals, nitric oxide and
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asymmetrical dimethylarginine shorten telomere length (11, 18-24). Despite the fact that ω-6 fatty acids are considered to be proinflammatory, some of their products do have anti-inflammatory actions. For instance, lipoxins (LXs) formed from arachidonic acid (AA, 20:4 ω-6) is a potent
SC
anti-inflammatory compound. Similarly, resolvins and protectins formed from EPA and DHA respectively are also anti-inflammatory in nature. It has been suggested
that
lipoxins,
resolvins
and
protectins
are
not
only
anti-
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inflammatory molecules but are essential to enhance wound healing and restore homeostasis (25-31, see figures 1 and 2 for metabolism of ω-6 and ω-3 fatty acids). These evidences suggest that formation of anti-inflammatory lipoxins, resolvins and protectins determine the resolution of inflammation and recovery from diseases.
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In this context, it is noteworthy that atherosclerosis, smoking, coronary heart disease, hypertension, metabolic syndrome (including type 2 diabetes mellitus) and ageing in which telomere shortening is known to occur are low-
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grade systemic inflammatory conditions accompanied by low plasma and/or tissue levels of AA, EPA and DHA and their products lipoxins, resolvins and protectins (25-27, 32). Furthermore, regular exercise that prevents telomere
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shortening (11) is anti-inflammatory in nature (33) and enhances LXA4 (lipoxin A4) formation (34), while ageing is characterized by decreased LXA4 formation (35).
Estrogen
that
increases
TERT
(Telomerase
reverse
transcriptase)
transcription and telomerase activity in human cells (7, 8) stimulates LXA4 formation (36). Reactive oxygen species that decrease telomere length are suppressed by lipoxins. In addition, lipoxins, resolvins and protectins enhance endothelial nitric oxide formation (25-27). Thus, endothelial senescence that is due to eNO deficiency that corresponds to the shorter telomere length seen in Page 3 of 15
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aged endothelial cells (23, 24) can be ameliorated by enhanced production of lipoxins, resolvins and protectins that, in turn, augment eNO generation. Exercise induced mitochondrial biogenesis is due to enhanced NO formation (37, 38) implying that lipoxins, resolvins and protectins may have a role in
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mitochondrial biogenesis. It is noteworthy that similar to exercise, statins also enhance LXA4 and eNO formation (39-42) that may explain their ability to prevent telomere shortening (21).
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Based on the preceding discussion, telomere shortening that is attenuated by ω-3 fatty acid supplementation (9, 10) can be attributed to increased formation of lipoxins, resolvins and protectins from AA, EPA and
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DHA and NO. This implies that inability to form adequate amounts of these bioactive lipids and eNO may result in shortening of telomere or negative results
seen
with
supplementation
of
ω-3
PUFAs
(16).
In
addition,
polymorphism of 5-, 12- and 15-lipoxygenases and cyclo-oxygenase-2 (COX-2) enzymes that are necessary for the formation of lipoxins, resolvins and
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protectins (see Figure 2) may account for variable results reported with various PUFAs. Several minerals, trace elements, hormones, drugs and epigenetic factors influence the activities of lipoxygenase and COX-2 (25, 27), one need to take note of these variables while studying the relationship between PUFAs and
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telomere length. The association of shorter telomere with diseases such as type 2 diabetes mellitus, hypertension, coronary heart disease and ageing can also
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be related to the decreased formation of lipoxins, resolvins and protectins and NO in these conditions (13, 15, 19, 27). In the light of this proposal, it will be interesting to study the effect of lipoxins, resolvins and protectins and NO on telomere length and human telomerase reverse transcriptase (hTERT) activity and preliminary evidence is in support of such an association (43, 44).
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Note added in proof: Indirect support to the concept proposed here is derived from the recent work of Kibe et al (45) who showed that oral administration of arginine to mice
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in combination with the probiotic bifidobacteria LKM512 long term suppressed inflammation, improved longevity and protected from age-induced memory impairment. They attributed this beneficial action to increased formation of putrescine in the colon and spermidine and spermin in the blood following
SC
arginine supplementation. Kibe et al (45) did not measure the length of telomere and NO generation in their study. Since arginine is the precursor of
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NO and NO can maintain the length of telomere, quench superoxide anion that is known to shorten telomere, prevent endothelial senescence and function as a neurotransmitter in the brain, I suggest that the beneficial actions observed by Kibe et al are also due to enhanced formation of NO. It is likely, though needs confirmation, that bifidobacteria may contain a secretable arachidonate 15lipoxygenase-like activity similar to the one seen in other bacteria (46) and/or
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have the ability to enhance formation of lipoxins, resolvins and protectins by the host tissues as was seen in bacteria-induced preterm labor that was associated with substantially increased expression of genes involved in
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References:
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prostaglandin synthesis (47) that modulate host defense and inflammation.
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n-6
n-3
Diet
Cis-LA, 18:2
α-ALA, 18:3 ∆6 Desaturase
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GLA, 18:3 Insulin, Folic Acid, Vitamin B12, B6, Vitamin C,Zn2+ , Se, Mg2+, Ca2+, Alcohol, Viruses, ageing
SC
DGLA, 20:3 ∆5 Desaturase
PGs of 1 series
Exercise
EPA, 20:5
DHA, 22:6
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AA, 20:4
Statins
E
PGs of 2 series, TXs, LTs of 4 series
Resolvins
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Lipoxins
PGs of 3 series, TXs, LTs of 5 series
Pro-inflammatory in Nature
eNO
Protectins (NPDs)
Anti-inflammatory in Nature
ROS
Telomere length maintained
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Telomere shortening
Figure 1. Scheme showing the metabolism of essential fatty acids, co-factors involved in their metabolism, and their role in the shortening or maintenance of telomere. E = Estrogen
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Legend to Figure 1: Dietary essential fatty acids (EFAs): linoleic acid (LA) and α-linolenic acid (ALA) are to form their long-chain metabolites: arachidonic acid (AA) and
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eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) respectively by ∆6 and ∆5 desaturases. 2 series prostaglandins, thromboxanes and 4 series leukotrienes thromboxanes
are
formed
and
5
from
series
AA;
whereas
leukotrienes
3
from
prostaglandins,
EPA.
Prostaglandins,
pro-inflammatory in nature
SC
thromboxanes and leukotrienes are, in general,
series
except that 3 series prostaglandins, thromboxanes and 5 series leukotrienes are less pro-inflammatory compared to those formed from AA. Lipoxins are
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derived from AA, resolvins from EPA and DHA (resolvins of E series from EPA and resolvins of D series from DHA) and protectins from DHA. DHA also forms precursor to maresins. Lipoxins, resolvins, protectins and maresins are antiinflammatory
compounds
that
antagonize
pro-inflammatory
actions
of
prostaglandins, thromboxanes and leukotrienes. Thus, there is a balance
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maintained between pro- and anti-inflammatory compounds formed form AA, EPA and DHA under normal physiological conditions. Anti-inflammatory cytokines such as IL-4 and IL-12 induce the formation of anti-inflammatory lipoxins, resolvins and protectins whereas pro-inflammatory cytokines IL-6 and
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TNF-α induce formation of pro-inflammatory prostaglandins, thromboxanes and leukotrienes. Thus, there is a close association between anti-inflammatory and pro-inflammatory bioactive lipids and cytokines. Production of adequate
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amounts of pro-inflammatory cytokines such as IL-6 is essential to trigger the induction of formation of anti-inflammatory lipoxins, resolvins and protectins. Exercise, statins and estrogen enhance the formation of anti-inflammatory lipoxins, resolvins and protectins and endothelial nitric oxide to bring about some (if not all) of their beneficial actions. Lipoxins, resolvins and protectins enhance the production of eNO and suppress that of reactive oxygen species (ROS). Telomere length is decreased by ROS and is maintained or increased by Page 13 of 15
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exercise, estrogen, statins and NO. The ability of EPA/DHA, exercise, statins and estrogen to maintain (or increase) the length of telomere could be attributed to their ability to enhance formation of lipoxins resolvins and protectins, eNO and suppress ROS. Controversial results reported with
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EPA/DHA on telomere length could be due to differences in the dose and duration employed in different studies and polymorphisms and differences in the activities of desaturases, COX and LOX enzymes in different subjects. Telomere length is shorter in subjects with type 2 diabetes mellitus,
SC
hypertension and coronary heart disease in whom plasma levels of proinflammatory cytokines IL-6 and TNF-α are increased; AA, EPA and DHA are
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low and consequently levels of lipoxins, resolvins and protectins will be lower; have decreased formation of eNO and enhanced levels of ROS, lipid peroxides and ADMA (asymmetrical dimethylarginine, which interferes with the formation of nitric oxide). The beneficial actions of exercise in type 2 diabetes mellitus, hypertension, coronary heart disease and other diseases could be attributed to enhanced formation of lipoxins, resolvins and protectins, eNO and decreased
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generation of ROS and pro-inflammatory cytokines.
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SC
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Figure 2. Scheme showing the formation of LXA4 from AA, resolvin E1 (RvE1) from EPA and protectin D1 (PD1) from DHA that are potent anti-inflammatory compounds and are probably involved in maintaining telomere length
Page 15 of 15
