Influencing Telomere Length: The Long and Short of It
November 1, 2013
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Aging
By Nancy J. Selfridge, MD
Associate Professor, Chair of the Department of Clinical Medicine and Assistant Dean, Clinical Sciences, Ross University School of Medicine, Commonwealth of Dominica, West Indies
Dr. Selfridge reports no financial relationships relevant to this field of study.
Summary Points
- Telomeres are nucleoprotein complexes that protect the ends of chromosomes from progressive loss of genetic material during DNA replication.
- Telomeres shorten with age, oxidative stress, and psychological stress until critical shortening leads to cell senescence and cell death; but telomerase, the RNA transcriptase responsible for adding nucleotides back on to telomeres, is also highly active in cancer cells and contributes to cancer cell immortality.
- Several dietary habits and supplements have shown a correlation with preserved or enhanced telomere length, but more research is needed before strong recommendations can be made promoting these as interventions solely based on their effects upon telomere length.
Telomeres are nucleoprotein complexes found at the extreme ends of eukaryotic chromosomes. They consist of repeats of a six nucleotide sequence and specialized telomere-binding proteins that form a stable T-loop structure, essentially capping the chromosome ends and protecting the genome from degradation during replication and the cell cycle.1 Since Elizabeth Blackburn elucidated the nature of telomeres in her Nobel Prize winning work in the mid-1970s, an explosion of research has followed focusing on interventions to preserve or enhance telomere length as anti-aging and chronic disease prevention strategies. Lifestyle interventions have been examined in both cross-sectional and longitudinal studies. A few nutrients have emerged as essential for telomere preservation in basic science research. One proprietary extract of astragalus has been widely commercially promoted to enhance telomere length. This article reviews recent research on factors affecting telomere length and examines marketing claims promoting telomere-preserving, anti-aging products.
Understanding Telomeres
Telomeres have been likened to the plastic caps at the ends of shoelaces in the way that they protect the ends of chromosomes. DNA replication is a tightly regulated process involving semi-discontinuous DNA synthesis. As DNA "unwinds" in regions to allow replication, both parent strands replicate at the same time but DNA polymerase, the replicating enzyme for this function, can only work in a 5’ to 3’ direction. This means that one strand (the "leading strand") will replicate completely and continuously in one direction from beginning to end, but the other strand (the "lagging strand") has to replicate in short fragments. RNA primers attach to the lagging strand segments and initiate replication by DNA polymerase, and these RNA primers later have to be removed and "back filled" with DNA nucleotides, a process that takes DNA polymerase, RNA nuclease, and DNA ligase. Once the RNA primer is placed on the last piece of the 5’ end of the lagging strand, there is no additional DNA on the parent strand to initiate this "back filling" process. This last RNA primer is eventually destroyed and the genes at this end of the parent strand fail to replicate in the daughter strand. Thus, these terminal genes are vulnerable to deletion with each replication, threatening loss of codons with each cell cycle.
The telomere gene sequences at the ends of chromosomes solve this problem by "taking the hit" — telomere gene loss of about 50 nucleotides and subsequent telomere shortening occur with every cell replication until the telomeres reach certain critical lengths that first result in senescence and finally result in the death of the cell (apoptosis).3 Telomeres also keep the ends of chromosomal DNA from being perceived as double-stranded DNA breaks during cell cycle damage control checkpoints, preventing loss of chromosomal material. Telomere DNA is able to serve this protective function as it is highly stable compared to chromosomal DNA, is not subject to recombination or fusion with other chromosomal DNA, and is not detected by systems of damage recognition of DNA.
Telomere shortening is attenuated to a degree by telomerase, an RNA transcriptase that adds base pairs to the telomeric DNA. Telomerase is present in germ cells, stem cells, and hematopoietic cells, but is inactive in most somatic cells. High levels of telomerase activity correlate with longer telomeres and prevention or postponement of cell senescence, theoretically resulting in cells and tissues with more youthful behavior in terms of health and phenotype. Shorter telomeres have been associated with aging, earlier all-cause mortality, and several chronic diseases, including cardiovascular disease, Alzheimer’s disease, Parkinson’s disease, diabetes, and depression.4,5 Telomere shortening is enhanced by free radicals and oxidative stress as well as psychological stress.4
On the surface, it would seem desirable to find ways to preserve and increase telomere length and telomerase activity in healthy somatic cells as an age- and mortality-prevention strategy. However, increased telomerase activity is also present in 90% of cancers and is one of the biological keys to cancer cell line immortality; telomerase inhibition has become a potential target for anticancer drug research. Some researchers hypothesize that telomeric shortening may be an adaptive mechanism: Planned cell senescence and death may play a role in suppressing cancer emergence, despite the association of short telomeres with increased risk of disease progression and premature mortality in several cancers including breast, prostate, head and neck, and colorectal. Thus, the relationships between telomere length, telomerase function, longevity, and susceptibility to cancer remain complex and unclear.3,4
Recent Research
Caloric restriction appears to extend lifespan in mammals. Kark et al performed a longitudinal study of a cohort of Israeli men (n = 405) and women (n = 204) assessing leukocyte telomere length over time correlated with caloric intake and polyunsaturated fatty acid intake. Dietary intake was assessed at baseline (mean age 30.1 years) by food questionnaire and telomere length was assessed by Southern Blot at baseline and follow up (mean age 43.2 years). This study found an inverse relationship between baseline energy intake and telomere length in men (P = 0.0005) but not in women. Between the highest and lowest quintiles of energy intake, telomere length was different by about 244 base pairs (95% confidence interval [CI], 59-429). Between the highest and lowest quintiles of telomere length, caloric intake difference was about 440 kcal (95% CI, 180-700).6
Mason et al assessed telomere length at baseline and after 12 months in 439 overweight menopausal women randomized to one of four arms: dietary weight loss, diet and aerobic exercise, aerobic exercise, or control. At baseline, measures of telomere length were inversely related to age (P < 0.01) and positively related with fitness measured by maximal oxygen uptake (P = 0.03) but not with body mass index (BMI) or percentage body fat. About 48% of the study cohort experienced a net increase in telomere length and this increase was greatest in subjects with lower telomere lengths at baseline. However, there was no change in telomere length in any intervention group compared to controls.7
Kiefer et al studied cohorts of premenopausal
(n = 36) and postmenopausal (n = 20) women to determine if telomere length was linked to self-reported dietary restraint, defined as chronic pre-occupation with weight and repeated attempts to reduce food intake. They hypothesized that this kind of dietary restraint creates physical and psychological stress and should be associated with shorter telomeres. In both of these small cohorts, higher levels of self-reported dietary restraint were associated with shorter telomere length independent of age, BMI, or smoking status (P < 0.01 for the younger cohort; P < 0.001 for the older cohort).8
Using data from 840 Hispanic, white, and black adults from the Multi-Ethnic Study of Atherosclerosis (MESA) in a cross-sectional study, Nettleton et al evaluated the relationship between telomere length and known dietary patterns, foods, and beverages associated with markers of inflammation. Only processed meat intake was inversely associated with telomere length (P = 0.006).9
Bocardi et al studied the effect of different levels of adherence to a Mediterranean diet in 217 elderly subjects on telomere length and telomerase activity. The high adherence group had longer leukocyte telomere length and higher telomerase activity (P = 0.003 and P = 0.013, respectively) than medium and low adherence groups. The correlation of the Mediterranean diet with telomere length and telomerase activity was independent of age, gender, and smoking status. Higher telomerase levels were associated with increased healthy status as measured by the Barthel Activities of Daily Living Index, a validated questionnaire to assess physical function
(P = 0.022).10
Ornish et al studied the effects of 3 months of intensive lifestyle changes on telomerase activity in peripheral blood mononuclear cells in 30 men with biopsy-proven, low-risk prostate cancer. This lifestyle intervention consisted of a very low fat, whole foods, plant-based diet, 30 minutes of walking 6 days per week, a stress management program 60 minutes daily 6 days per week, and a 1-hour group support session per week. Diet was supplemented with soy (tofu plus soy protein powder), 3 g of fish oil daily, 100 IU of vitamin E daily, 200 mcg of selenium daily, and 2 g of vitamin C daily. Telomerase activity increased significantly from baseline (P = 0.031), and increases in telomerase activity were associated with decreases in low-density lipoprotein cholesterol (P = 0.041) and psychological distress (P = 0.047).11 In a follow-up study 5 years after the original data were collected, blood samples from 10 men in the intervention cohort were evaluated for relative telomere length and telomerase activity again and compared to baseline. They were compared to a control group of 25 men with low-risk prostate cancer who underwent only active surveillance during the study period. The degree of change in telomere length and telomerase activity was studied in relationship to the degree of lifestyle change over this 5-year interval. Relative telomere length increased in the intervention group and decreased in the controls (P = 0.03). Adherence to the lifestyle intervention was determined using a "lifestyle adherence score" and for each percentage increase in this score, relative telomere length increased by 0.07 T/S units (telomere to single copy gene ratio) with a 95% CI of 0.02-0.12 and P value of 0.005. Telomerase activity decreased from baseline in both the intervention and control groups, but significantly less so in the intervention group: average decrease of 0.25 units in the lifestyle intervention group vs 1.08 units in the control group. This difference was not statistically significant (P = 0.64) and was independent of adherence to lifestyle changes.12
Several supplements have been studied for their effects on telomere length and telomerase activity. In a randomized, double-blind, placebo-controlled study of 106 healthy sedentary, overweight, middle-aged, older adults, Kiecolt-Glaser et al found that telomere length increased with decreasing dietary omega-6:omega-3 ratios (P = 0.02).13 In a longitudinal study of 608 subjects with stable coronary artery disease, Farzaneh-Far et al showed that patients with higher omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels had the slowest rate of telomere shortening over 5 years. For each standard deviation of increase in DHA+EPA levels, there was a 32% decrease in the odds of telomere shortening (adjusted odds ratio [OR], 0.68; 95% CI, 0.47-0.98).14
Xu et al performed a cross-sectional analysis of data from 586 participants in the Sister Study, a prospective cohort study of healthy sisters of breast cancer patients, correlating multivitamin and nutrient intake to leukocyte telomere length. Multivitamin use was associated with an average increase in telomere length of 5.1% compared to nonusers (P = 0.002). Higher intakes of vitamins C and E from foods were also associated with greater telomere length independent of multivitamin use.15
Using data from the Long Island Breast Cancer Study project, Shen et al assessed telomere length in 1067 cases and 1110 controls. Breast cancer risk was moderately increased in women with the shortest telomere length and low dietary and supplemental intakes of beta-carotene, vitamin C, and vitamin E (OR [95% CI], 1.48 [1.08-2.03], 1.39 [1.01-1.92], and 1.57 [1.14-2.18], respectively).16
Two recent studies have shown that higher serum 25-hydroxyvitamin D concentrations correlate with longer leukocyte telomere length. Richards et al found that this positive correlation persisted after adjustment for age and other covariates (P ≤ 0.003) in a cohort of 2160 women aged 18-79.17 Liu et al drew their sample of 1424 from participants of the Nurses’ Health Study, further noting that longer telomeres were not associated with 1,25-dihydroxyvitamin D.18
| Table 1: Summary of Interventions Purported to Influence Telomere Length | |
|---|---|
| Intervention | Reaserch |
| Calorie Restriction | Kark et al: longintudinal study in men and women; telomere length inversely associated with caloric intake in men only. |
| Mediterranean diet | Bocardi et al: high adherence to a Mediterranean diet in elderly subjects correlated with longer telomere length independent of age, gender, and smoking status. |
| Intensive lifestyle changes | Ornish et al: an intensive lifestyle program consisting of very low-fat, plant-based diet, 30 minutes of walking 6 days per week, a stress management program 60 minutes daily 6 days per week, and a 1-hour group support session per week correlated with increased telomerase activity after 3 months and a slower decrease in telomerase activity after 5 years; relative telomere length positively correlated with degree of adherence to intensive lifestyle program. |
| Omega-3 fats |
Keicolt-Glaser et al: lower omega-6:omega-3 ratios correlated with longer telomere length. Farzaneh-Far et al: highest omega-3 levels correlated with slowest rates of telomere shortening in subjects with stable coronary artery disease. |
| Multivitamin use | Xu et al: multivitamin use correlated with an average increase in telomere length of 5.1% compared to nonusers in healthy sisters of breast cancer patients. |
| Vitamin D |
Richards et al: higher 25 OH vitamin D levels correlated with longer telomere length. Liu et al: also noted longer telomere length correlated with higher serum 25 OH vitamin D levels but not higher 1,25-dihydroxy vitamin D levels. |
| Astragalus | Harley et al: astragalus root extract activated telomerase activity in vitro in human keratinocytes, fibroblasts, and immune cells; in study subjects provided a proprietary supplement pack including an astragalus root extract, mean telomere length was stable after 1 year, though percent of short telomeres was decreased compared to baseline. |
| Curcumin | Khaw et al: curcumin inhibited telomerase activity and induced telomere shortening in brain cancer cells in vitro. |
| Genistein | Khaw et al: genistein inhibited telomerase activity and induced telomere shortening in brain cancer cells in vitro. |
| Epigallocatechin gallate (EGCG) | Sheng et al: EGCG reduced heart weight indices and inhibited telomere attrition in cardiomyocytes in rats with induced cardiac hypertrophy as well as quercetin and carvidilol. |
| Chlorella vulgaris | Makpol et al: pre- and post-treatment of cells with Chlorella vulgaris prevented peroxide-induced telomere shortening and reduction of telomerase activity in human fibroblasts in vitro. |
Harley et al reported data from 114 subjects (age 63 ± 12 years; 72% male) on a commercial health maintenance program consisting of a comprehensive dietary supplement pack including a proprietary extract of astragalus root. In their study, the astragalus root extract was shown to activate telomerase in vitro in cultured human keratinocytes, fibroblasts, and immune cells. In addition, study subjects demonstrated a reduction in percent of short telomeres compared to baseline after 1 year, though mean telomere length was stable in the cohort. No adverse effects of the proprietary formula were noted at doses of 10-50 mg daily. Several of the authors were subjects in the study and/or had financial interests in the product at the time of publication.19 The proprietary product is marketed by the developers in a 6-month supply package that includes blood work and biomarker tests assessed at baseline and after 6 months of product use, and consultation with an expert age management doctor (ta-sciences.com). The full package is expensive, advertised at $6000 for 6 months, not including the physician consultation or Quest Lab costs.
A few in vitro and basic science studies suggest that additional supplements may affect telomere length in both healthy and cancerous cells. In vitro studies have shown that curcumin and genistein (a soy isoflavone) inhibit telomerase activity and induce telomere shortening in cultured brain tumor cells.20,21 Epigallocatechin gallate (EGCG) compared favorably to quercetin, losartan, captopril, and carvedilol in its ability to reduce heart weight indices and cardiomyocyte apoptosis in rats with induced cardiac hypertrophy. However, only EGCG, quecetin, and carvedilol inhibited telomere attrition.22 Carly et al present convincing biochemical information that folate deficiency induced hypomethylation of DNA and elevated homocysteine levels have a deleterious effect on telomerase activity and telomere length.4
Makpol et al noted that DNA damage, telomere shortening, and reduction of telomerase activity could be induced in human fibroblasts subjected to free radical oxidative stress induced by peroxide. Pre- and post-treatment of the cells with Chlorella vulgaris prevented these effects (P < 0.05).23
Conclusion
It is hard to interpret cross-sectional studies on telomere length because of the large degree of inter-individual difference in telomere length at any given age. Longitudinal studies comparing measures to baselines are better at compensating for these natural differences in telomere length, but still only tell us about correlations. As can be seen, most research to date describes correlations between habits, dietary status, or supplement use and telomere length, and few randomized, controlled trials have been conducted for interventions. Correlations simply don’t tell us about causation and don’t give us enough information to make decisions for our patients or ourselves.
What we know about telomere biology lends testimony to the amazing adaptive nature of the multitude of checks and balances that contribute to cell homeostasis and our health. Because of the complex relationships between telomerase activity, longevity, cell senescence, and cancer biology, it is unwise to say that enhancing telomere length by any pharmacological or nutraceutical means is advisable. However, there are a number of lifestyle habits that appear to positively influence telomere length and are supported by other research as health promoting. Enjoying a Mediterranean diet, avoiding eating too many calories, and consuming fruits and vegetables with high antioxidant levels can all be endorsed, and if these strategies happen to increase telomere length as part of their gift to longevity and health, so much the better. Omega-3 fish oil supplementation, adequate folate through diet, and maintaining high vitamin D serum levels also have proven health-promoting effects and can similarly be endorsed. Until further research is done assessing long-term effects on carcinogenesis, substances specifically taken to increase telomerase activity should be viewed with caution.
References
- Longo D. Chapter 84. Cancer cell biology and angiogenesis. In: Longo R, et al, eds. Harrison’s Principles of Internal Medicine. 18th ed. New York, McGraw-Hill Medical; 2012:674-675.
- Weil P. Chapter 35. DNA Organization, Replication, & Repair. In: Bender DA, et al, eds. Harper’s Illustrated Biochemistry. 29th ed. New York: McGraw-Hill; 2011. Available at: www.accessmedicine.com/content.aspx?aID=55884201. Accessed August 23, 2013.
- Gomez DE, et al. Telomere structure and telomerase in health and disease (review). Int J Oncol 2012;41:1561-1569.
- Puterman E, et al. An intricate dance: Life experience, multisystem resiliency, and rate of telomere decline throughout the lifespan. Soc Personal Psychol Compass 2012:6:807-825.
- Moores CJ, et al. Telomere dynamics: The influence of folate and DNA methylation. Ann NY Acad Sci 2011;1229:76-88.
- Kark JD, et al. Energy intake and leukocyte telomere length in young adults. Am J Clin Nutr 2012;95:479-487.
- Mason C, et al. Independent and combined effects of dietary weight loss and exercise on leukocyte telomere length in postmenopausal women. Obesity 2013 May 3. doi: 10.1002/oby.20509. [Epub ahead of print].
- Kiefer A, et al. Dietary restraint and telomere length in pre- and post-menopausal women. Psychosom Med 2008;70:845-849.
- Nettleton JA, et al. Dietary patterns, food groups and telomere length in the multi-ethnic study of atherosclerosis (MESA). Am J Clin Nutr 2008;88:1405-1412.
- Bocardi V, et al. Mediterranean diet, telomere maintenance and health status among elderly. PLoS ONE 2013; e62781.doi:10.1371/journal.pone.0062781.
- Ornish D, et al. Increased telomerase activity and comprehensive lifestyle changes: A pilot study. Lancet Oncol 2008;9:1048-1057.
- Ornish D, et al. Effect of comprehensive lifestyle changes on telomerase activity and telomerase length in men with biopsy-proven low-risk prostate cancer: 5 year follow-up of a descriptive pilot study. Lancet Oncol 2013;14:1112-1120.
- Kiecolt-Glaser JK, et al. Omega-3 fatty acids, oxidative stress, and leukocyte telomere length: A randomized controlled trial. Brain Behav Immun 2013;28:16-24.
- Farzaneh-Far R, et al. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA 2010;303:250.doi:10.1001/jama.2009.2008.
- Xu Q, et al. Multivitamin use and telomere length in women. Am J Clin Nutr 2009;89:1857-1863.
- Shen J, et al. Telomere length, oxidative damage, antioxidants and breast cancer risk. Int J Cancer 2009;124:1637-1643.
- Richards JB, et al. Higher serum vitamin D levels are associated with longer telomere length in women. Am J Clin Nutr 2007;86:1420-1425.
- Liu JJ, et al. Plasma vitamin D markers and leukocyte telomere length. Am J Epidemiol 2013;177:1411-1417.
- Harley CB, et al. A natural product telomerase activator as part of a health maintenance program. Rejuv Res 2011;14:45-56.
- Khaw AK, et al. Curcumin inhibits telomerase and induces telomere shortening and apoptosis in brain tumor cells. J Cell Biochem 2013;114:1257-1270.
- Khaw AK, et al. Genistein induces growth arrest and suppresses telomerase activity in brain tumor cells. Genes Chromosomes Cancer 2012;51:961-974.
- Sheng R, et al. Epigallocatechin gallate, the major component of polyphenols in green tea, inhibits telomere attrition mediated cardiomyoctye apoptosis in cardiac hypertrophy. Int J Cardiol 2013;162:199-209.
- Makpol S, et al. Chlorella vulgaris modulates hydrogen peroxide-induced DNA damage and telomere shortening of human fibroblasts derived from different aged individuals. Afr J Trad CAM 2009;6:560-572.
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