International Journal of Nutrition

Current Issue Volume No: 1 Issue No: 2

ISSN: 2379-7835
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Review Article Open Access
  • Available online freely Peer Reviewed
  • Oxidative Telomere Attrition, Nutritional Antioxidants and Biological Aging

    Michael J. Glade Ph.D. 1  

    1The Nutrition Doctor,Kailua-Kona, HI, USA


    Telomeres are strings of DNA that are not themselves genes but that extend every chromosome beyond its last gene. Terminal telomeres are sacrificed during every mitotic event in human cells (“telomere attrition”), preserving the functional genome despite the “end replication problem.” However, the “telomeric theory of biological aging” suggests that when an individual cell has reproduced itself a sufficient number of times (the “Hayflick limit”), some the its telomeres have become critically shortened (“telomeric crisis”) and cannot completely “cap off” a chromosome, and any further attempts to replicate such a chromosome would produce damaged DNA and a dysfunctional cell (“cellular aging”). As cells enter telomeric crisis, they usually initiate intracellular signaling cascades that arrest DNA replication and mitotic activity, converting biologically active cells into inactive cells (“cellular senescence”). The progressive accumulation of senescent cells impairs the healthy functioning of tissues and produces “biological aging.”

    Oxidative stress damages telomeres and accelerates telomere attrition and biological aging. Premature biological aging is associated with degenerative diseases and diminished quality of life. Reducing the level of systemic oxidative stress can ease the oxidative drive toward cellular senescence and premature biological aging. Increased intakes of antioxidant-rich foods and specific antioxidant nutrients (such as fruits and vegetables, α -lipoic acid, astaxanthin, eicosapentaenoic acid, docosahexaenoic acid, trans-resveratrol, N-acetylcysteine, methylsulfonylmethane, lutein, vitamin C, vitamin D, vitamin E, and γ-tocotrienol) may decrease cellular and systemic oxidative stress and decelerate biological aging.

    Author Contributions
    Received 30 May 2014; Accepted 08 Mar 2014; Published 21 Jan 2015;

    Academic Editor: Marcello Iriti, Milan State University

    Checked for plagiarism: Yes

    Review by: Single-blind

    Copyright ©  2015 Amanda Unanski Enright, et al

    Creative Commons License     This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

    Competing interests

    The authors have declared that no competing interests exist.


    Michael J. Glade Ph.D. (2015) Oxidative Telomere Attrition, Nutritional Antioxidants and Biological Aging. International Journal of Nutrition - 1(2):1-37.

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    DOI 10.14302/issn.2379-7835.ijn-14-606


    Telomeres, Senescence and Biological Aging

    Human telomeres are strings of nucleotides located on the tips of chromosomes that repeat the “nonsense” sequence, TTAGGG, thousands of times.1 Instead of providing genetic information, telomeres protect chromosomal integrity. The last telomeres on the 3’ end of a chromosome combine with a set of proteins (the shelterin complex) to form loop-like structures that prevent 1) the “loose” ends of chromosomal DNA strings from being mistakenly identified by the DNA repair machinery as broken DNA strands that require repairing, and 2) subsequent well-intentioned but misguided repair attempts that could produce harmful mutations.1,2,3,4,5,6

    When a cell is replicating its DNA prior to undergoing mitosis, the DNA polymerase-containing replication complex cannot fully replicate the 3’ end of linear duplex DNA during DNA replication (the “end-replication problem”). Any genetic nformation at that end of the molecule would be replicated in a truncated, potentially dysfunctional form.7 Telomeres protect terminal genes from truncation by serving as expendable terminal nucleotide sequences.7 However, the terminal telomere/shelterin complex prevents the required relationship between DNA polymerase and the DNA strand, and must be excised before DNA replication can occur. Because the excised telomeric DNA is not replaced, the number of telomeric TTAGGG repeats on the end of each chromosome decreases with each round of DNA replication (telomere attrition).1,2,4,6,8 However, no genetic information is lost, and the shelterin complex and remaining terminal telomeres reassociate, resuming their protective role.1,7

    A consequence of this process is that the average lengths of telomeres in most populations of reproducing human cells (such as the fibroblasts that form a scar, or the circulating leukocytes that fight infections) decline steadily with increasing chronological age, reflecting increasing numbers of previous replication cycles.9,17 This phenomenon has been observed in human peripheral blood mononuclear cells,16,18,21 leukocytes,9,11,13,19,22,54 lymphocytes,12,55,58 bone marrow-derived hematopoietic stem cells,59,60 oral cavity buccal cells,16 skeletal muscle cells,9,24 skin epidermal cells,15,61 skin keratinocytes,9,24 fibroblasts,62 vascular endothelial cells,19,63,65 adipocytes,9,24 pituitary neurons,66 and cells in the colon.41,66,67 The rates of telomere shortening in different tissues appear to remain highly correlated and, on average, approximately linear throughout adult life.9,17 However, tissues with more rapid cellular turnover (such as intestinal epithelial cells) exhibit more rapid rates of telomere shortening.9,68,69

    At any given time, within a cell that is not terminally differentiated, the length of the remaining telomere string reflects the number of previous replication cycles the cell has experienced and limits the number of future cycles of DNA replication (and therefore the number of mitotic cycles and cell divisions) that remain available to the cell (the “Hayflick limit”).4,7,8,62,70 Thus, telomeres act as a molecular clock (“replicometer”) tracking the reproductive history of a cell.8 The progressive telomere shortening that occurs during repeated cycles of cell division moves a cell toward its Hayflick limit (replicative aging).8 After a critical cell type-specific number of telomeric repeats have been lost, the telomere/shelterin complex destabilizes, sheds shelterin (telomere uncapping), and can no longer prevent the detection of a (false) DNA break and the initiation of a DNA damage response (DDRb).8,71,72

    The DDR begins with the detection of DNA strand breaks and triggers a DNA replication-arresting cascade.71, 72,73,74,75 Activation of the p16INK4A tumor suppressor protein inhibits the D-type cyclin-dependent kinases, CDK4 and CDK6, that deactivate via phosphorylation the retinoblastoma tumor suppressor protein (Rb); Rb deactivation releases cells from arrest in the G1 phase of the cell cycle while p16INK4A-initiated inhibition of Rb deactivation arrests DNA replication and mitosis.68,73,79 Consequently, initiation of the p16INK4A/Rb cascade by the DDR prevents both potentially mutant DNA replication and the reproduction of a cell potentially containing mutant DNA.68,73,79 Consistent with the hypothesis that there is an association between replicative aging and biological aging, the expression of p16INK4a (and, therefore, the likelihood of irreversible cessation of replication; replicative senescence) increases in human lymphocytes with increasing chronological age.58

    The DDR also activates the tumor suppressor protein 53 (p53) – p21 (CDK-inhibitor 1A; CDKN1A) pathway to cell cycle arrest.80 Activated p53 activates p21, triggering a cascade, sequentially involving the growth arrest and DNA-damage inducible protein 45 (GADD45), mitogen-activated protein kinase 14 (MAPK14), growth factor receptor-bound protein 2 (GRB2), transforming growth factor-β receptor 2 (TGFBR2), steroid receptor coactivator (Src), the disabled-2 (Dab2) intracellular adaptor protein, and transforming growth factor-β (TGF-β), that induces a positive feedback loop of mitochondrial dysfunction, increased oxidative DNA damage, and inability to perform replicative functions that drives the cell toward replicative senescence.4,7,73,74,80,82

    Replicative senescence can be delayed. Replicating cells express telomerase, a constitutive ribonucleoprotein complex containing at least 6 and as many as 16 distinct proteins that is present at low activity in all cells that are not terminally differentiated.22,83 The RNA component of telomerase (TERC) serves as a template for the “replacement” of telomeric DNA, while the catalytic subunit of telomerase (TERT) acts as a cellular reverse transcriptase, elongating replication-shortened telomeres by adding 5’-TTAGGG-3’ repeats.7,22,84,85,86 Upregulation of telomerase activity is vital to the prevention, postponement or elimination of the continued shortening and inevitable replication-arresting uncapping of key telomeres (telomere crisis).4,7,22,84,88 All healthy replicating human cells eventually experience a terminal telomere crisis, chromosomal instability, and apoptotic death.87 The interplay between telomere attrition, telomerase upregulation, and the DDR, and the intensity and duration of their initiating stimuli, determines the eventual fate of the cell – resumed replication, replicative senescence, or apoptosis.

    Telomerase activity and telomere lengthening are directly correlated with the expression of TERT.88 Conversely, humans with mutated (inactive) TERT have proliferating cells with very short telomeres that, even during childhood, have average lengths similar to those of unmutated telomeres of adults years older;22,89,90 these cells exhibit significantly reduced replicative capacities, with fewer cell divisions until replicative senescence.91

    The activation of telomerase may be thought of as a mechanism to slow down the rate of progressive genomic instability that results from dysfunctional telomeres and the consequences of that instability.92 For example, mice with epidermal stem cells lacking telomerase and exhibiting very short telomeres experienced delayed wound healing, stunted hair growth, epidermal thinning, dwarfism, stunting of individual internal organs, and reduced longevity,93 which were reversed upon restoration of telomerase activity.94 Consistent with these data, aging murine neuronal stem cells, in which the expression of telomerase is downregulated and telomeres are critically short and dysfunctional, produce daughter neurons that are fewer in number and unable to develop fully mature neurite arbors (differentiation failure).95

    The limited life span of many human cell types that are not capable of replicating themselves results from their inability to express telomerase (because they are fully differentiated and not dividing) and maintain telomeres at sufficient lengths to suppress DDRs.96 On the other hand, there is evidence that initially longer telomeres decrease in length most rapidly18,97,98 and that a “telomere trimming” mechanism releases telomeric DNA from elongated telomeric chains despite the presence of active telomerase, counteracting “excessive” telomere lengthening and possibly setting upper limits on maximum telomere length and the number of future replication cycles until senescence will be reached.99,102

    Organismal longevity may reflect the integration of the replicative histories of all of the cell populations of the organism. Because the rates of telomere shortening in different tissues are highly correlated throughout adult life,9,10,15,17 the mean lengths of telomeres in easily obtained peripheral blood mononuclear cells (PBMC) or circulating leukocytes (mean leukocyte telomere length; LTL) may serve as biomarkers of remaining biological lifespan in humans. For example, among a subset of the participants in the prospective Cardiovascular Health Study, those with the shortest age- and sex-adjusted LTL at the beginning of the study were 60% less likely to be alive years later (95% confidence interval: 22%, 112%).32 In contrast, mice that have been genetically engineered to overexpress telomerase experienced greater overall health and extended life span.103

    The available observational and experimental data support the conclusion that cellular replicative capacity decreases, senescent cells accumulate, and functional senescence increases as humans grow older.68 For example, when freshly-harvested human vascular smooth muscle cells and endothelial cells were studied, the numbers of cell divisions until permanent mitotic arrest and cellular senescence were inversely correlated with donor age.104 In another study, compared to findings in men and women aged 20 to 39 years, a loss of replicative capacity was detected in the skin of men and women over 68 years old.105 In contrast, pharmacological elimination of p16INK4A-positive cells in mice delayed the appearance of typical “age-associated” degenerative changes, including reduction in DNA synthesis within skeletal muscle, loss of skeletal muscle diameter, decreased exercise ability, and increased numbers of apoptotic cells within the eyes.106 Together, these findings suggest that cellular aging (biological aging) increases with chronological age and may be a consequence of cumulative telomere attrition.

    Oxidative Stress and Replicative Senescence

    The biological and physiologic processes associated with aging reflect the rate of whole-body free radical production,107,111 and an imbalance in the body’s oxidant and antioxidant status is an important etiologic factor for human degenerative diseases of aging.107,112 Reproductively-senescent human cells in many tissues produce increased amounts of reactive oxygen species (ROS)113 and contain oxidatively modified proteins that disrupt pathways involved in the inflammatory response, carbohydrate metabolism, nucleic acid metabolism, amino acid metabolism, protein synthesis, free radical scavenging, cell migration, and apoptotic cell death.114,116 In addition, ROS contribute to the induction of replicative senescence through the creation of foci of oxidatively-modified DNA, including at telomeres.117

    The telomere strand of TTAGGG repeats is particularly sensitive to oxidative stress because these strands are rich in guanine residues that are readily oxidatively modified to 8-oxyguanosine (8-OHdG; 8-oxo-dG).118 8-OHdG results in mostly G→T transverse mutations that can accelerate telomere shortening by reducing the protective binding of shelterin proteins to the altered telomere.61,119 In addition, adjacent oxidatively-modified telomeres form clusters of oxidized DNA lesions that are less likely to be repaired successfully.120,121 In a case-control study, telomere lengths in aortic endothelial cells, vascular smooth muscle cells, lymphocytes, and keratinocytes were inversely correlated with intracellular 8-OHdG content.16 Cellular senescence also can result from telomere-independent oxidative chromosomal disruption, including DNA damage from radiation, oxidants, alkylating agents, and drugs that generate double-strand DNA breaks.122

    Experiments with human dermal fibroblasts,80,123,128 human adipocytes,129 human vascular smooth muscle cells,130,131,132 human arterial endothelial cells,113 human umbilical vein endothelial cells,132 and human retinal pigment epithelial cells133 have provided evidence that oxidatively damaged DNA is a characteristic associated with accelerated telomere attrition and premature replicative senescence. In response to continuous exposure to sublethal concentrations of hydrogen peroxide (H2O2), human cells increase superoxide production, experience elevated intracellular oxidative stress, and exhibit oxidative telomere shortening that accelerates with each subsequent replicative cycle. As shown in experiments with cultured human fibroblasts and endothelial cells exposed to H2O2, loss of telomerase activity results from export of the oxidatively-damaged reverse transcriptase subunit of telomerase out of the nucleus and into the cytosol through nuclear pores, preventing telomere length maintenance within the nucleus during replicative cycles.113,134,135 In addition, shortened telomeres are more sensitive to oxidizing conditions.130,136 These responses are accompanied by reductions in the numbers of cell divisions until replicative capacity is lost and cellular senescence ensues.

    Exposing human vascular smooth muscle cells to superoxide anion-promoting angiotensin II130,131 or exposing cultured human dermal fibroblasts to ultraviolet-A irradiation128 resulted in increased generation of ROS and oxidative DNA damage that were accompanied by accelerated telomere attrition and premature replicative senescence. In cross-sectional48 and case-control80 studies, age-adjusted LTL were inversely correlated with the plasma concentration of total oxidizing compounds48 and with an established biomarker of the level of systemic oxidative stress, the plasma concentration ratio of F2-isoprostane lipid peroxidation products to the antioxidant, ascorbic acid.80,137 Among a cohort of healthy premenopausal women, those with the greatest degree of chronic oxidative stress (reflected in the ratio of total isoprostanes to vitamin E within circulating leukocytes) had age-adjusted LTL that were shorter by an amount equivalent to an additional decade of biological aging.138 Consistent with the hypothesis that oxidative stress accelerates telomere attrition, in a cross-sectional study of men aged 79 to 98 years, age-adjusted LTL was directly correlated with total circulating antioxidant capacity, suggesting that reducing systemic oxidative stress contributes to the preservation of telomere length.58

    Environmental sources of oxidative stress also induce premature senescence. Pesticides such as DDT (dichlorodiphenyltrichloroethane; 1,1,-trichloro-2,2-bis-chlorophenylethane) stimulate lipid peroxidation, increase free radical generation, accelerate the formation of 8-OHdG, and reduce the length of telomeres in buccal cells.139,141 Humans exposed to large amounts of vehicular emissions exhibit increased systemic oxidative stress142,144 that accelerates telomere attrition,113,134 accelerating cellular biological aging26 and organismal aging.145 Vehicular emissions have been found to be highly tissue-oxidizing in several case-control studies142,144 and age-adjusted LTL have been reported to be inversely correlated with the degree of exposure to vehicular emissions in a cross-sectional study in Milan, Italy,146 and in the prospective Veterans Affairs Normative Aging Study.147

    Cigarette smoke contains many oxidizing chemicals, including nitric oxide, nitrogen disulfide, nitric and nitrous oxide esters, and the superoxide-generating semiquinone radical.148 Cigarette smoke produces systemic oxidative stress, depleting ascorbate, α -tocopherol, β-carotene, and glutathione reserves and stimulating the production of tissue-degenerating114 and DNA strand-breaking148 lipid peroxides, carbonylated proteins, and oxidized tyrosine residues.149 Human fibroblasts express many proteins that are sensitive to oxidative stress115 and upon reaching senescence, fibroblasts contain oxidatively modified proteins that disrupt pathways involved in the inflammatory response, carbohydrate metabolism, nucleic acid metabolism, amino acid metabolism, protein synthesis, amino acid metabolism, free radical scavenging, cell migration, and apoptotic cell death.114 By increasing the oxidative modification of cellular proteins, cigarette smoking accelerates the biological aging of human tissues with probable negative impact on maximum chronological age.

    Cigarette smoking also accelerates telomere attrition. In a cross-sectional study, age-adjusted LTL was inversely correlated with the number of cigarettes smoked lifetime, while DNA damage and lymphocyte p16INK4a expression were directly correlated with the number of cigarettes smoked lifetime and inversely correlated with age-adjusted LTL.58 Cigarette smoking was associated with significantly accelerated rates of telomere attrition in the prospective Prevention of Renal and Vascular End-stage Disease study,52 the cross-sectional Health, Aging and Body Composition27 and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial21 studies, a case-control study conducted in Poland,39 a cross-sectional study nested within the prospective Helsinki Businessmen Study150 and case-control studies nested within the prospective all-male Health Professionals Follow-up Study and all-female Nurses’ Health Study.151 In addition, at the end of a 12-year prospective observational study, subjects who had quit smoking during the study exhibited significantly less continuing loss of telomere length than was experienced by continuing smokers.47

    Cigarette-induced cellular senescence may be sufficiently severe to override the processes of replicative senescence. For example, in a study of arterial endothelial cells harvested from smoking and nonsmoking patients undergoing coronary artery bypass graft surgery, even though cells harvested from smokers exhibited increased production of 4-hydroxynonenal (HNE, a product of lipid peroxidation), impaired resistance to H2O2-induced oxidation of cellular contents, and increased expression of p53, these cells had experienced less telomere attrition prior to surgical harvest (possible reflecting the younger chronological age of the smoking patients at the time of life-saving surgery, which may have been preceded by fewer cell doublings).152

    Telomere Attrition and Cancer

    Excessive telomere attrition triggers a response that induces the expression of proteins that block the cell cycle and limits the replicative potential of cells.4,7,8,71,73,74,80,81,82. In so doing, telomere attrition may protect against carcinogenesis by preventing the proliferation of cancerous cells. Observations of telomere shortening, genomic instability, and upregulated telomerase expression in many cancer tissues compared to adjacent normal tissue suggest that survival through a telomere crisis is a widespread crucial early event in malignant transformation.153 Cells that escape crisis upregulate telomerase expression, reversing telomere loss,62,154 or express telomerase variants that stabilize shortened telomeres.55,155,156,157 Telomere stabilization at adequate but suboptimal levels can continue through an indefinite number of additional replication cycles, protecting genetically damaged DNA from normal cell senescence or apoptosis and allowing immortalized but damaged DNA to persist.158 Alternatively, spontaneously immortalized cells that do not express telomerase (e.g., chromosomally stable microsatellite stable rectal cancer cells159) can maintain telomeres beyond “crisis” length through the telomerase-independent process of “alternative lengthening of telomeres” (ALT) during which new telomeric DNA is synthesized from a DNA template.158,159,160,161,162

    Nonetheless, the telomeres in circulating leukocytes and in mixtures of peripheral blood mononuclear cells are shorter in humans with many types of cancers,163 including gastrointestinal cancers, pancreatic cancer, bladder cancer, esophageal cancer, ovarian cancer, and lung cancer.151,158,164,165,166,167,168,169,170 Premalignant lesions and tumors in which telomere lengths in cancer cells have been reported to be shortened even in the presence of active telomerase within the cancer cells include glioblastoma multiforme,171 oral cancers,172 and a variety of gastrointestinal tract cancers,39,158 including esophageal squamous dysplasia and squamous cell carcinoma, Barrett’s esophagus and esophageal adenocarcinoma, atrophic gastritis and gastric adenocarcinoma, pancreatic intraepithelial neoplasia and pancreatic adenocarcinoma and intraductal papillary mucinous neoplasm, and adenomatous polyp and colorectal adenocarcinoma. Telomere length in tumor cells appears to shorten early in the development of some cancers (e.g., low grade astrocytomas,156 colorectal cancer,173 oral cancers,173 cervical cancer,173 prostate cancer,174 esophageal squamous cell carcinoma158,173 and the observation that telomere lengths in normal human esophageal158 and mammary gland175 epithelial cells adjacent to cancerous lesions are shorter than in normal epithelial cells from individuals who do not have cancerous lesions suggests that telomere length stabilization after a period of accelerated telomere attrition is an early initiating event in these cancers.

    The telomeres in circulating leukocytes and in mixtures of PBMC are shorter in the presence of many types of premalignant lesions and human cancers163 and shortened age-adjusted LTL may serve as a biomarker of increased predisposition to carcinogenesis.158,163,164 Although intralesional data are not available, age-adjusted LTL have been reported to be significantly shorter in individuals with oral premalignant lesions than in unaffected adults, and significantly shorter in patients with oral squamous cell carcinoma than in patients with premalignant lesions, and the risks of developing either lesions increased as age-adjusted LTL decreased.176 Similar relationships have been reported for age-adjusted LTL and Barrett’s esophagus and age-adjusted LTL and esophageal adenocarcinoma.177 Consistent with the hypothesis that risk for cancer and age-adjusted LTL are inversely correlated, the combined results obtained from 47,102 Danish men and women in the 20-year prospective Copenhagen City Heart and Copenhagen General Population Studies indicated that survival after any cancer diagnosis was directly correlated with age-adjusted LTL.45

    However, short LTL are not consistently associated with all cancers and accelerated telomere attrition may not be a general characteristic of precarcinogenesis. For example, in case-control studies nested within the all-male Physicians’ Health Study,178 the all-female Women’s Health Study179 and the male and female Norfolk cohort of the European Prospective Investigation into Cancer and nutrition study,180 age-adjusted LTL were not correlated with risk for developing colorectal cancer. In a prospective study of prostate cancer risk, the risk of developing prostate cancer was not associated with short LTL;40 in a New England case-control study, the risk for developing ovarian cancer was not correlated with age-adjusted LTL;43 and in a case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, the risk for developing glioma was not correlated with age-adjusted average buccal cell telomere length.15 In addition, premature telomere shortening is not a feature of noncancerous colonocytes adjacent to colon carcinoma cells with shortened telomeres66,181,182 or of noncancerous buccal mucosal cells adjacent to cancerous buccal mucosal cells with shortened telomeres.174 Furthermore, short age-adjusted LTL have been associated with reduced risk for developing cutaneous melanoma41 and short age-adjusted average telomere lengths in peripheral blood mononuclear cells have been associated with reduced risk for developing breast cancer.20

    Telomere Attrition and Age-Associated Conditions

    Replicative and cellular senescence are characteristic of human degenerative diseases.48,183 For example, cardiovascular diseases that involve endothelial disruption or injury (including atherosclerosis,63,64,65,69,184,185 coronary artery disease,51,186 arterial trauma,187 and abdominal aortic aneurysm17) are associated with accelerated telomere shortening in vascular endothelial cells, suggesting that the acceleration of telomere shortening may be a senescence-initiating response to endothelial injury. In addition, vascular smooth muscle cells harvested from human atherosclerotic plaques exhibit significantly shorter telomeres and significantly more oxidatively-damaged DNA than similar cells harvested from healthy tissue.188

    Accelerated systemic telomere attrition is an attribute of most forms of cardiovascular disease. Significantly shorter age-adjusted LTL have been reported in individuals with coronary heart disease,37 the odds of developing symptomatic peripheral arterial disease were inversely correlated with the age-adjusted LTL,38,90 with a 15% increase in risk for every 10% decrease from the population mean in the age-adjusted LTL,90 the maximum ultrasonically-measured thickness of the internal carotid artery wall (a biomarker for the extent of vascular disease189) was inversely correlated with the age-adjusted LTL,26 and the odds of experiencing a stroke or of developing hypertension were significantly increased among adults with age-adjusted LTL shorter than the population median.34,51

    When the data from a pair of 19-year prospective studies of 19,838 Danes (the Copenhagen City Heart Study; the Copenhagen General Population Study) were combined, it was calculated that for every 1000 base pair decrease in age-adjusted average leukocyte telomere length, the risk for experiencing a myocardial infarction increased 10% (95% CI: 1%, 19%), the risk for developing ischemic heart disease increased 6% (95% CI: 0%. 11%), and the risk for suffering premature death increased 9% (95% CI: 5%, 13%).190 Among 203 men in Salamanca, Spain, with symptomatic acute coronary syndrome and aged 50 to 75 years, the likelihood of survival was significantly lower for patients with age-adjusted LTL that were shorter than the median length for this cohort of men.191 A study of patients referred for coronary angiography found a direct correlation between age-adjusted average peripheral blood mononuclear cell telomere length and years of survival post-angiography.192

    Accelerated telomere attrition also may contribute to the etiology of osteoarthritis. Men and women in the TwinsUK Adult Twin Registry with hand osteoarthritis had significantly shorter leukocyte telomere lengths.193 In addition, senescent chondrocytes have been observed within osteoarthritic articular cartilage lesions.194 In articular cartilage tissues harvested from both morphologically healthy and osteoarthritic human femoral heads, the number of short telomeres (consisting of less than 1500 base pairs) per unit surface area was directly correlated with the degree of apparent cartilage degeneration.195 Human articular chondrocytes are sensitive to oxidative stress and respond to H2O2 with increased production of ROS and increased cellular senescence, reflected in shortening of telomeres, reduced replicative capacity, and suppressed production and increased degradation of extracellular matrix macromolecules.196

    Glucoregulation also is affected by telomere attrition. In the 5.5-year prospective observational Strong Heart Family Study of 2328 initially normoglycemic male and female Native Americans, the multivariate-adjusted hazard ratio for the development of type 2 diabetes was doubled for those individuals with the shortest age-adjusted LTL.197 Consistent with these data, type 2 diabetes was associated with significantly shorter age-adjusted LTL in a cross-sectional study of Caucasian, South Asian, and Afro-Carribean men and women.53 A meta-analysis of 9 case-control studies concluded that the risk for developing type 2 diabetes is 12% greater (95% CI: 0%, 25%) when the age-adjusted LTL is less than the average length among adults without impaired glucose homeostasis.198However, it is not clear whether telomere shortening disrupts glucoregulation or loss of glucoregulation produces an increase in systemic oxidative stress that disrupts telomere length homeostasis.199

    Human lung function is correlated with age-adjusted LTL. The results of a meta-analysis of the results of previously published case-control and cross-sectional studies indicated that the odds of developing chronic obstructive pulmonary disease (COPD) or asthma were inversely correlated with the age-adjusted LTL.200 In addition, both forced vital capacity and forced expiratory volume in one second were directly correlated with the age-adjusted LTL.200

    Cognitive abilities may be reflected in age-adjusted LTL. For example, among a group of men and women aged 33 to 79 years, performance on an intelligence test was correlated with age-adjusted LTL.35 In other studies, men 65 years old and older living in Hong Kong201 and women 19 to 78 years old living in the United Kingdom202 exhibited memory recall speed and accuracy that were correlated with age-adjusted LTL. Furthermore, among a group of men and women aged 64 to 75 years and exhibiting no signs of dementia, the degrees of subcortical cerebral atrophy (a correlate of cognitive decline) and of white matter hyperintensities (a correlate of cerebral infarcts) were each inversely correlated with the age-adjusted LTL.203

    Diet, Nutritional Antioxidants, Telomere Attrition, and Replicative Senescence

    Because exposure to ROS-induced oxidative stress accelerates telomere shortening,123,124 and telomere shortening is associated with accelerated biological aging and premature replicative senescence,123,124,204,205,206 reducing the generation of ROS and increasing antioxidant availability should provide potent mechanisms to retard telomere attrition, decelerate cellular aging, and delay the onset of replicative senescence.61,206,207 For example, in a short nonblinded, randomized trial, the effects of 3 diets on telomere attrition were examined in men and women over 65 years old.208 Serum drawn from the subjects while consuming the diet with the lowest content of saturated fatty acids was associated with the slowest rate of telomere attrition when the serum was added to the culture medium of human umbilical vein endothelial cells. This finding is consistent with results from several cross-sectional studies in which the age-adjusted LTL was inversely correlated with habitual daily intake of saturated fatty acids,48,49,209,210 and a small 5-year prospective intervention in which a reduction in saturated fatty acid intake was associated with arrest of age-associated telomere shortening.211

    There also is evidence that dietary enhancement of systemic antioxidant capacity can beneficially influence cellular and biological aging. In retrospective observational studies, age-adjusted LTL was significantly shortened among those subjects with the smallest routine daily intakes of fruits39,48,49,209 and was directly correlated with total daily fruit and vegetable intakes.21,48,49,209 In the cross-sectional Sister Study, the mean multivariate-adjusted leukocyte telomere length was directly correlated with the daily consumption of a multivitamin supplement and, individually, with the daily intakes from foods of vitamin A, vitamin C, vitamin E, and folate.212 In agreement with the results of the Sister Study,212 a growing body of scientific evidence also supports the hypothesis that the addition of supplemental nutrients can contribute to a reduction in the rates of cellular and biological aging.

    α-Lipoic Acid

    α-Lipoic acid (5-(1,2-dithiolan-3-yl)-pentanoic acid) is a naturally-occuring component of human mitochondria that is able to penetrate both cell membranes and aqueous compartments, allowing it to act as a multi-purpose nonenzymatic antioxidant that protects mitochondria and surrounding cellular elements from oxidation by the free radicals produced by mitochondria during oxidative metabolism.213,214,215,216,217,218,219,220, 221,222,223,224,225 The sulfhydryl groups on the α -lipoic acid molecule provide strong antioxidant potency, directly exchanging free protons for free radical electrons in lipophillic environments (e.g., biological membranes) and exchanging free protons with hydroxyl ions and water during the deactivating reduction of free radical electrons in aqueous environments (e.g., biological fluids).214

    In addition to reducing ROS, α -lipoic acid can recycle (reduce) other nonenzymatic antioxidants after they have become oxidized, prompting the descriptor, “antioxidant of antioxidants.”226,228 α -Lipoic acid also directly stimulates increased activities of a set of endogenous antioxidant enzymes, including superoxide dismutase (SOD), catalase, glutathione peroxidase, and heme oxygenase-1 (HO-1).216,220,223,229

    α -Lipoic acid can delay the onset of cellular senescence by downregulating the phosphorylation of Rb in cells with oxidatively damaged DNA, arresting cell cycle progression and redirecting the cells toward apoptotic death.230 In addition, the initiation of oxidative damage to DNA can be prevented by α -lipoic acid, which has been shown to inhibit the formation of 8-OHdG by the α,β-unsaturated aldehydes created during the free radical-induced oxidation of the membrane-associated ω-3 polyunsaturated fatty acid, docosahexaenoic acid (DHA).231


    Astaxanthin is a red carotenoid pigment found in salmon, crabs, and shrimp.232, 233 Following the consumption of astaxanthin by adults, peak plasma astaxanthin concentrations of 10-8M to 10-6M have been observed; these peak concentrations were proportional to the amount of astaxanthin that was ingested.234,235,236,237,238 Absorbed astaxanthin is taken up by most tissues of the body, including the kidneys, heart, liver, skin, skeletal muscle, eyes, lungs, brain, brain stem, and erythrocytes.239,240,241,242,243,244,245

    The structure of astaxanthin confers extremely potent antioxidant powers. Its conjugated polyene structure allows astaxanthin to intercalate within the lipid bilayers of biological membranes246 while its terminal hydroxylated ring structures remain exposed on the inner and outer surfaces of the membranes,246,247 further increasing the number of free radical electrons that can be quenched by each molecule of astaxanthin247 and preventing oxidative degradation of membrane structural integrity.248,249,250 The spontaneous reactions of astaxanthin with oxidizing

    ROS240,246,251,252,253,254,255,256,257,258,259,260,261,262,263,264,265,266,267,268,269 allow astaxanthin to exhibit free radical quenching potency that is double that of β-carotene,246,255,270,271 2 to 5 times that of DHA or eicosapentaenoic acid (EPA),272 about 100-fold greater than that of α -tocopherol,255,256,257 and approximately 6000 times the potency of ascorbic acid.257 Astaxanthin also inhibits ROS formation by inhibiting spontaneous lipid peroxidation,248,2, 49,250,259,273,274,275 peroxyl radical-induced lipid peroxidation,259,276 iron-induced oxidation of membrane phospholipids,277.280 and the oxidation of low-density lipoprotein (LDL) particles.281,282 Furthermore, exposure to astaxanthin increased the activities of the antioxidant enzymes, SOD, catalase, glutathione peroxidase, and glutathione reductase, and the intracellular concentration of the intracellular antioxidant, reduced glutathione, in human umbilical vein endothelial cells,280,283 human neuroblastoma cells,275 and murine retinal ganglion cells266

    Absorbed astaxanthin is an active antioxidant in humans. Adolescent male soccer players exhibited significantly increased serum antioxidant capacity after 90 days of daily dietary supplementation with 4 mg of astaxanthin.282 After supplementing their diets for 2 weeks with 6 mg of astaxanthin daily, men and women experienced a significant increase in the superoxide anion scavenging activity in the visual aqueous humor.284 Supplementation with 20 mg of astaxanthin for 3 weeks238 or 12 weeks285 produced significant reductions in the plasma concentrations of the lipid peroxidation products, malondialdehyde (MDA) and F2-isoprostane, reflecting reductions in whole-body cellular lipid peroxidation,286,287 and significant increases in measured total circulating antoxidant capacity in 2 groups of overweight and obese men and women. Similarly, after 8 weeks of consuming 2 mg of astaxanthin daily, a group of healthy postmenopausal women exhibited a significantly greater increase in total plasma antioxidant status than was elicited by placebo, as well as a significantly greater reduction in the plasma concentration of thiobarbituric acid reactive substances (TBARS; mixed reaction products of nonenzymatic oxidative lipid peroxidation).283,288 Another group of healthy postmenopausal women exhibited a significant increase in total circulating antioxidant activity after consuming 12 mg of astaxanthin daily for 8 weeks.289

    Together these data indicate that astaxanthin reduces the level of oxidative stress throughout the body. Consistent with the hypothesis that oxidative stress increases the oxidative modification of DNA, shortens telomeres and promotes cellular senescence, while a reduction in systemic oxidative stress attenuates or reverses these responses, geriatric dogs fed 20 mg of astaxanthin daily for 16 weeks290 and healthy young women who consumed 2 mg of astaxanthin daily for 8 weeks291 experienced significant decreases in whole-body DNA oxidation.

    ω -3 Fatty Acids

    EPA (20:5 ω 3) and DHA (22:6 ω 3) are very long-chain polyunsaturated fatty acids that are dietary essentials because α -linolenic acid (18:3 ω 3), the immediate precursor of EPA, cannot be synthesized de novo in humans and must be consumed in the diet.292, 293, 294 However, although it is the only known function of α -linolenic acid,295,296,297 the conversion of α -linolenic acid to EPA is inefficient298 299 300 3012 302 and may not be adequate to fulfill physiological requirements for EPA and DHA.303 A small, biologically insignificant amount of DHA can be produced in humans by sequential elongation and desaturation of EPA.292,293,294

    EPA and DHA contribute to telomere maintenance. In a 5-year prospective study of ambulatory outpatients with stable coronary artery disease, the multivariate-adjusted rate of leukocyte telomere shortening was inversely correlated with the combined whole blood concentrations of EPA and DHA.304 In a double-blind, randomized placebo-controlled trial, daily supplementation with 180 mg of EPA plus 120 mg of DHA for 3 months reduced serum 8-OHdG concentrations and increased total circulating antioxidant capacity in cigarette smokers.305 In another double-blind, randomized placebo-controlled trial, during which subjects consumed 2085 mg of supplemental EPA plus 348 mg of DHA daily for 4 months, lymphocyte telomere length was directly correlated with the increase in the combined plasma concentrations of EPA and DHA.306 DHA may be the telomerically-relevant nutrient; among men and women over 65 years old, increased erythrocyte DHA content accompanying 6 months of increased DHA intake was inversely correlated with the rate of telomere shortening in whole blood.307


    trans-Resveratrol (trans-3,4’,5-trihydroxystilbene) is a polyphenol produced by many plants, including raspberries, blueberries, grapeskins, peanuts, and certain pine trees.207,308,309,310 Adding trans-resveratrol to the diet of laboratory animals or to the growth medium of cell cultures has been shown to support a number of physiologic systems,311 including fatty acid mobilization from adipose stores,312 energy metabolism in skeletal muscle313, 314, 315 and articular cartilage,316 reduction of oxidative damage and inflammation in metabolically active tissues,313,316,317,318,319,320,321,322,323,32, 4,325 and mitochondrial biogenesis with accelerated ATP regeneration and increased aerobic capacity, exercise tolerance, and endurance.326, 327 Rats fed trans-resveratrol at a rate of 20 mg to 50 mg per kg body weight (100 kg adult human equivalent daily intake: 30 to 80 mg328) increased the survival of hypoxia-challenged cardiac muscle,329,330 attenuated cigarette smoke-induced and cardiovascular disease-producing loss of compliance by the carotid arteries,331,332 prevented experimentally-induced autoimmune myocarditis,333 stimulated the growth of new capillaries within the myocardium,334 and attenuated the expression of biomarkers of aging in the heart.335

    Other components of the cardiovascular system also benefit from trans-resveratrol consumption. Arterial endothelial cells harvested from rats exhibit attenuation of cigarette smoke-induced generation of ROS and secretion of the pro-inflammatory cytokines, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), in the presence of 10-4Mtrans-resveratrol.336 At a lower concentration (10-5M), trans-resveratrol has attenuated oxidative DNA fragmentation and cellular death induced by TNF-α, H2O2, and oxidized LDL in rat arterial endothelial cells via increased expression of glutathione peroxidase, catalase, and heme oxygenase-1 (HO-1).337

    Evidence from cultured human lung epithelial cells,338 vascular endothelial cells339 and human platelets308,340, 341, 342, 343 indicates that trans-resveratrol (10-5M) stimulates glutathione synthesis and reduces the generation of ROS. Exposure of human arterial endothelial cells to trans-resveratrol (10-7M) attenuates H2O2-induced endothelial cell adhesion to monocytes.344trans-Resveratrol (10-8M) also inhibits superoxide production by human neutrophils345 and vascular endothelial cells,346 preventing ROS production by vascular smooth muscle cells.347trans-Resveratrol crosses the blood-brain barrier348 and physiologic and near-physiologic concentrations of trans-resveratrol (10-7M to 10-5M) inhibit the neuronal production of ROS.349,350, 351,352

    These properties of trans-resveratrol combine to retard the rate of cellular senescence. Human peritoneal mesothelial cells exposed to trans-resveratrol (0.5 x 10-6M) experienced increased recruitment into cell cycle progression and replication, reduced telomere attrition, increased SOD activity, decreased oxidative damage to DNA with less formation of 8-OHdG, upregulation of DNA repair enzymes, and an increased number of cell divisions before becoming senescent.353


    N-acetylcysteine is an acetylated variant and precursor of the amino acid, L-cysteine, serves as a precursor to glutathione (an endogenous reducer of lipid peroxides283), and is associated with free radical scavenging activity that may be related to its sulfhydryl groups.354 Human trabecular meshwork cells grown in culture with a high concentration of oxidizing glycated albumin produced increased amounts of superoxide and total ROS and exhibited evidence of accelerated telomere attrition; these effects were attenuated when N-acetylcysteine was added to the culture medium.355 The addition of N-acetylcysteine to cultures of human lymphocytes exposed to irradiation356 and human astrocytoma cells infected with the human immunodeficiency virus357 has attenuated increases in ROS production and decreases in the ratio of reduced to oxidized glutathione while maintaining longer telomere lengths. In addition, human arterial endothelial cells and human pluripotent stem cells respond to N-acetylcysteine with reduced production of ROS, less oxidative modification of DNA, a decrease in the number of genomic aberrations, increased telomerase activity, prevention of cell doubling-associated telomere attrition, delayed upregulation of the DDR pathway, and increased replicative capacity.113,354,358,359 These responses are consistent with the conclusion that N-acetylcysteine delays cellular aging.

    Methylsulfonyl methane

    Methylsulfonyl methane (MSM) is an organic sulfur-containing compound that occurs naturally in a variety of fruits, vegetables, grains, and animals.360 The ingestion of MSM stimulates glutathione activity and reduces the lipid peroxidation caused by exercise. Sport horses given supplemental MSM during a season of competition exhibited significant increases in the plasma concentration of reduced glutathione and in the plasma activities of glutathione peroxidase, glutathione reductase, and glutathione transferase, and a significant decrease in the plasma concentration of total lipid peroxides.361 Consistent with that report, healthy men participating in a randomized double-blind, placebo-controlled trial experienced significantly greater plasma concentrations of reduced glutathione and significantly lower plasma concentrations of lipid peroxidation products and protein carbonyls at the end of a 14 km run following 10 days of dietary supplementation with 50 mg of MSM per kg bodyweight.362

    Vitamin C

    Vitamin C is an essential nutrient that must be supplied through the diet because humans lack the enzyme, gulonolactone oxidase, and therefore cannot synthesize vitamin C de novo.363Ascorbate, the dominant form of vitamin C in humans, contains 2 enolic hydrogen atoms that provide electrons that are available for nonenzymatic transfer to ROS. The availability of two reducing equivalents per molecule of ascorbate provides the basis for the antioxidant properties of vitamin C, which readily scavenges ROS.364Oxidized ascorbate can be reduced back to ascorbate by transfer of its free radical electron to another receptor molecule or can be further oxidized to dehydroascorbate. In turn, dehydroascorbate can be recycled to ascorbate or can be converted into the excretory end product, 2,3-diketogulonate.364

    In the cross-sectional Austrian Stroke Prevention Study, age-adjusted LTL was directly correlated with the plasma ascorbate concentration in elderly men and women.365 Articular chondrocytes harvested from patients with osteoarthritis responded to ascorbic acid with increased production of extracellular matrix macromolecules, decreased degradation of extracellular matrix macromolecules, decreased production of ROS, and improved maintenance of replicative capacity and telomere length.196 These reports are consistent with a positive association between vitamin C intake, systemic antioxidant status, and telomere preservation.

    Vitamin D

    Vitamin D status, reflected in the serum concentration of 25-hydroxycholecalciferol (25-OHD3),366367 itself a reflection of vitamin D intake, 368,369 affects human telomere attrition and cellular aging. For example, in a cross-sectional study of women aged 18 to 79 years in the UK, age-adjusted LTL was directly correlated with the serum 25-OHD3 concentration and, compared to concentrations greater than 50 ng/mL, concentrations less than 25 ng/mL were associated with excessive telomere shortening equivalent to 5 additional years of telomere (and cellular) aging.370 In another cross-sectional study, among vitamin D-deficient men and women, age-adjusted telomere attrition in PBMC was directly correlated with the degree of vitamin D deficiency.371 In contrast, in a double-blind, randomized, placebo-controlled trial, 4 months of dietary supplementation with 60,000 IU of vitamin D once monthly increased the serum 25-OHD3 concentration and was associated with significantly less telomere attrition in PBMC.372

    Vitamin E

    Vitamin E is a chain-breaking lipophillic antioxidant that reduces the lipid peroxyl radical produced during lipid peroxidation, interrupting self-sustaining sponaneous lipid peroxidation in a chain termination event.283 By arresting lipid peroxidation cascades, vitamin E also slows human telomere attrition and cellular aging.Freshly harvested human skin fibroblasts grown in ex vivo culture exhibited increased resistance to H2O2-induced oxidative modification of DNA and acceleration of telomere attrition in the presence of 10-5M α -tocopherol,373 a physiologic concentration found in the plasma of adults who do not consume supplemental vitamin E.374

    γ -Tocotrienol

    The tocotrienols (α-,β-, γ -, δ -) are a group of naturally occurring, bioavailable, fat-soluble derivatives of vitamin E that exhibit antioxidant potency similar to or greater than that of α tocopherol.375 In a series of experiments in which skin fibroblasts were freshly harvested from young human foreskins and grown in cell culture until they reached senescence, γ -tocotrienol alone,376, 377 or as a component of a mixture of tocotrienols obtained from Malaysian palm oil,378, 379 increased the expression of antioxidant enzymes and of proteins required for cell proliferation; decreased ROS production, oxidative damage to DNA, and senescence-associated telomere shortening; and increased the number of cells that were released from cell cycle arrest. When similarly-obtained cells were cultured with H2O2 and γ-tocotrienol, telomere shortening and cell cycle arrest associated with increased intracellular oxidative stress were attenuated .380,381 Coincubation with γ -tocotrienol also attenuated H2O2-induced cell cycle arrest in cultured young human myoblasts.382 These data demonstrate that γ -tocotrienol retards telomere attrition and cell aging.


    The xanthophyllic carotenoid phytonutrient, lutein, accumulates in the macula lutea of the human retina.383 In addition to causing the yellow color of that part of the eye, lutein protects the retina from the oxidizing effects of some of the ultraviolet light entering the eye.383 In healthy women, compared to placebo, dietary supplementation with lutein (10 mg daily) for 12 weeks reduced by half the degree of epidermal lipid peroxidation while the resistance to ultraviolet light-induced erythema was increased 4- to 5-fold.384 The antioxidant properties of lutein were evident in the cross-sectional Austrian Stroke Prevention Study, in which age-adjusted LTL was directly correlated with the serum lutein concentration in elderly men and women.365 These results demonstrate that dietary lutein increases systemic antioxidant capacity and resistance to ultraviolet light-induced oxidative damage and contributes to telomere preservation.

    Superoxide dismutase

    SOD is an endogenous enzyme that reduces the superoxide anion to produce H2O2 (which is then reduced to H2O and O2 by catalase).283,385 While the superoxide anion stimulates the oxidative drive toward cellular senescence,130 its detoxification can promote delay of cellular senescence. For example, exposing human fibroblasts to exogenous SOD significantly reduced both the production of lipid peroxides and the rate of subsequent telomere shortening.386 There also is a report that cells that are approaching senescence can be “cleared” by SOD-initiated conversion to the apoptotic pathway.387


    Cellular oxidative stress accelerates telomere attrition and promotes cellular aging. Oxidatively damaged DNA predisposes individual cells to become senescent. The accumulation of senescent cells progressively impairs physiological functioning, is associated with degenerative diseases, and characterizes biological aging. Premature biological aging impairs health and diminishes the quality of life. Increasing the intakes of antioxidant-rich fruits and vegetables and supplementing the diet with α -lipoic acid, astaxanthin, EPA, DHA, trans-resveratrol, N-acetylcysteine, methylsulfonylmethane, lutein, vitamin C, vitamin D, vitamin E, and γ -tocotrienol may decrease cellular oxidative stress and decelerate biological aging.


    This project was funded by Youngevity International, Inc., Chula Vista, CA.

    Conflict of Interest

    This project was funded by Youngevity International, Inc., Chula Vista, CA, a manufactiurer of dietary supplements, and with whom Dr. Glade maintains a consultancy.


    8-OHdG, 8-oxyguanosine;

    8-oxo-dG, 8-oxyguanosine;

    25-OHD3, 25-hydroxycholecalciferol;

    ALT, alternative lengthening of telomeres;

    CDK4, cyclin-dependent kinase-4;

    CDK6, cyclin-dependent kinase-6;

    CDKN1A, cyclin-dependent kinase inhibitor 1A;

    CI, confidence interval;

    COPD, chronic obstructive pulmonary disease;

    Dab2, diasabled adaptor protein 2;

    DDR, DNA damage response;

    DDT, dichlorodiphenyltrichloroethane; 1,1,-trichloro-2,2-bis-chlorophenylethane;

    DHA, docosahexaenoic acid;

    EPA, eicosapentaenoic acid;

    GADD45, growth arrest and DNA-damage inducible protein 45;

    GRB2, growth factor receptor-bound protein 2;

    H2O2, hydrogen peroxide;

    HNE, 4-hydroxynonenal;

    HO-1, heme oxygenase-1;

    LDL, low-density lipoprotein;

    LTL, mean leukocyte telomere length;

    MAPK14, mitogen-activated protein kinase 14;

    MDA, malondialdehyde;

    MSM, methylsulfonylmethane;

    p21, cyclin-dependent kinase inhibitor 1A;

    p53, tumor suppressor protein 53;

    PBMC, peripheral blood mononuclear cells;

    Rb, retinoblastoma tumor suppressor protein;

    ROS, reactive oxygen species;

    Src, steroid receptor coactivator;

    SOD, superoxide dismutase;

    TBARS, thiobarbituric acid reactive substances;

    TERC, RNA component of telomerase;

    TERT, catalytic subunit of telomerase;

    TGF-β, transforming growth factor-β;

    TGFBR2, transforming growth factor-β receptor 2;

    TNF-α, tumor necrosis factor-α

    Note: Prior to undertaking a program of dietary supplementation, individuals should consult with a professional nutritionist or other healthcare professional trained in nutritional therapeutics.


    1.R K Moyzis, J M Buckingham, L S Cram, Dani M, L. (1988) A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. , Proc Natl. Acad. Sci. U. S. A 85, 6622-6626.
    2.Diotti R, Loayza D. (2011) Shelterin complex and associated factors at human telomeres. , Nucleus 2, 119-135.
    3.T de Lange. (2005) The protein complex that shapes and safeguards human telomeres. , Genes Dev 19, 2100-2110.
    4.Galati A, Micheli E, Cacchione S. (2013) Chromatin structure in telomere dynamics. doi10.3389/fonc.2013.00046. Front. Oncol
    5.Subramanian L, T M Nakamura. (2010) To fuse or not to fuse: How do checkpoint and DNA repair proteins maintain telomeres?. , Front. Biosci 15, 1105-1118.
    6.R T Calado, N S Young. (2009) Telomere diseases. , N. Engl. J. Med 361, 2353-2365.
    7.McClintock B. (1941) The stability of broken ends of chromosomes in Zea mays. , Genetics 26, 234-282.
    8.Hayflick L. (2000) The illusion of cell immortality. , Br. J. Cancer 83, 841-846.
    9.Daniali L, Benetos A, Susser E, J D Kark, Labat C. (2013) Telomeres shorten at equivalent rates in somatic tissues of adults. doi: 10.1038/ncomms2602. , Nat. Commun
    10.Ahmad S, Heraclides A, Sun Q, Elgzyri T, Rönn T. (2012) Telomere length in blood and skeletal muscle in relation to measures of glycaemia and insulinaemia. , Diabet. Med 29, 377-381.
    11.Bendix L, Thinggaard M, Fenger M, Kolvraa S, Avlund K. (2014) Longitudinal changes in leukocyte telomere length and mortality in humans. , J. Gerontol. A Biol. Sci. Med. Sci 69, 231-239.
    12.Yamaguchi H, R T Calado, Ly H, Kajigaya S, G M Baerlocher. (2005) Mutations in TERT, the gene for telomerase reverse transcriptase, in aplastic anemia. , N. Engl. J. Med 352, 1413-1424.
    13.Muezzinler A, A K Zaineddin, Brenner H. (2013) A systematic review of leukocyte telomere length and age in adults. Ageing Res. , Rev 12, 509-519.
    14.R W Frenck, E H Blackburn, K M Shannon. (1998) The rate of telomere sequence loss in human leukocytes varies with age. , Proc. Natl. Acad. Sci. U. S. A 95, 5607-5610.
    15.Lindsey J, N I McGill, Lindsey L A, D K Green, H J Cooke. (1991) In vivo loss of telomeric repeats with age in humans. , Mutat. Res 256, 45-48.
    16.Walcott F, Rajaraman P, S M Gadalla, P D Inskip, M P Purdue. (2013) Telomere length and risk of glioma. , Cancer Epidemiol 37, 935-938.
    17.Cafueri G, Parodi F, Pistorio A, Bertolotto M, Ventura F. (2012) Endothelial and smooth muscle cells from abdominal aortic aneurysm have increased oxidative stress and telomere attrition. doi: 10.1371/journal.pone.0035312. PLoS. One .
    18.Nordfjäll K, Svenson U, K F Norrback, Adolfsson R, Lenner P. (2009) The individual blood cell telomere attrition rate is telomere length dependent. doi: 10.1371/journal.pgen.1000375. PLoS. Genet
    19.Svenson U, Nordfjäll K, Baird D, Roger L, Osterman P. (2011) Blood cell telomere length is a dynamic feature. doi:. 10.1371/journal.pone.0021485. PLoS. One
    20.Svenson U, Nordfjäll K, Stegmayr B, Manjer J, Nilsson P. (2008) Breast cancer survival is associated with telomere length in peripheral blood cells. , Cancer Res 68, 3618-3623.
    21.Mirabello L, W Y Huang, J Y Wong, Chatterjee N, Reding D. (2009) The association between leukocyte telomere length and cigarette smoking, dietary and physical variables, and risk of prostate cancer. , Aging Cell 8, 405-413.
    22.Aubert G, P M Lansdorp. (2008) Telomeres and aging. , Physiol. Rev 88, 557-579.
    23.Chen W, Kimura M, Kim S, Cao X, Srinivasan S R. (2011) Longitudinal versus cross-sectional evaluations of leukocyte telomere length dynamics: Age-dependent telomere shortening is the rule. , J. Gerontol. A Biol. Sci. Med. Sci 66, 312-319.
    24.K I Aston, S C Hunt, Susser E, Kimura M, Factor-Litvak P. (2012) Divergence of sperm and leukocyte age-dependent telomere dynamics: Implications for male-driven evolution of telomere length in humans. , Mol. Hum. Reprod 18, 517-522.
    25.Steenstrup T, J V Hjelmborg, L H Mortensen, Kimura M, Christensen K. (2013) Leukocyte telomere dynamics in the elderly. , Eur. J. Epidemiol 28, 181-187.
    26.J L Sanders, A L Fitzpatrick, R M Boudreau, Arnold A M, Aviv A. (2012) Leukocyte telomere length is associated with noninvasively measured age-related disease: The Cardiovascular Health Study. , J. Gerontol. A Biol. Sci. Med. Sci 67, 409-416.
    27.Adler N, M S Pantell, O'Donovan A, Blackburn E, Cawthon R. (2013) Educational attainment and late life telomere length in the Health, Aging and Body Composition Study. , Brain Behav. Immun 27, 15-21.
    28.Bansal N, M A Whooley, Regan M, C E Mc, J H Ix. (2012) Association between kidney function and telomere length: The Heart and Soul Study. , Am. J. Nephrol 36, 405-411.
    29.Kim S, Bi X, Czarny-Ratajczak M, Dai J, D A Welsh. (2012) Telomere maintenance genes SIRT1 and XRCC6 impact age-related decline in telomere length but only SIRT1 is associated with human longevity. , Biogerontology 13, 119-131.
    30.Deelen J, Beekman M, Codd V, Trompet S, Broer L. (2014) Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers. doi: 10.1093/ije/dyt267. , Int. J. Epidemiol
    31.Denham J, C P Nelson, B J O', S A Nankervis, Denniff M. (2013) Longer leukocyte telomeres are associated with ultra-endurance exercise independent of cardiovascular risk factors. doi;. 10.1371/journal.pone.0069377. PloS. One
    32.A L Fitzpatrick, R A Kronmal, Kimura M, J P Gardner, B M al.(2011) Leukocyte telomere length and mortality in the Cardiovascular Health Study. , J. Gerontol. A Biol. Sci. Med. Sci 66, 421-429.
    33.L S Honig, M S Kang, Schupf N, J H Lee, Mayeux.R.(2012) Association of shorter leukocyte telomere repeat length with dementia and mortality. , Arch. Neurol 69, 1332-1339.
    34.Jiang X, Dong M, Cheng J, Huang. (2013) Decreased leukocyte telomere length (LTL) is associated with stroke but unlikely to be causative, doi: 10.1371/journal.pone.0068254. PLoS. One
    35.E M Kingma, P de Jonge, Harst P van der, Ormel J, J G Rosmalen. (2012) The association between intelligence and telomere length: A longitudinal population based study. doi: 10.1371/journal.pone.0049356. PLoS. One
    36.Kozlitina J, C K Garcia. (2012) Red blood cell size is inversely associated with leukocyte telomere length in a large multi-ethnic population. doi: 10.1371/ PLoS. One
    37.C G Maubaret, K D Salpea, Jain A, J A Cooper, Hamsten al.(2010) Telomeres are shorter in myocardial infarction patients compared to healthy subjects: Correlation with environmental risk factors. , J. Mol. Med 88, 785-794.
    38.Raschenberger J, Kollerits B, Hammerer-Lercher A, Rantner B, Stadler M. (2013) The association of relative telomere length with symptomatic peripheral arterial disease: Results from the CAVASIC study. , Atherosclerosis 229, 469-474.
    39.Hou L, Savage S A, M J Blaser, Perez-Perez G, Hoxha M. (2009) Telomere length in peripheral leukocyte DNA and gastric cancer risk. , Cancer Epidemiol. Biomarkers. Prev 18, 3103-3109.
    40.L M Hurwitz, C M Heaphy, C E Joshu, W B Isaacs, Konishi al.(2014) Telomere length as a risk factor for hereditary prostate cancer. , Prostate 74, 359-364.
    41.Nan H, Du M, I De Vivo, J E Manson, Liu S. (2011) Shorter telomeres associate with a reduced risk of melanoma development. , Cancer Res 71, 6758-6763.
    42.Qu S, Wen W, X O Shu, W H Chow, Y B Xiang. (2013) Association of leukocyte telomere length with breast cancer risk: Nested case-control findings from the Shanghai Women's Health Study. , Am. J. Epidemiol 177, 617-624.
    43.K L Terry, Tworoger S S, A F Vitonis, Wong J, Titus-Ernstoff L. (2012) Telomere length and genetic variation in telomere maintenance genes in relation to ovarian cancer risk. Cancer Epidemiol. Biomarkers Prev. 21, 504-512.
    44.Wang S, Chen Y, Qu F, He S, Huang X. (2014) Association between leukocyte telomere length and glioma risk: A case-control study. , Neuro. Oncol 16, 505-512.
    45.Weischer M, B G Nordestgaard, R M Cawthon, J, Tybjærg-Hansen A. (2013) Short telomere length, cancer survival, and cancer risk in 47102 individuals. , J. Natl. Cancer Inst 105, 459-468.
    46.Mirabello L, Garcia-Closas M, Cawthon R, Lissowska J, L A Brinton. (2010) Leukocyte telomere length in a population-based case-control study of ovarian cancer: A pilot study. , Cancer Causes Control 21, 77-82.
    47.Benetos A, J D Kark, Susser E, Kimura M, Sinnreich R. (2013) Tracking and fixed ranking of leukocyte telomere length across the adult life course. , Aging Cell 12, 615-621.
    48.Boccardi V, Esposito A, M R Rizzo, Marfella R, Barbieri M. (2013) Mediterranean diet, telomere maintenance and health status among elderly. doi: 10.1371/journal.pone.0062781. PLoS. One
    49.J A Nettleton, Diez-Roux A, N S Jenny, A L Fitzpatrick, D R Jacobs. (2008) Dietary patterns, food groups, and telomere length in the Multi-Ethnic Study of Atherosclerosis (MESA). , Am. J. Clin. Nutr 88, 1405-1412.
    50.D J Kurz, Kloeckener-Gruissem B, Akhmedov A, F R Eberli, Bühler I. (2006) Degenerative aortic valve stenosis, but not coronary disease, is associated with shorter telomere length in the elderly. , Arterioscler. Thromb. Vasc. Biol 26, 114-117.
    51.A L Fitzpatrick, R A Kronmal, J P Gardner, B M Psaty, N S Jenny. (2007) Leukocyte telomere length and cardiovascular disease in the Cardiovascular Health Study. , Am. J. Epidemiol 165, 14-21.
    52.Huzen J, L S Wong, D J vanveldhuisen, N J Samani, A H Zwinderman. (2014) Telomere length loss due to smoking and metabolic traits. , J. Intern. Med 275, 155-163.
    53.K D Salpea, P J Talmud, J A Cooper, C G Maubaret, J W Stephens. (2010) Association of telomere length with type 2 diabetes, oxidative stress and UCP2 gene variation. , Atherosclerosis 209, 42-50.
    54.Vos-Houben J M de, N R Ottenheim, Kafatos A, Buijsse B, G J Hageman. (2012) Telomere length, oxidative stress, antioxidant status in elderly men in Zutphen and Crete.Mech. Ageing Dev. 133, 373-377.
    55.L S Burke, P L Hyland, R M Pfeiffer, Prescott J, Wheeler W. (2013) Telomere length and the risk of cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations. doi: 10.1371/journal.pone.0071121 PLoS. , One
    56.Vaziri H, Schächter F, Uchida I, Wei L, Zhu X. (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. , Am. J. Hum. Genet 52, 661-66772.
    57.Y L Zheng, Zhou X, C A Loffredo, P G Shields, Sun B. (2011) Telomere deficiencies on chromosomes 9p, 15p, 15q and Xp: Potential biomarkers for breast cancer risk. , Hum. Mol. Genet 20, 378-386.
    58.Song Z, G von Figura, Liu Y, J M Kraus, Torrice C. (2010) Lifestyle impacts on the aging-associated expression of biomarkers of DNA damage and telomere dysfunction in human blood. , Aging Cell 9, 607-615.
    59.Gutmajster E, Witecka J, Wyskida M, Koscinska-Marczewska J, Szwed M.(October7,2013) Telomere length in elderly Caucasians weakly correlates with blood cell counts. doi: 10.1155/2013/153608 Scientific World Journal.
    60.Vaziri H, Dragowska W, R C Allsopp, Thomas T E, C B Harley. (1994) Evidence for a mitotic clock in human hematopoietic stem cells: Loss of telomeric DNA with age. , Proc. Natl. Acad. Sci. U. S. A 91, 9857-9860.
    61.E M Buckingham, A J Klingelhutz. (2011) The role of telomeres in the ageing of human skin. , Exp. Dermatol 20, 297-302.
    62.R C Allsopp, Vaziri H, Patterson C, Goldstein S, E V Younglai. (1992) Telomere length predicts replicative capacity of human fibroblasts. , Proc. Natl. Acad. Sci. U. S. A 89, 10114-10118.
    63.Ogami M, Ikura Y, Ohsawa M, Matsuo T, Kayo S. (2004) Telomere shortening in human coronary artery diseases. , Arterioscler. Thromb. Vasc. Biol 24, 546-550.
    64.Okuda K, M Y Khan, Skurnick J, Kimura M, Aviv H. (2000) Telomere attrition of the human abdominal aorta: Relationships with age and atherosclerosis. , Atherosclerosis 152, 391-398.
    65.Aviv H, M Y Khan, Skurnick J, Okuda K, Kimura M. (2001) Age dependent aneuploidy and telomere length of the human vascular endothelium. , Atherosclerosis 159, 281-287.
    66.Ishikawa N, Nakamura K, Izumiyama N, Aida J, Sawabe M. (2012) Telomere length dynamics in the human pituitary gland: Robust preservation throughout adult life to centenarian age. , Age 34, 795-804.
    67.Rampazzo E, Bertorelle R, Serra L, Terrin L, Candiotto C. (2010) Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers. , Br. J. Cancer 13, 1300-1305.
    68.Jeyapalan J C, Ferreira M, J M Sedivy, Herbig U. (2007) Accumulation of senescent cells in mitotic tissue of aging primates. , Mech. Ageing Dev 128, 36-44.
    69.Chang E, C B Harley. (1995) Telomere length and replicative aging in human vascular tissues. , Proc. Natl. Acad. Sci. U. S. A 92, 11190-11194.
    70.Kuilman T, Michaloglou C, W J Mooi, D S Peeper. (2010) The essence of senescence. , Genes Dev 24, 2463-2479.
    71.J W Harper, S J Elledge. (2007) The DNA damage response: Ten years after. , Mol. Cell 28, 739-745.
    72.Correia-Melo C, Hewitt G, J F Passos. (2014) Telomeres, oxidative stress and inflammatory factors: Partners in cellular senescence?. doi: 10.1186/2046-2395-3-1. Longev. Healthspan
    73.M S Huen, Chen J. (2010) Assembly of checkpoint and repair machineries at DNA damage sites. , Trends Biochem. Sci 35, 101-108.
    74.X Q Ge, Blow J J. (2010) Chk1 inhibits replication factory activation but allows dormant origin firing in existing factories. , J. Cell. Biol 191, 1285-1297.
    75.Jacobs J J, T de Lange. (2005) p16INK4a as a second effector of the telomere damage pathway. , Cell Cycle 4, 1364-1368.
    76.Herbig U, Ferreira M, Condel L, Carey D, J M Sedivy. (2006) Cellular senescence in aging primates. , Science 311, 1257.
    77.Ohtani N, Yamakoshi K, Takahashi A, Hara E. (2004) The p16INK4a-RB pathway: Molecular link between cellular senescence and tumor suppression. , J. Med. Invest 51, 146-153.
    78.Narita M, Nũnez S, Heard E, Narita M, Lin A W. (2003) Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. , Cell 113, 703-716.
    79.Blow J J, X Q Ge, D A Jackson. (2011) How dormant origins promote complete genome replication. , Trends Biochem. Sci 36, 405-414.
    80.J F Passos, Nelson G, Wang C, Richter T, Simillion C. (2010) Feedback between p21 and reactive oxygen production is necessary for cell senescence. doi: 10.1038/msb.2010.5. , Mol. Syst. Biol
    81.Fujita K, A M Mondal, Horikawa I, G H Nguyen, Kumamoto K. (2009) p53 isoforms Δ133p53 and p53β are endogenous regulators of replicative cellular senescence. , Nat. Cell. Biol 11, 1135-1142.
    82.J A Hackett, C W Greider. (2003) End resection initiates genomic instability in the absence of telomerase. , Mol. Cell. Biol 23, 8450-8461.
    83.R F Newbold. (2002) The significance of telomerase activation and cellular immortalization in human cancer. , Mutagenesis 17, 539-550.
    84.A G Bodnar, Ouellette M, Frolkis M, S E Holt, Chiu C P. (1998) Extension of life-span by introduction of telomerase into normal human cells. , Science 279, 349-352.
    85.Vaziri H, Benchimol S. (1998) Reconstitution of telomerase activity in normal human cells leads to elongation of telomeres and extended replicative life span. , Curr. Bio 8, 279-282.
    86.Blackburn E H, Collins K. (2011) Telomerase: An RNP enzyme synthesizes DNA. doi: 10.1101/cshperspect.a003558.Cold Spring Harb. Perspect. Biol
    87.J W Shay, Wright W E. (2005) Senescence and immortalization: Role of telomeres and telomerase. , Carcinogenesis 26, 867-874.
    88.Counter C M, W C Hahn, Wei W, S D Caddle, R L Beijersbergen. (1998) Dissociation among in vitro telomerase activity, telomere maintenance, and cellular immortalization. , Proc. Natl. Acad. Sci. U. S. A 95, 14723-14738.
    89.C K Garcia, Wright W E, J W Shay. (2007) Human diseases of telomerase dysfunction: Insights into tissue aging. , Nucleic Acids Res 35, 7406-7416.
    90.Zhang W, Chen Y, Yang X, Fan J, Mi X. (2012) Functional haplotypes of the hTERT gene, leukocyte telomere length shortening, and the risk of peripheral arterial disease. doi: 10.1371/journal.pone.0047029. PLoS. One
    91.D J Kurz, Hong Y, Trivier E, Huang H L, Decary S. (2003) Fibroblast growth factor-2, but not vascular endothelial growth factor, upregulates telomerase activity in human endothelial cells. , Arterioscler. Thromb. Vasc. Biol 23, 748-754.
    92.Flores I, Canela A, Vera E, Tejera A, Cotsarelis G. (2008) The longest telomeres: A general signature of adult stem cell compartments. , Genes Dev 22, 654-667.
    93.Flores I, M A Blasco.(March19,2009) A p53-dependent response limits epidermal stem cell functionality and organismal size in mice with short telomeres. doi: 10.1371/journal.pone.0004934. PLoS. One
    94.Siegl-Cachedenier I, Flores I, Klatt P, Blasco M A. (2007) Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres. , J. Cell. Biol 179, 277-290.
    95.S R Ferrón, Marqués-Torrejón M A, Mira H, Flores I, Taylor K. (2009) Telomere shortening in neural stem cells disrupts neuronal differentiation and neuritogenesis. , J. Neurosci 29, 14394-14407.
    96.Masutomi K, E Y Yu, Khurts S, Ben-Porath I, J L Currier. (2003) Telomerase maintains telomere structure in normal human cells. , Cell 114, 241-253.
    97.Verhulst S, Aviv A, Benetos A, Berenson G S, J D Kark. (2013) Do leukocyte telomere length dynamics depend on baseline telomere length? An analysis that corrects for 'regression to the mean. , Eur. J. Epidemiol 28, 859-866.
    98.Farzaneh-Far R, Lin J, Epel E, Lapham K, Blackburn E.(January8,2010) Telomere length trajectory and its determinants in persons with coronary artery disease: Longitudinal findings from the Heart and Soul Study. doi: 10.1371/journal.pone.0008612. PLoS. One
    99.H A Pickett, J D Henson, Au A Y, Neumann A A, Reddel R R. (2011) Normal mammalian cells negatively regulate telomere length by telomere trimming. , Hum. Mol. Genet 20, 4684-4692.
    100.H A Pickett, Reddel R R. (2012) The role of telomere trimming in normal telomere length dynamics. , Cell Cycle 11, 1309-1315.
    101.H A Pickett, A J Cesare, R L Johnston, Neumann A A, Reddel R R. (2009) Control of telomere length by a trimming mechanism that involves generation of t-circles. , EMBO. J 28, 799-809.
    102.Engelhardt M, Kumar R, Albanell J, Pettengell R, Han al.(1997b) Telomerase regulation, cell cycle, and telomere stability in primitive hematopoietic cells. , Blood 90, 182-193.
    103.Tomás-Loba A, Flores I, P J Fernández-Marcos, M L Cayuela, Maraver A. (2008) Telomerase reverse transcriptase delays aging in cancer-resistant mice. , Cell 135, 609-622.
    104.M E Karavassilis, Faragher R. (2013) A relationship exists between replicative senescence and cardiovascular health. doi: 10.1186/2046-2395-2-3. Longev. Healthspan
    105.G P Dimri, Lee X, Basile G, Acosta M, Scott G. (1995) A biomarker that identifies senescent human cells in culture and in aging skin in vivo. , Proc. Natl. Acad. Sci. U. S. A 92, 9363-9367.
    106.D J Baker, Wijshake T, Tchkonia T, N K LeBrasseur, B G Childs. (2011) Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. , Nature 479, 232-236.
    107.Y H Wei, H C Lee. (2002) Oxidative stress, mitochondrial DNA mutation, and impairment of antioxidant enzymes in aging. , Exp. Biol. Med 227, 671-682.
    108.K A Laderman, J R Penny, Mazzucchelli F, Bresolin N, Scarlato G. (1996) Aging-dependent functional alterations of mitochondrial DNA (mtDNA) from human fibroblasts transferred into mtDNA-less cells. , J. Biol. Chem 271, 15891-15897.
    109.M O Dietrich, T L Horvath. (2010) The role of mitochondrial uncoupling proteins in lifespan. , Pflugers Arch 459, 269-275.
    110.Harman D. (1972) Free radical theory of aging: Dietary implications. , Am. J. Clin. Nutr 25, 839-843.
    111.Harman D. (1981) The aging process. , Proc. Natl. Acad. Sci. U. S. A 78, 7124-7128.
    112.B N Ames, M K Shigenaga, T M Hagen. (1993) Oxidants, antioxidants, and the degenerative diseases of aging. , Proc. Natl. Acad. Sci. U. S. A 90, 7915-7922.
    113.Haendeler J, Hoffmann J, J F Diehl, Vasa M, Spyridopoulos I. (2004) Antioxidants inhibit nuclear export of telomerase reverse transcriptase and delay replicative senescence of endothelial cells. , Circ. Res 94, 768-775.
    114.M A Baraibar, Liu L, E K Ahmed, Friguet B. (2012) Protein oxidative damage at the crossroads of cellular senescence, aging, and age-related diseases. doi: 10.1155/2012/919832.Oxid. , Med. Cell. Longev
    115.M A Baraibar, Friguet B. (2013) Oxidative proteome modifications target specific cellular pathways during oxidative stress, cellular senescence and aging. , Exp. Gerontol 48, 620-625.
    116.E K Ahmed, Rogowska-Wrzesinska A, Roepstorff P, A L Bulteau, Friguet B. (2010) Protein modification and replicative senescence of WI-38 human embryonic fibroblasts. , Aging Cell 9, 252-272.
    117.J F Passos, Saretzki G, T von Zglinicki. (2007) DNA damage in telomeres and mitochondria during cellular senescence: Is there a connection? Nucleic Acids Res. 35, 7505-7513.
    118.D B Rhee, Ghosh A, Lu J, V A Bohr, Liu Y. (2011) Factors that influence telomeric oxidative base damage and repair by DNA glycosylase OGG1. , DNA Repair 10, 34-44.
    119.S T Mayne. (2003) Antioxidant nutrients and chronic disease: Use of biomarkers of exposure and oxidative stress status in epidemiologic research. , J. Nutr;133(Suppl.3): 933-940.
    120.Eot-Houllier G, Eon-Marchais S, Gasparutto D, Sage E. (2005) Processing of a complex multiply damaged DNA site by human cell extracts and purified repair proteins. , Nucleic Acids Res 33, 260-271.
    121.L J Eccles, M E Lomax, O'Neill P. (2010) Hierarchy of lesion processing governs the repair, double-strand break formation and mutability of three-lesion clustered DNA damage. , Nucleic Acids Res 38, 1123-1134.
    122.J D Erusalimsky, Skene C. (2009) Mechanisms of endothelial senescence. , Exp. Physiol 94, 299-304.
    123.Chen Q, B N Ames. (1994) Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. , Proc. Natl. Acad. Sci. U. S. A 91, 4130-4134.
    124.Q M Chen, J C Bartholomew, Campisi J, Acosta M, J D Reagan. (1998) Molecular analysis of H2O2-induced senescent-like growth arrest in normal human fibroblasts: p53 and Rb control G1 arrest but not cell replication. , Biochem. J 332, 43-50.
    125.D M Boesten, J M deVosHouben, Timmermans L, Hartog G J den, Bast A.(September23,2013) Accelerated aging during chronic oxidative stress: A role for PARP-1. Oxid. Med. doi: 10.1155/2013/680414. Cell. Longev
    126.Hewitt G, Jurk D, F D Marques, Correia-Melo C, Hardy T. (2012) Telomeres are favoured targets of a persistent DNA damage response in ageing and stress-induced senescence. doi: 10.1038/ncomms1708. , Nat. Commun
    127.Makpol S, Yaacob N, Zainuddin A, Yusof Y A, W Z Ngah. (2009) Chlorella vulgaris modulates hydrogen peroxide-induced DNA damage and telomere shortening of human fibroblasts derived from different aged individuals. , Afr. J. Tradit. Complement. Altern. Med 6, 560-572.
    128.Yin B, Jiang X. (2013) Telomere shortening in cultured human dermal fibroblasts is associated with acute photodamage induced by UVA irradiation. , Postepy. Dermatol. Alergol 30, 13-18.
    129.Monickaraj F, Aravind S, Nandhini P, Prabu P, Sathishkumar C. (2013) Accelerated fat cell aging links oxidative stress and insulin resistance in adipocytes. , J. Biosci 38, 113-122.
    130.Mistry Y, Poolman T, Williams B, K E Herbert. (2013) A role for mitochondrial oxidants in stress-induced premature senescence of human vascular smooth muscle cells. , Redox Biol 1, 411-417.
    131.K E Herbert, Mistry Y, Hastings R, Poolman T, Niklason L. (2008) Angiotensin II-mediated oxidative DNA damage accelerates cellular senescence in cultured human vascular smooth muscle cells via telomere-dependent and independent pathways. , Circ. Res 102, 201-208.
    132.D J Kurz, Decary S, Hong Y, Trivier E, Akhmedov A. (2004) Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. , J. Cell Sci 117, 2417-2426.
    133.Honda S, L M Hjelmeland, J T Handa. (2001) Oxidative stress--induced single-strand breaks in chromosomal telomeres of human retinal pigment epithelial cells in vitro. , Invest. Ophthalmol. Vis. Sci 42, 2139-2144.
    134.Haendeler J, Hoffmann J, R P Brandes, A M Zeiher, Dimmeler S. (2003) Hydrogen peroxide triggers nuclear export of telomerase reverse transcriptase via Src kinase family-dependent phosphorylation of tyrosine 707. , Mol. Cell. Biol 23, 4598-4610.
    135.Ahmed S, J F Passos, M J Birket, Beckmann T, Brings S. (2008) Telomerase does not counteract telomere shortening but protects mitochondrial function under oxidative stress. , J. Cell Sci 121, 1046-1053.
    136.Drissi R, Wu J, Hu Y, Bockhold C, Dome J S. (2011) Telomere shortening alters the kinetics of the DNA damage response after ionizing radiation in human cells. , Cancer Prev. Res 4, 1973-1981.
    137.Block G, Dietrich M, E P Norkus, J D Morrow, Hudes M. (2002) Factors associated with oxidative stress in human populations. , Am. J. Epidemiol 156, 274-285.
    138.Epel E S, E H Blackburn, Lin J, F S Dhabhar, N E Adler. (2004) Accelerated telomere shortening in response to life stress. , Proc. Natl. Acad. Sci. U. S. A 101, 17312-17315.
    139.Hou L, Andreotti G, Baccarelli A A, Savage S, J A Hoppin. (2013) Lifetime pesticide use and telomere shortening among male pesticide applicators in the Agricultural Health Study. Environ. Health Perspect. 121, 919-924.
    140.Canales-Aguirre A, Padilla-Camberos E, Gómez-Pinedo U, Salado-Ponce H, Feria-Velasco A. (2011) Genotoxic effect of chronic exposure to DDT on lymphocytes, oral mucosa and breast cells of female rats. , Int. J. Environ. Res. Public Health 8, 540-553.
    141.Harada T, Yamaguchi S, Ohtsuka R, Takeda M, Fujisawa H. (2003) Mechanisms of promotion and progression of preneoplastic lesions in hepatocarcinogenesis by DDT in F344 rats. , Toxicol. Pathol 31, 87-98.
    142.Li Y, Nie J, Beyea J, C B Rudra, R W Browne. (2013) Exposure to traffic emissions: Associations with biomarkers of antioxidant status and oxidative damage. , Environ. Res 121, 31-38.
    143.R J Delfino, Staimer N, Tjoa T, Polidori A, Arhami M. (2008) Circulating biomarkers of inflammation, antioxidant activity, and platelet activation are associated with primary combustion aerosols in subjects with coronary artery disease. , Environ. Health Perspect 116, 898-906.
    144.R J Delfino, Staimer N, Tjoa T, D L Gillen, Polidori A. (2009) Air pollution exposures and circulating biomarkers of effect in a susceptible population: Clues to potential causal component mixtures and mechanisms. , Environ. Health Perspect 117, 1232-1238.
    145.T J Grahame, R B Schlesinger. (2012) Oxidative stress-induced telomeric erosion as a mechanism underlying airborne particulate matter-related cardiovascular disease. doi: 10.1186/1743-8977-9-21. Part. Fibre Toxicol.
    146.Hoxha M, Dioni L, Bonzini M, A C Pesatori, Fustinoni S.(September21,2009) Association between leukocyte telomere shortening and exposure to traffic pollution: A cross-sectional study on traffic officers and indoor office workers. doi: 10.1186/1476-069X-8-41. Environ. Health
    147.McCracken J, Baccarelli A, Hoxha M, Dioni L, Melly S. (2010) Annual ambient black carbon associated with shorter telomeres in elderly men: Veterans Affairs Normative Aging Study. Environ. Health Perspect. 118, 1564-1570.
    148.W A Pryor. (1997) Cigarette smoke radicals and the role of free radicals in chemical carcinogenicity. Environ. Health Perspec;105(Suppl.4): 875-882.
    149.J P Eiserich, vandervliet A, G J Handelman, Halliwell B, Cross C E. (1995) Dietary antioxidants and cigarette smoke-induced biomolecular damage: A complex interaction. , Am. J. Clin. Nutr;62(Suppl.): 1490-1500.
    150.T E Strandberg, Saijonmaa O, R S Tilvis, K H Pitkälä, A Y Strandberg. (2011) Association of telomere length in older men with mortality and midlife body mass index and smoking. , J. Gerontol. A Biol. Sci. Med. Sci 66, 815-820.
    151.McGrath M, J Y Wong, Michaud D, D J Hunter, I De Vivo. (2007) Telomere length, cigarette smoking, and bladder cancer risk in men and women. Cancer Epidemiol. Biomarkers Prev. 16, 815-819.
    152.Farhat N, Thorin-Trescases N, Voghel G, Villeneuve L, Mamarbachi M. (2008) Stress-induced senescence predominates in endothelial cells isolated from atherosclerotic chronic smokers. , Can. J. Physiol. Pharmacol 86, 761-769.
    153.Prescott J, I M Wentzensen, Savage S A, I De Vivo. (2012) Epidemiologic evidence for a role of telomere dysfunction in cancer etiology. , Mutat. Res 730, 75-84.
    154.Samper E, J M Flores, M A Blasco. (2001) Restoration of telomerase activity rescues chromosomal instability and premature aging in Terc-/- mice with short telomeres. , EMBO. Rep 2, 800-807.
    155.K G Griewank, Murali R, Schilling B, Schimming T, Möller I.(November18,2013) TERT promoter mutations are frequent in cutaneous basal cell carcinoma and squamous cell carcinoma. doi:. 10.1371/journal.pone.0080354. PLoS. One
    156.LaTorre D, Conti A, Aguennouz M H, De Pasquale MG, Romeo S.(May14,2013) Telomere length modulation in human astroglial brain tumors. doi:. 10.1371/journal.pone.0064296. PLoS. One
    157.Mocellin S, Verdi D, K A Pooley, M T Landi, K M Egan. (2012) Telomerase reverse transcriptase locus polymorphisms and cancer risk: A field synopsis and meta-analysis. , J. Natl. Cancer Inst 104, 840-854.
    158.Basu N, H G Skinner, Litzelman K, Vanderboom R, Baichoo E. (2013) Telomeres and telomere dynamics: Relevance to cancers of the GI tract. Expert Rev. , Gastroenterol. Hepatol 7, 733-748.
    159.L A Boardman, R A Johnson, K B Viker, K A Hafner, R B Jenkins.(November21,2013) Correlation of chromosomal instability, telomere length and telomere maintenance in microsatellite stable rectal cancer: A molecular subclass of rectal cancer. doi: 10.1371/journal.pone.0080015. PloS. One
    160.J D Henson, Neumann A A, Yeager T R, Reddel R R. (2002) Alternative lengthening of telomeres in mammalian cells. , Oncogene 21, 598-610.
    161.T M Bryan, Marusic L, Bacchetti S, Namba M, Reddel R R. (1997) The telomere lengthening mechanism in telomerase-negative immortal human cells does not involve the telomerase RNA subunit. , Hum. Mol. Genet 6, 921-926.
    162.T M Bryan, Englezou A, Gupta J, Bacchetti S, Reddel R R. (1995) Telomere elongation in immortal human cells without detectable telomerase activity. , EMBO. J 14, 4240-4248.
    163.I M Wentzensen, Mirabello L, R M Pfeiffer, Savage S A. (2011) The association of telomere length and cancer: A meta-analysis. Cancer Epidemiol. Biomarkers Prev. 20, 1238-1250.
    164.Ma H, Zhou Z, Wei S, Liu Z, K A Pooley. (2011) Shortened telomere length is associated with increased risk of cancer: A meta-analysis. doi:. 10.1371/journal.pone.0020466. PLoS. One
    165.A J Pellatt, R K Wolff, Lundgreen A, Cawthon R, M L Slattery. (2012) Genetic and lifestyle influence on telomere length and subsequent risk of colon cancer in a case control study. , Int. J. Mol. Epidemiol. Genet 3, 184-194.
    166.H G Skinner, R E Gangnon, Litzelman K, R A Johnson, S T Chari. (2012) Telomere length and pancreatic cancer: A case-control study. Cancer Epidemiol. Biomarkers Prev. 21, 2095-2100.
    167.Xing J, J A Ajani, Chen M, Izzo J, Lin J. (2009) Constitutive short telomere length of chromosome 17p and 12q but not 11q and 2p is associated with an increased risk for esophageal cancer. , Cancer Prev. Res 2, 459-465.
    168.Mirabello L, Garcia-Closas M, Cawthon R, Lissowska J, L A Brinton. (2010) Leukocyte telomere length in a population-based case-control study of ovarian cancer: A pilot study. , Cancer Causes Control 21, 77-82.
    169.Broberg K, Björk J, Paulsson K, Höglund M, Albin M. (2005) Constitutional short telomeres are strong genetic susceptibility markers for bladder cancer. , Carcinogenesis 26, 1263-1271.
    170.Qin Q, Sun J, Yin J, Liu L, Chen J. (2014) Telomere length in peripheral blood leukocytes is associated with risk of colorectal cancer in Chinese population. doi: 10.1371/journal.pone.0088135. PLoS. One
    171.Torre La, Aguennouz D, Conti M, Giusa A, Raffa M et al. (2011) Potential clinical role of telomere length in human glioblastoma. , Transl. Med. UniSa 1, 243-270.
    172.R N Sainger, S D Telang, Shukla S N, Patel P S. (2007) Clinical significance of telomere length and associated proteins in oral cancer. , Biomark. Insights 2, 9-19.
    173.A K Meeker, J L Hicks, C A Iacobuzio-Donahue, E A Montgomery, W H.(2004a) Telomere length abnormalities occur early in the initiation of epithelial carcinogenesis. , Clin. Cancer Res 10, 3317-3326.
    174.A K Meeker, J L Hicks, E A Platz, G E March, C J Bennett. (2002) Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis. , Cancer Res 62, 6405-6409.
    175.A K Meeker, J L Hicks, Gabrielson E, W M Strauss, Demarzo A al.(2004b) Telomere shortening occurs in subsets of normal breast epithelium as well as in situ and invasive carcinoma. , Am. J. Pathol 164, 925-935.
    176.D T Bau, S M Lippman, Xu E, Gong Y, Lee J J. (2013) Short telomere lengths in peripheral blood leukocytes are associated with an increased risk of oral premalignant lesion and oral squamous cell carcinoma. , Cancer 119, 4277-4283.
    177.Risques R A, T L Vaughan, Li X, R D Odze, P L Blount. (2007) Leukocyte telomere length predicts cancer risk in Barrett's esophagus. Cancer Epidemiol. Biomarkers Prev. 16, 2649-2655.
    178.R Y Zee, A J Castonguay, N S Barton, J E Buring. (2009) Mean telomere length and risk of incident colorectal carcinoma: A prospective, nested case-control approach. Cancer Epidemiol. Biomarkers Prev. 18, 2280-2282.
    179.I M Lee, Lin J, A J Castonguay, N S Barton, J E Buring. (2010) Mean leukocyte telomere length and risk of incident colorectal carcinoma in women: A prospective, nested case-control study. , Clin. Chem. Lab. Med 48, 259-262.
    180.K A Pooley, M S Sandhu, Tyrer J, Shah M, K E Driver. (2010) Telomere length in prospective and retrospective cancer case-control studies. , Cancer Res 70, 3170-3176.
    181.Tatsumoto N, Hiyama E, Murakami Y, Imamura Y, J W Shay. (2000) High telomerase activity is an independent prognostic indicator of poor outcome in colorectal cancer. , Clin. Cancer Res 6, 2696-2701.
    182.Gertler R, Rosenberg R, Stricker D, Friederichs J, Hoos A. (2004) Telomere length and human telomerase reverse transcriptase expression as markers for progression and prognosis of colorectal carcinoma. , J. Clin. Oncol 22, 1807-1814.
    183.Armanios M, E H Blackburn. (2012) The telomere syndromes. , Nat. Rev. Genet 13, 693-704.
    184.Minamino T, Miyauchi H, Yoshida T, Ishida Y, Yoshida H. (2002) Endothelial cell senescence in human atherosclerosis: Role of telomere in endothelial dysfunction. , Circulation 105, 1541-1544.
    185.Vasile E, Tomita Y, L F Brown, Kocher O, H F Dvorak. (2001) Differential expression of thymosin β-10 by early passage and senescent vascular endothelium is modulated by VPF/VEGF: Evidence for senescent endothelial cells in vivo at sites of atherosclerosis. , FASEB J 15, 458-466.
    186.Vemparala K, Roy A, V K Bahl, Prabhakaran D, Nath N.(November19,2013) Early accelerated senescence of circulating endothelial progenitor cells in premature coronary artery disease patients in a developing country - a case control study. doi: 10.1186/1471-2261-13-104.BMC Cardiovasc. Disord
    187.Fenton M, Barker S, D J Kurz, J D Erusalimsky. (2001) Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. , Arterioscler. Thromb. Vasc. Biol 21, 220-226.
    188.Matthews C, Gorenne I, Scott S, Figg N, Kirkpatrick P. (2006) Vascular smooth muscle cells undergo telomere-based senescence in human atherosclerosis: Effects of telomerase and oxidative stress. , Circ. Res 99, 156-164.
    189.D H O'Leary, J F Polak, Wolfson SK Jr, M G Bond, Bommer W. (1991) Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. , CHS Collaborative Research Group. Stroke 22, 1155-1163.
    190.Weischer M, S E Bojesen, R M Cawthon, Freiberg J J, Tybjærg-Hansen A. (2012) Short telomere length, myocardial infarction, ischemic heart disease, and early death. , Arterioscler. Thromb. Vasc. Biol 32, 822-829.
    191.J A Perez-Rivera, Pabon-Osuna P, Cieza-Borrella C, Duran-Bobin O, Martin-Herrero F. (2014) Effect of telomere length on prognosis in men with acute coronary syndrome. , Am. J. Cardiol 113, 418-421.
    192.Carlquist J, Knight S, R M Cawthon, Horne B, Rollo J. (2013) Telomere length is associated with survival among patients referred for angiography. , J. Am. Coll. Cardiol 61, 10.
    193.Zhai G, Aviv A, D J Hunter, D J Hart, J P Gardner. (2006) Reduction of leucocyte telomere length in radiographic hand osteoarthritis: A population-based study. , Ann. Rheum. Dis 65, 1444-1448.
    194.J S Price, J G Waters, Darrah C, Pennington C, D R Edwards. (2002) The role of chondrocyte senescence in osteoarthritis. , Aging Cell 1, 57-65.
    195.Harbo M, J M Delaisse, Kjaersgaard-Andersen P, F B Soerensen, Koelvraa S. (2013) The relationship between ultra-short telomeres, aging of articular cartilage and the development of human hip osteoarthritis. , Mech. Ageing Dev 134, 367-372.
    196.Yudoh K, N van Trieu, Nakamura H, Hongo-Masuko K, Kato T. (2005) Potential involvement of oxidative stress in cartilage senescence and development of osteoarthritis: Oxidative stress induces chondrocyte telomere instability and downregulation of chondrocyte function. , Arthritis Res. Ther 7, 380-391.
    197.Zhao J, Zhu Y, Lin J, Matsuguchi T, Blackburn E. (2014) Short leukocyte telomere length predicts risk of diabetes in American Indians: The Strong Heart Family Study. , Diabetes 63, 354-362.
    198.Zhao J, Miao K, Wang H, Ding H, D W Wang. (2013) Association between telomere length and type 2 diabetes mellitus: A meta-analysis. doi:. 10.1371/journal.pone.0079993. PLoS. One
    199.C E Elks, R A Scott. (2014) The long and short of telomere length and diabetes. , Diabetes 63, 65-67.
    200.Albrecht E, Sillanpää E, Karrasch S, Alves A C, Codd V. (2013) Telomere length in circulating leukocytes is associated with lung function and disease. doi: 10.1183/09031936.00046213. , Eur. Respir. J
    201.S L Ma, E S Lau, E W Suen, L C, P C Leung. (2013) Telomere length and cognitive function in southern Chinese community-dwelling male elders. , Age Ageing 42, 450-455.
    202.A M Valdes, I J Deary, Gardner J, Kimura M, Lu X. (2010) Leukocyte telomere length is associated with cognitive performance in healthy women. , Neurobiol. Aging 31, 986-992.
    203.Wikgren M, Karlsson T, Söderlund H, Nordin A, Roos G. (2013) Shorter telomere length is linked to brain atrophy and white matter hyperintensities. , Age Ageing 43, 212-217.
    204.Moiseeva O, Bourdeau V, Roux A, Deschênes-Simard X, Ferbeyre G. (2009) Mitochondrial dysfunction contributes to oncogene-induced senescence. , Mol. Cell. Biol 29, 4495-4507.
    205.A C Lee, B E Fenster, Ito H, Takeda K, N S Bae. (1999) Ras proteins induce senescence by altering the intracellular levels of reactive oxygen species. , J. Biol. Chem 274, 7936-7940.
    206.Chen Q, Fischer A, J D Reagan, L J Yan, B N Ames. (1995) Oxidative DNA damage and senescence of human diploid fibroblast cells. , Proc. Natl. Acad. Sci. U. S. A 92, 4337-4341.
    207.J S Allard, Perez E, Zou S, R de Cabo. (2009) Dietary activators of Sirt1. , Mol. Cell. Endocrinol 299, 58-63.
    208.Marin C, Delgado-Lista J, Ramirez R, Carracedo J, Caballero J. (2012) Mediterranean diet reduces senescence-associated stress in endothelial cells. , Age 34, 309-1316.
    209.Dai J, D P Jones, Goldberg J, T R Ziegler, R M Bostick. (2008) Association between adherence to the Mediterranean diet and oxidative stress. , Am. J. Clin. Nutr 88, 1364-1370.
    210.Song Y, N C You, Song Y, M K Kang, Hou L. (2013) Intake of small-to-medium-chain saturated fatty acids is associated with peripheral leukocyte telomere length in postmenopausal women. , J. Nutr 143, 907-914.
    211.Ornish D, Lin J, J M Chan, Epel E, Kemp C. (2013) Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study. , Lancet Oncol 14, 1112-1120.
    212.Xu Q, C G Parks, L A DeRoo, R M Cawthon, D P Sandler. (2009) Multivitamin use and telomere length in women. , Am. J. Clin. Nutr 89, 1857-1863.
    213.T M Hagen, R T Ingersoll, Lykkesfeldt J, Liu J, C M Wehr. (1999) (R)-α-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. , FASEB J 13, 411-418.
    214.Szeląg M, Mikulski D, Molski M. (2012) Quantum-chemical investigation of the structure and the antioxidant properties of α-lipoic acid and its metabolites. , J. Mol. Model 18, 2907-2916.
    215.Ruktanonchai U, Bejrapha P, Sakulkhu U, Opanasopit P, Bunyapraphatsara N. (2009) Physicochemical characteristics, cytotoxicity, and antioxidant activity of three lipid nanoparticulate formulations of α-lipoic acid. , AAPS PharmSciTech 10, 227-234.
    216.Wang Y, Dong W, Ding X, Wang F, Wang Y. (2012) Protective effect of α-lipoic acid on islet cells co-cultured with 3T3L1 adipocytes. , Exp. Ther. Med 4, 469-474.
    217.Wang L, C G Wu, C Q Fang, Gao J, Y Z Liu. (2013) The protective effect of α-lipoic acid on mitochondria in the kidney of diabetic rats. , Int. J. Clin. Exp. Med 6, 90-97.
    218.T M Hagen, Liu J, Lykkesfeldt J, C M Wehr, R T Ingersoll. (2002) Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. , Proc. Natl. Acad. Sci. U. S. A 99, 1870-1875.
    219.Feng B, X F Yan, J L Xue, Xu L, Wang H. (2013) The protective effects of α-lipoic acid on kidneys in type 2 diabetic Goto-Kakisaki rats via reducing oxidative stress. , Int. J. Mol. Sci 14, 6746-6756.
    220.Jia L, Liu Z, Sun L, Miller S S, B N Ames. (2007) Acrolein, a toxicant in cigarette smoke, causes oxidative damage and mitochondrial dysfunction in RPE cells: Protection by (R)-α-lipoic acid. , Invest. Ophthalmol. Vis. Sci 48, 339-348.
    221.Liu J, Head E, A M Gharib, Yuan W, R T Ingersoll.(2002a) Memory loss in old rats is associated with brain mitochondrial decay and RNA/DNA oxidation: Partial reversal by feeding acetyl-L-carnitine and/or R-α-lipoic acid. , Proc. Natl. Acad. Sci. U. S. A 99, 2356-2361.
    222.Liu J, D W Killilea, B N Ames. (2002) Age-associated mitochondrial oxidative decay: Improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L-carnitine and/or R-α-lipoic acid. , Proc. Natl. Acad. Sci. U. S. A 99, 1876-1881.
    223.Goraca A, Skibska B. (2008) Beneficial effect of α-lipoic acid on lipopolysaccharide-induced oxidative stress in bronchoalveolar lavage fluid. , J. Physiol. Pharmacol 59, 379-386.
    224.H Y Kim, Oi Y, Kim M, Yokozawa T. (2008) Protective effect of lipoic acid against methylglyoxal-induced oxidative stress in LLC-PK1 cells. , J. Nutr. Sci. Vitaminol 54, 99-104.
    225.L A Voloboueva, Liu J, J H Suh, B N Ames, Miller S S. (2005) (R)-α-lipoic acid protects retinal pigment epithelial cells from oxidative damage. , Invest. Ophthalmol. Vis. Sci 46, 4302-4310.
    226.Akpinar D, Yargiçoğlu P, Derin N, Alicigüzel Y, Ağar A. (2008) The effect of lipoic acid on antioxidant status and lipid peroxidation in rats exposed to chronic restraint stress. , Physiol. Res 57, 893-901.
    227.J H Suh, Shenvi S V, B M Dixon, Liu H, A K Jaiswal. (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. , Proc. Natl. Acad. Sci. U. S. A 101, 3381-3386.
    228.Bilska A, Włodek L. (2005) Lipoic acid - the drug of the future?. , Pharmacol. Rep 57, 570-577.
    229.D M Inman, W S Lambert, D J Calkins, P J Horner. (2013) α-Lipoic acid antioxidant treatment limits glaucoma-related retinal ganglion cell death and dysfunction. doi: 10.1371/journal.pone.0065389. PLoS. One
    230.Selvakumar E, T C Hsieh. (2008) Regulation of cell cycle transition and induction of apoptosis in HL-60 leukemia cells by lipoic acid: Role in cancer prevention and therapy. , J. Hematol. Oncol 10-1186.
    231.R G Nath, M Y Wu, Emami A, F L Chung. (2010) Effects of epigallocatechin gallate, L-ascorbic acid, α-tocopherol, and dihydrolipoic acid on the formation of deoxyguanosine adducts derived from lipid peroxidation. , Nutr. Cancer 62, 622-629.
    232.Kishimoto Y, Tani M, Uto-Kondo H, Iizuka M, Saita E. (2010) Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages. , Eur. J. Nutr 49, 119-126.
    233.Ambati R R, S M Phang, Ravi S, R G Aswathanarayana. (2014) Astaxanthin: Sources, extraction, stability, biological activities and its commercial applications - review. , Mar. Drugs 12, 128-152.
    234.Okada Y, Ishikura M, Maoka T. (2009) Bioavailability of astaxanthin in Haematococcus algal extract: The effects of timing of diet and smoking habits. , Biosci. Biotechnol. Biochem 73, 1928-1932.
    235.Karppi J, T H Rissanen, Nyyssönen K, Kaikkonen J, A G Olsson. (2007) Effects of astaxanthin supplementation on lipid peroxidation. , Int. J. Vitam. Nutr. Res 77, 3-11.
    236.Mercke Odeberg J, Lignell A, Pettersson A, Höglund P. (2003) Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. , Eur. J. Pharm. Sci 19, 299-304.
    237.Osterlie M, Bjerkeng B, Liaaen-Jensen S. (2000) Plasma appearance and distribution of astaxanthin E/Z and R/S isomers in plasma lipoproteins of men after single dose administration of astaxanthin. , J. Nutr. Biochem 11, 482-490.
    238.Choi H D, J H Kim, M J Chang, Kyu-Youn Y, W G Shin.(2011a) Effects of astaxanthin on oxidative stress in overweight and obese adults. , Phytother. Res 25, 1813-1818.
    239.Wolz E, Liechti H, Notter B, Oesterhelt G, Kistler A. (1999) Characterization of metabolites of astaxanthin in primary cultures of rat hepatocytes. , Drug Metab. Dispos 27, 456-462.
    240.Camera E, Mastrofrancesco A, Fabbri C, Daubrawa F, Picardo M. (2009) Astaxanthin, canthaxanthin and β-carotene differently affect UVA-induced oxidative damage and expression of oxidative stress-responsive enzymes. , Exp. Dermatol 18, 222-231.
    241.Naito Y, Uchiyama K, Aoi W, Hasegawa G, Nakamura N. (2004) Prevention of diabetic nephropathy by treatment with astaxanthin in diabetic db/db mice. , Biofactors 20, 49-59.
    242.Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H. (2003) Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. , Antioxid. Redox. Signal 5, 139-144.
    243.Miyazawa T, Nakagawa K, Kimura F, Satoh A, Miyazawa T. (2011) Erythrocytes carotenoids after astaxanthin supplementation in middle-aged and senior Japanese subjects. , J. Oleo Sci 60, 495-499.
    244.Miyazawa T, Nakagawa K, Kimura F, Satoh A, Miyazawa.T.(2011b) Plasma carotenoid concentrations before and after supplementation with astaxanthin in middle-aged and senior subjects. , Biosci. Biotechnol. Biochem 75, 1856-1858.
    245.Nakagawa K, Kiko T, Miyazawa T, Burdeos Carpentero, Kimura G et al. (2011) Antioxidant effect of astaxanthin on phospholipid peroxidation in human erythrocytes. , Br. J. Nutr 105, 1563-1571.
    246.Goto S, Kogure K, Abe K, Kimata Y, Kitahama K. (2001) Efficient radical trapping at the surface and inside the phospholipid membrane is responsible for highly potent antiperoxidative activity of the carotenoid astaxanthin. , Biochim. Biophys. Acta 1512, 251-258.
    247.Guerin M, M E Huntley, Olaizola M. (2003) Haematococcus astaxanthin: Applications for human health and nutrition. , Trends Biotechnol 21, 210-216.
    248.McNulty H, R F Jacob, R P Mason. (2008) Biologic activity of carotenoids related to distinct membrane physicochemical interactions. , Am. J. Cardiol 101, 20-29.
    249.H P McNulty, Byun J, S F Lockwood, R F Jacob, R P Mason. (2007) Differential effects of carotenoids on lipid peroxidation due to membrane interactions: X-ray diffraction analysis. , Biochim. Biophys. Acta 1768, 167-174.
    250.R P Mason, M F Walter, H P McNulty, S F Lockwood, Byun J. (2006) Rofecoxib increases susceptibility of human LDL and membrane lipids to oxidative damage: A mechanism of cardiotoxicity. , J. Cardiovasc. Pharmacol;47(Suppl.1): 7-14.
    251.Hayakawa T, Kulkarni A, Terada Y, Maoka T, Etoh H. (2008) Reaction of astaxanthin with peroxynitrite. , Biosci. Biotechnol. Biochem 72, 2716-2722.
    252.Etoh H, Suhara M, Tokuyama S, Kato H, Nakahigashi R. (2012) Auto-oxidation products of astaxanthin. , J. Oleo Sci 61, 17-21.
    253.B A Guerra, Otton R. (2011) Impact of the carotenoid astaxanthin on phagocytic capacity and ROS/RNS production of human neutrophils treated with free fatty acids and high glucose. , Int. Immunopharmacol 11, 2220-2226.
    254.Hama S, Uenishi S, Yamada A, Ohgita T, Tsuchiya H. (2012) Scavenging of hydroxyl radicals in aqueous solution by astaxanthin encapsulated in liposomes. , Biol. Pharm. Bull 35, 2238-2242.
    255.P Di Mascio, T P Devasagayam, Kaiser S, Sies H. (1990) Carotenoids, tocopherols and thiols as biological singlet molecular oxygen quenchers. , Biochem. Soc. Trans 18, 1054-1056.
    256.Shimidzu N, Goto M, Miki W. (1996) Carotenoids as singlet oxygen quenchers in marine organisms. , Fish Sci 62, 134-137.
    257.Nishida Y, Yamashita E, Miki W. (2007) Quenching activities of common hydrophilic and lipophilic antioxidants against singlet oxygen using chemiluminescence detection system. , Carotenoid Sci 11, 16-20.
    258.Miki W. (1991) Biological functions and activities of animal carotenoids. , J. Pure. Appl. Chem 63, 141-146.
    259.Chang C S, Chang C L, Lai G H. (2013) Reactive oxygen species scavenging activities in a chemiluminescence model and neuroprotection in rat pheochromocytoma cells by astaxanthin, β-carotene, and canthaxanthin. , Kaohsiung J. Med. Sci 29, 412-421.
    260.Kobayashi M, Kakizono T, Nishio N, Nagai S, Kurimura Y. (1997) Antioxidant role of astaxanthin in the green alga Haematococcus pluvialis. , Appl. Microbiol. Biotechnol 48, 351-356.
    261.S K Khan, Malinski T, R P Mason, Kubant R, R F Jacob. (2010) Novel astaxanthin prodrug (CDX-085) attenuates thrombosis in a mouse model. , Thromb. Res 126, 299-305.
    262.Li Z, Dong X, Liu H, Chen X, Shi H. (2013) Astaxanthin protects ARPE-19 cells from oxidative stress via upregulation of Nrf2-regulated phase II enzymes through activation of PI3K/Akt. , Mol. Vis 19, 1656-1666.
    263.F H Comhaire, Y El Garem, Mahmoud A, Eertmans F, Schoonjans F. (2005) Combined conventional/antioxidant “Astaxanthin” treatment for male infertility: A double blind, randomized trial. , Asian J. Androl 7, 257-262.
    264.J H Kim, Choi W, J H Lee, S J Jeon, Y H Choi. (2009) Astaxanthin inhibits H2O2-mediated apoptotic cell death in mouse neural progenitor cells via modulation of P38 and MEK signaling pathways. , J. Microbiol. Biotechnol 19, 1355-1363.
    265.Franceschelli S, Pesce M, Ferrone A, Lutiis M A De, Patruno A. (2014) Astaxanthin treatment confers protection against oxidative stress in U937 cells stimulated with lipopolysaccharide reducing O2- production. doi: 10.1371/journal.pone.0088359. PLoS. One
    266.L Y Dong, Jin J, Lu G, X L Kang. (2013) Astaxanthin attenuates the apoptosis of retinal ganglion cells in db/db mice by inhibition of oxidative stress. , Mar. Drugs 11, 960-974.
    267.O'Connor I, O'Brien N. (1998) Modulation of UVA light-induced oxidative stress by β-carotene, lutein and astaxanthin in cultured fibroblasts. , J. Dermatol. Sci 16, 226-230.
    268.N M Lyons, N M O'Brien. (2002) Modulatory effects of an algal extract containing astaxanthin on UVA-irradiated cells in culture. , J. Dermatol. Sci 30, 73-84.
    269.Otsuka T, Shimazawa M, Nakanishi T, Ohno Y, Inoue Y. (2013) The protective effects of a dietary carotenoid, astaxanthin, against light-induced retinal damage. , J. Pharmacol. Sci 123, 209-218.
    270.Beutner S, Bloedorn B, Frixel S, Blanco Hernandez, Hoffmann I et al. (2001) Quantitative assessment of antioxidant properties of natural colorants and phytochemicals: Carotenoids, flavonoids, phenols and indigoids. The role of β-carotene in antioxidant functions. , J. Sci. Food Agric 81, 559-568.
    271.Rodrigues E, L R Mariutti, A Z Mercadante. (2012) Scavenging capacity of marine carotenoids against reactive oxygen and nitrogen species in a membrane-mimicking system. , Mar. Drugs 10, 1784-1798.
    272.C L Saw, A Y Yang, Guo Y, A N Kong. (2013) Astaxanthin and omega-3 fatty acids individually and in combination protect against oxidative stress via the Nrf2-ARE pathway. Food Chem. , Toxicol 62, 869-875.
    273.J G Bell, McEvoy J, D R Tocher, J R Sargent. (2000) Depletion of α-tocopherol and astaxanthin in Atlantic salmon (Salmo salar) affects autoxidative defense and fatty acid metabolism. , J. Nutr 130, 1800-1808.
    274.Palozza P, N I Krinsky. (1992) Astaxanthin and canthaxanthin are potent antioxidants in a membrane model. , Arch. Biochem. Biophys 297, 291-295.
    275.D H Lee, C S Kim, Y J Lee. (2011) Astaxanthin protects against MPTP/MPP+-induced mitochondrial dysfunction and ROS production in vivo and in vitro. , Food Chem. Toxicol 49, 271-280.
    276.Woodall A A, Britton G, M J Jackson. (1997) Carotenoids and protection of phospholipids in solution or in liposomes against oxidation by peroxyl radicals: Relationship between carotenoid structure and protective ability. , Biochim. Biophys. Acta 1336, 575-586.
    277.B P Lim, Nagao A, Terao J, Tanaka K, Suzuki T. (1992) Antioxidant activity of xanthophylls on peroxyl radical-mediated phospholipid peroxidation. , Biochim. Biophys. Acta 1126, 178-184.
    278.Nakagawa K, S D Kang, D K Park, G J Handelman, Miyazawa T. (1997) Inhibition of β-carotene and astaxanthin of NADPH-dependent microsomal phospholipid peroxidation. , J. Nutr. Sci. Vitaminol 43, 345-355.
    279.Kurashige M, Okimasu E, Inoue M, Utsumi K. (1990) Inhibition of oxidative injury of biological membranes by astaxanthin. , Physiol. Chem. Phys. Med. NMR 22, 27-38.
    280.Nishigaki I, Rajendran P, Venugopal R, Ekambaram G, Sakthisekaran D. (2010) Cytoprotective role of astaxanthin against glycated protein/iron chelate-induced toxicity in human umbilical vein endothelial cells. , Phytother. Res 24, 54-59.
    281.Iwamoto T, Hosoda K, Hirano R, Kurata H, Matsumoto A. (2000) Inhibition of low-density lipoprotein oxidation by astaxanthin. , J. Atheroscler. Thromb 7, 216-222.
    282.Baralic I, Djordjevic B, Dikic N, Kotur-Stevuljevic J, Spasic S. (2013) Effect of astaxanthin supplementation on paraoxonase 1 activities and oxidative stress status in young soccer players. , Phytother. Res 27, 1536-1542.
    283.Kalyanaraman B. (2013) Teaching the basics of redox biology to medical and graduate students: Oxidants, antioxidants and disease mechanisms. , Redox. Biol 1, 244-257.
    284.Hashimoto H, Arai K, Hayashi S, Okamoto H, Takahashi J. (2013) Effects of astaxanthin on antioxidation in human aqueous humor. , J. Clin. Biochem. Nutr 53, 1-7.
    285.H D Choi, Youn Y K, Shin W G.(2011b) Positive effects of astaxanthin on lipid profiles and oxidative stress in overweight subjects. Plant Foods Hum. , Nutr 66, 363-369.
    286.A T Jacobs, L J Marnett. (2010) Systems analysis of protein modification and cellular responses induced by electrophile stress. , Acc. Chem. Res 43, 673-683.
    287.F J Romero, Bosch-Morell F, M J Romero, E J Jareño, Romero B. (1998) Lipid peroxidation products and antioxidants in human disease. , Environ. Health Perspect 106, 1229-1234.
    288.Y K Kim, Chyun J-H. (2004) The effects of astaxanthin supplements on lipid peroxidation and antioxidant status in postmenopausal women. , Nutr. Sci 7, 41-46.
    289.Iwabayashi M, Fujioka N, Nomoto K, Miyazaki R, Takahashi H. (2009) Efficacy and safety of eight-week treatment with astaxanthin in individuals screened for increased oxidative stress burden. , J. Anti-Aging Med 6, 15-21.
    290.J S Park, B D Mathison, M G Hayek, Zhang J, G A Reinhart. (2013) Astaxanthin modulates age-associated mitochondrial dysfunction in healthy dogs. , J. Anim. Sci 91, 268-275.
    291.J S Park, J H Chyun, Y K Kim, Line L L, B P Chew. (2010) Astaxanthin decreased oxidative stress and inflammation and enhanced immune response in human.Nutr.doi:. 10-1186.
    292.K W Lee, Lip G Y H. (2003) The role of omega-3 fatty acids in the secondary prevention of cardiovascular disease. , Quart. J. Med 96, 465-480.
    293.R de Caterina, Madonna R, Zucchi R, Rovere La, T M. (2003) Antiarrhythmic effects of omega-3 fatty acids: From epidemiology to bedside. , Am. Heart J 146, 420-430.
    294.Leaf A, J X Kang, Xiao Y-F, G E Billman, R A Voskuyl. (1999) The antiarrhythmic and anticonvulsant effects of dietary n-3 fatty acids. , J. Membrane Biol 172, 1-11.
    295.Food, Board Nutrition. Institute (2005) Dietary Fats: Total Fat and Fatty Acids. In: Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). A Report of the Panel on Macronutrients. Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. National Academy of Sciences, National Academy Press , Washington DC 422-541.
    296.G C Burdge, Y E Finnegan, A M Minihane, C M Williams, S A Wootton. (2003) Effect of altered dietary n-3 fatty acid intake upon plasma lipid fatty acid composition, conversion of [13C]α-linolenic acid to longer-chain fatty acids and partitioning towards beta-oxidation in older men. , Br. J. Nutr 90, 311-321.
    297.W E Connor. (1999) α-linolenic acid in health and disease. , Am. J. Clin. Nutr 69, 827-828.
    298.G C Burdge, S A Wootton. (2002) Conversion of α-linolenic acid to eicosapentaenoic, docosapentaenoic and docosahexaenoic acids in young women. , Br. J. Nutr 88, 411-420.
    299.C R Harper, M J Edwards, A P DeFilipis, T A Jacobson. (2006) Flaxseed oil increases the plasma concentrations of cardioprotective (n-3) fatty acids in humans. , J. Nutr 136, 83-87.
    300.G C Burdge, P C Calder. (2005) Conversion of α-linolenic acid to longer-chain polyunsaturated fatty acids in human adults. , Reprod. Nutr. Dev 45, 581-597.
    301.J T Brenna. (2002) Efficiency of conversion of α-linolenic acid to long chain n-3 fatty acids in man. , Curr. Opin. Clin. Nutr. Metab. Care 5, 127-132.
    302.Hussein N, Ah-Sing E, Wilkinson P, Leach C, B A Griffin. (2005) Long-chain conversion of [13C]linoleic acid and α-linolenic acid in response to marked changes in their dietary intake in men. , J. Lipid Res 46, 269-280.
    303.Salem N, Pawlosky R, Wegher B, Hibbeln J. (1999) In vivo conversion of linoleic acid to arachidonic acid in human adults. , Prostaglandins Leukot. Essent. Fatty Acids 60, 407-410.
    304.Farzaneh-Far R, Lin J, Epel E S, W S Harris, E H Blackburn. (2010) Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. , JAMA 303, 250-257.
    305.Ghorbanihaghjo A, Safa J, Alizadeh S, Argani H, Rashtchizadeh N. (2013) Protective effect of fish oil supplementation on DNA damage induced by cigarette smoking. , J. Health Popul. Nutr 31, 343-349.
    306.J K Kiecolt-Glaser, Epel E S, M A Belury, Andridge R, Lin J. (2013) Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. , Brain Behav. Immun 28, 16-24.
    307.O’Callaghan N, Parletta N, C M Milte, Benassi-Evans B, Fenech M. (2014) Telomere shortening in elderly individuals with mild cognitive impairment may be attenuated with ω-3 fatty acid supplementation: A randomized controlled pilot study. , Nutrition 30, 489-491.
    308.Labinskyy N, Csiszar A, Veress G, Stef G, Pacher P. (2006) Vascular dysfunction in aging: Potential effects of resveratrol, an anti-inflammatory phytoestrogen. , Curr. Med. Chem 13, 989-996.
    309.Condori J, Sivakumar G, Hubstenberger J, M C Dolan, V S Sobolev. (2010) Induced biosynthesis of resveratrol and the prenylated stilbenoids arachidin-1 and arachidin-3 in hairy root cultures of peanut: Effects of culture medium and growth stage. , Plant Physiol. Biochem 48, 310-318.
    310.Fan E, Zhang K, Jiang S, Yan C, Bai Y. (2008) Analysis of trans-resveratrol in grapes by micro-high performance liquid chromatography. , Anal. Sci 24, 1019-1023.
    311.Pirola L, Fröjdö S. (2008) Resveratrol: One molecule, many targets. , IUBMB Life 60, 323-332.
    312.Rayalam S, M A Della-Fera, J Y Yang, H J Park, Ambati S. (2007) Resveratrol potentiates genistein's antiadipogenic and proapoptotic effects in 3T3-L1 adipocytes. , J. Nutr 137, 2668-2673.
    313.Ikizler M, Ovali C, Dernek S, Erkasap N, Sevin B. (2006) Protective effects of resveratrol in ischemia-reperfusion injury of skeletal muscle: A clinically relevant animal model for lower extremity ischemia. , Chin. J. Physiol 49, 204-209.
    314.Smith J J, R D Kenney, D J Gagne, B P Frushour, Ladd W. (2009) Small molecule activators of SIRT1 replicate signaling pathways triggered by calorie restriction in vivo. , BMC Syst. Biol 10-1186.
    315.K J Pearson, J A Baur, K N Lewis, Peshkin L, N L Price. (2008) Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span. , Cell Metab 8, 157-168.
    316.Dave M, Attur M, Palmer G, H E Al-Mussawir, Kennish L. (2008) The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production. , Arthritis Rheum 58, 2786-2797.
    317.L E Donnelly, Newton R, G E Kennedy, P S Fenwick, R H Leung. (2004) Anti-inflammatory effects of resveratrol in lung epithelial cells: Molecular mechanisms. , Am. J. Physiol. Lung Cell Mol. Physiol 287, 774-783.
    318.S V Culpitt, D F Rogers, P S Fenwick, Shah P, C De Matos. (2003) Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. , Thorax 58, 942-946.
    319.Zhang H, Shih A, Rinna A, H J Forman. (2009) Resveratrol and 4-hydroxynonenal act in concert to increase glutamate cysteine ligase expression and glutathione in human bronchial epithelial cells. , Arch. Biochem. Biophys 481, 110-115.
    320.S H Tsai, S Y Lin, J K Lin. (1999) Suppression of nitric oxide synthase and the down-regulation of the activation of NFκB in macrophages by resveratrol. , Br. J. Pharmacol 126, 673-680.
    321.S A Gatz, Keimling M, Baumann C, Dörk T, K M Debatin.(2008a) Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR-p53- and -Nbs1-dependent manner. , Carcinogenesis 29, 519-527.
    322.S A Gatz, Wiesmüller L. (2008) Take a break--resveratrol in action on DNA. , Carcinogenesis 29, 321-332.
    323.Tan Y, Lim L H. (2008) trans-Resveratrol, an extract of red wine, inhibits human eosinophil activation and degranulation. , Br. J. Pharmacol 155, 995-1004.
    324.Kennedy A, Overman A, Lapoint K, Hopkins R, West T. (2009) Conjugated linoleic acid-mediated inflammation and insulin resistance in human adipocytes are attenuated by resveratrol. , J. Lipid Res 50, 225-232.
    325.A M Gonzales, R A Orlando.(June12,2008) Curcumin and resveratrol inhibit nuclear factor-kappaB-mediated cytokine expression in adipocytes. doi:. 10-1186.
    326.J A Baur, K J Pearson, N L Price, H A Jamieson, Lerin C. (2006) Resveratrol improves health and survival of mice on a high-calorie diet. , Nature 444, 337-342.
    327.Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C. (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1α. , Cell 127, 1109-1122.
    328.Food, Administration Drug. (2005) Guidance for Industry: Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. , Rockville MD
    329.Bezstarosti K, Das S, J M Lamers, Das D K. (2006) Differential proteomic profiling to study the mechanism of cardiac pharmacological preconditioning by resveratrol. , J. Cell Mol. Med 10, 896-907.
    330.M V Blagosklonny. (2009) Inhibition of S6K by resveratrol: In search of the purpose. , Aging 1, 511-514.
    331.Csiszar A, Labinskyy N, Podlutsky A, P M Kaminski, M S Wolin. (2008) Vasoprotective effects of resveratrol and SIRT1: Attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. , Am. J. Physiol. Heart Circ. Physiol 294, 2721-2735.
    332.Wingler K, Schmidt H H. (2009) Good stress, bad stress--the delicate balance in the vasculature. , Dtsch. Arztebl. Int 106, 677-684.
    333.Yoshida Y, Shioi T, Izumi T. (2007) Resveratrol ameliorates experimental autoimmune myocarditis. , Circ. J 71, 397-404.
    334.S V Penumathsa, Thirunavukkarasu M, Koneru S, Juhasz B, Zhan L. (2007) Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. , J. Mol. Cell Cardiol 42, 508-516.
    335.S K Park, Kim K, G P Page, D B Allison, Weindruch R. (2009) Gene expression profiling of aging in multiple mouse strains: Identification of aging biomarkers and impact of dietary antioxidants. , Aging Cell 8, 484-495.
    336.Csiszar A, Labinskyy N, Podlutsky A, P M Kaminski, M S Wolin. (2008) Vasoprotective effects of resveratrol and SIRT1: Attenuation of cigarette smoke-induced oxidative stress and proinflammatory phenotypic alterations. , Am. J. Physiol. Heart Circ. Physiol 294, 2721-2735.
    337.Ungvari Z, Orosz Z, Rivera A, Labinskyy N, Xiangmin Z. (2007) Resveratrol increases vascular oxidative stress resistance. , Am. J. Physiol. Heart Circ. Physiol 292, 2417-2424.
    338.Kode A, Rajendrasozhan S, Caito S, S R Yang, I L Megson. (2008) Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells. , Am. J. Physiol. Lung Cell. Mol. Physiol 294, 478-488.
    339.Cai H, D G Harrison. (2000) Endothelial dysfunction in cardiovascular diseases: The role of oxidant stress. , Circ. Res 87, 840-844.
    340.Olas B, Nowak P, Ponczek M, Wachowicz B. (2006) Resveratrol, a natural phenolic compound may reduce carbonylation proteins induced by peroxynitrite in blood platelets. , Gen. Physiol. Biophys 25, 215-222.
    341.Olas B, Nowak P, Wachowicz B. (2004) Resveratrol protects against peroxynitrite-induced thiol oxidation in blood platelets. , Cell. Mol. Biol. Lett 9, 577-587.
    342.Olas B, H M Zbikowska, Wachowicz B, Krajewski T, Buczyński A. (1999) Inhibitory effect of resveratrol on free radical generation in blood platelets. , Acta Biochim. Pol 46, 961-966.
    343.Gresele P, Pignatelli P, Guglielmini G, Carnevale R, A M Mezzasoma. (2008) Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. , J. Nutr 138, 1602-1608.
    344.Csiszar A, Smith K, Labinskyy N, Orosz Z, Rivera A. (2006) Resveratrol attenuates TNF-α-induced activation of coronary arterial endothelial cells: Role of NF-κB inhibition. , Am. J. Physiol. Heart Circ. Physiol 291, 1694-1699.
    345.Cavallaro A, Ainis T, Bottari C, Fimiani V. (2003) Effect of resveratrol on some activities of isolated and in whole blood human neutrophils. , Physiol. Res 52, 555-562.
    346.S E Chow, Y C Hshu, J S Wang, J K Chen. (2007) Resveratrol attenuates oxLDL-stimulated NADPH oxidase activity and protects endothelial cells from oxidative functional damages. , J. Appl. Physiol 102, 1520-1527.
    347.Zhang G, Zhang F, Muh R, Yi F, Chalupsky K. (2007) Autocrine/paracrine pattern of superoxide production through NAD(P)H oxidase in coronary arterial myocytes. , Am. J. Physiol. Heart Circ. Physiol 292, 483-495.
    348.Mokni M, Elkahoui S, Limam F, Amri M, Aouani E. (2007) Effect of resveratrol on antioxidant enzyme activities in the brain of healthy rat. , Neurochem. Res 32, 981-987.
    349.S C Barber, Higginbottom A, R J Mead, Barber S, P J Shaw. (2009) An in vitro screening cascade to identify neuroprotective antioxidants in ALS. Free Radic. , Biol. Med 46, 1127-1138.
    350.Lee M, H J You, S H Cho, C H Woo, M H Yoo. (2002) Implication of the small GTPase Rac1 in the generation of reactive oxygen species in response to β-amyloid in C6 astroglioma cells. , Biochem. J 366, 937-943.
    351.Wendeburg L, deOliveira A C, H S Bhatia, Candelario-Jalil E, Fiebich. (2009) Resveratrol inhibits prostaglandin formation in IL-1β-stimulated SK-N-SH neuronal cells. doi: 10.1186/1742-2094-6-26. , J. Neuroinflammation
    352.Candelario-Jalil E, A C deOliveira, Gräf S, H S Bhatia, Hüll M.(October10,2007) Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide-activated primary rat microglia. doi: 10.1186/1742-2094-4-25. , J. Neuroinflammation
    353.Mikula-Pietrasik J, Kuczmarska A, Rubis B, Filas V, Murias M. (2012) Resveratrol delays replicative senescence of human mesothelial cells via mobilization of antioxidative and DNA repair mechanisms. Free Radic. , Biol. Med 52, 2234-2245.
    354.Voghel G, Thorin-Trescases N, Farhat N, A M Mamarbachi, Villeneuve L. (2008) Chronic treatment with N-acetyl-cystein delays cellular senescence in endothelial cells isolated from a subgroup of atherosclerotic patients. , Mech. Ageing Dev 129, 261-270.
    355.C H Park, J W Kim. (2012) Effect of advanced glycation end products on oxidative stress and senescence of trabecular meshwork cells. , Korean J. Ophthalmol 26, 123-131.
    356.Pereboeva L, Westin E, Patel T, Flaniken I, Lamb L. (2013) DNA damage responses and oxidative stress in dyskeratosis congenita. doi: 10.1371/journal.pone.0076473. PLoS. One
    357.Pollicita M, Muscoli C, Sgura A, Biasin A, Granato T. (2009) Apoptosis and telomeres shortening related to HIV-1 induced oxidative stress in an astrocytoma cell line. 10-1186.
    358.Voghel G, Thorin-Trescases N, A M Mamarbachi, Villeneuve L, F A Mallette. (2010) Endogenous oxidative stress prevents telomerase-dependent immortalization of human endothelial cells. , Mech. Ageing Dev 131, 354-363.
    359.Ji J, Sharma V, Qi S, M E Guarch, Zhao P. (2014) Antioxidant supplementation reduces genomic aberrations in human induced pluripotent stem cells. , Stem Cell Reports 2, 44-51.
    360.Anonymous. (2003) Methylsulfonylmethane (MSM). , Altern. Med. Rev 8, 438-441.
    361.Maranon G, Muñoz-Escassi B, Manley W, García C, Cayado P. (2008) The effect of methyl sulphonyl methane supplementation on biomarkers of oxidative stress in sport horses following jumping exercise. doi: 10.1186/1751-0147-50-45.Acta Vet.
    362.Nakhostin-Roohi B, Barmaki S, Khoshkhahesh F, Bohlooli S. (2011) Effect of chronic supplementation with methylsulfonylmethane on oxidative stress following acute exercise in untrained healthy men. , J. Pharm. Pharmacol 63, 1290-1294.
    363.Food, Board Nutrition. Institute (2000) Vitamin C. In: Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. A Report of the Panel on Dietary Antioxidants and Related Compounds. Subcommittees on Upper Reference Levels of Nutrients and of Interpretation and Use of Dietary Reference Intakes, and the Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. National Academy of Sciences, National Academy Press , Washington DC 95-185.
    364.Frei B, England L, B N Ames. (1989) Ascorbate is an outstanding antioxidant in human blood plasma. , Proc. Natl. Acad. Sci. U. S. A 86, 6377-6381.
    365.Sen A, Marsche G, Freudenberger P, Schallert M, A M Toeglhofer. (2014) Association between higher plasma lutein, zeaxanthin, and vitamin C concentrations and longer telomere length: results of the Austrian Stroke Prevention Study. , J. Am. Geriatr. Soc 62, 222-229.
    366.Cranney A, H A Weiler, O'Donnell S, Puil L. (2008) Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health. , Am. J. Clin. Nutr 88, 513-519.
    367.J E Zerwekh. (2008) Blood biomarkers of vitamin D status. , Am. J. Clin. Nutr 87, 1087-1091.
    368. (2011) Food and Nutrition Board, Institute of Medicine. Overview of Vitamin D. In:. Dietary Reference Intakes for Calcium and Vitamin D. National Academy of Sciences, National Academy Press , Washington DC 75-124.
    369.E A Yetley, Brulé D, M C Cheney, C D Davis, K A Esslinger. (2009) Dietary reference intakes for vitamin D: Justification for a review of the 1997 values. , Am. J. Clin. Nutr 89, 719-727.
    370.J B Richards, A M Valdes, J P Gardner, Paximadas D, Kimura M. (2007) Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. , Am. J. Clin. Nutr 86, 1420-1425.
    371.B M Hoffecker, L M Raffield, D L Kamen, T K Nowling. (2013) Systemic lupus erythematosus and vitamin D deficiency are associated with shorter telomere length among African Americans: A case-control study. doi: 10.1371/journal.pone.0063725. PLoS. One
    372.Zhu H, Guo D, Li K, Pedersen-White J, I S Stallmann-Jorgensen. (2012) Increased telomerase activity and vitamin D supplementation in overweight African Americans. , Int. J. Obes 36, 805-809.
    373.Makpol S, Zainuddin A, N A Rahim, Yusof Y A, Ngah W Z.(2010a)Alpha-tocopherol modulates hydrogen peroxide-induced DNA damage and telomere shortening of human skin fibroblasts derived from differently aged individuals. , Planta Med 76, 869-875.
    374.Talegawkar S A, Johnson E J, Carithers T, Taylor H A, Bogle M L. (2007) Total α-tocopherol intakes are associated with serum α-tocopherol concentrations in African American adults. , J. Nutr 137, 2297-2303.
    375.Schaffer S, W E Müller, G P Eckert. (2005) Tocotrienols: Constitutional effects in aging and disease. , J. Nutr 135, 151-154.
    376.Makpol S, Zainuddin A, Chua K H, Yusof Mohd, Ngah Y A et al. (2013) Gamma-tocotrienol modulated gene expression in senescent human diploid fibroblasts as revealed by microarray analysis. doi: 10.1155/2013/454328. Oxid. Med. Cell Longev
    377.Makpol S, Zainuddin A, K H Chua, Y A, Ngah W Z. (2012) Gamma-tocotrienol modulation of senescence-associated gene expression prevents cellular aging in human diploid fibroblasts. , Clinics 67, 135-143.
    378.Makpol S, Yeoh T W, Ruslam F A, Arifin K T, Yusof Y A. (2013) Comparative effect of Piper betle, Chlorella vulgaris and tocotrienol-rich fraction on antioxidant enzymes activity in cellular ageing of human diploid fibroblasts. , BMC Complement. Doi: 10-1186.
    379.Makpol S, L W Durani, K H Chua, Mohd Yusof YA, W Z Ngah. (2011) Tocotrienol-rich fraction prevents cell cycle arrest and elongates telomere length in senescent human diploid fibroblasts. , J. doi: 10.1155/2011/506171.Biomed. Biotechnol
    380.Makpol S, Rahim Abdul, N Hui CK, Ngah W Z.(2012b) Inhibition of mitochondrial cytochrome c release and suppression of caspases by gamma-tocotrienol prevent apoptosis and delay aging in stress-induced premature senescence of skin fibroblasts. doi: 10.1155/2012/785743. Oxid. Med. Cell. Longev
    381.Makpol S, A Z, Sairin K, Mazlan M, G M Top.(2010b) γ-Tocotrienol prevents oxidative stress-induced telomere shortening in human fibroblasts derived from different aged individuals. , Oxid.Med. Cell. Longev 3, 35-43.
    382.Lim J J, W Z Ngah, Mouly V, Abdul Karim N. (2013) Reversal of myoblast aging by tocotrienol rich fraction posttreatment. doi: 10.1155/2013/978101. Oxid. Med. Cell. Longev
    383.A J Whitehead, J A Mares, R P Danis. (2006) Macular pigment: A review of current knowledge. , Arch. Ophthalmol 124, 1038-1045.
    384.Palombo P, Fabrizi G, Ruocco V, Ruocco E, Fluhr J. (2007) Beneficial long-term effects of combined oral/topical antioxidant treatment with the carotenoids lutein and zeaxanthin on human skin: A double-blind, placebo-controlled study. , Skin Pharmacol. Physiol 20, 199-210.
    385.Haines D D, Juhasz B, Tosaki A. (2013) Management of multicellular senescence and oxidative stress. , J. Cell. Mol. Med 17, 936-957.
    386.Serra V, T von Zglinicki, Lorenz M, Saretzki G. (2003) Extracellular superoxide dismutase is a major antioxidant in human fibroblasts and slows telomere shortening. , J. Biol. Chem 278, 6824-6830.
    387.Deruy E, Gosselin K, Vercamer C, Martien S, Bouali F. (2010) MnSOD upregulation induces autophagic programmed cell death in senescent keratinocytes. doi: 10.1371/journal.pone.0012712. PLoS. One

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