Health-e-Solutions-House-of-HealthHealth-e-Solutions comment: Lise Alschuler, ND, FABNO, is a naturopathic physician with board certification in naturopathic oncology. She provides “eloquent evidence of how whole person, lifestyle-based health optimization powerfully translates into healthy longevity” through its telomere-lengthening capacity. Indeed, it provides convincing evidence that our 5 pillars of thriving health – nutrition,that put the body in a position of strength may also play a critical role in preventing the progression of chronic lifestyle diseases.

(Source)

Abstract
Telomeres are protective caps on the end of chromosomes that confer genomic stability. With each cell division, the telomere is shortened, until ultimately reaching a length that destabilizes the chromosome. At this point, the cell dies. Systemically and over a lifespan, abnormal telomere shortening predicts risk for chronic diseases, namely cardiovascular disease and cancer. The opportunity to improve healthy longevity lies in preventing premature telomere shortening. The enzyme telomerase preserves telomere length and is modifiable by various lifestyle factors. The impact of various components of lifestyle on telomerase activity validates a whole-person, preventive approach to health optimization and disease risk reduction.

Introduction
The fact that we are not immortal beings may be deduced down to the unique tips of our chromosomes, known as telomeres. Discovered in 1938 by Hermann Muller,1telomeres are DNA structures at the ends of our chromosomes that are not coding regions, and thus do not express any proteins. In the 1960s, researchers recognized the fact that the ends of chromosomes, the telomeres, did not replicate fully during cell division, and, in fact, shortened with each division. This observation led to the understanding that these end caps served a critical function in cell division and that their gradual disappearance was correlated with the senescence of the cell.

Telomeres were granted a biological clock function and provided an explanation of the finite nature of cell division and ultimately the unavoidable mortality of the host organism.

Further investigation in the 1970s and 1980s led to the discovery of an enzyme whose sole purpose is to preserve the length of the telomere end cap on replicating DNA. This enzyme, found by Carol Greider and Elizabeth Blackburn, was dubbed “telomerase.”2Telomerase elongates telomeres, an activity critically important in cells that must preserve immortality, such as germ cells and stem cells. Telomerase, once thought to be inactive in normal somatic cells,3 is now known to have minimal, but detectable levels in various adult cells including epithelial and endothelial cells, as well as fibroblasts.

The expression of telomerase may be modified by various lifestyle factors, such as smoking and perceived stress.4,5 The emerging paradigm is that telomerase activity is highly adaptive, and understanding influences on telomerase has become an important avenue to understanding cellular health and longevity.

Cellular Health

Telomeres are often referred to as protective caps on the ends of chromosomes, because their double-looped structure prevents chromosomal end-to-end fusions and chromosomal erosion. Prevention of these chromosomal events is critical to maintaining chromosomal stability, particularly through the very fragile event of cell division. Without such protection, cellular divisions are more at risk of creating aneuploid daughter cells (cells with an abnormal number of chromosomes), a hallmark of many cancers.

A chromosome with abnormally shortened telomeres to the point of leaving the chromosome essentially uncapped will result in highly unstable DNA and activation of p53 gene. The p53 gene initiates apoptosis (cell suicide). Thus, while shortened telomeres are part of the normal senescence of cells, premature shortening can threaten the integrity and viability of the cell.

Interestingly, telomere length is not consistent. Telomere length varies between individuals, organs, cell types, and even between chromosomes.6What is universal is the steady decline in telomere length over the lifespan of an organism. It is also true that telomeres shorten in an accelerated fashion with the onset of disease.7  One hypothesis for this is that many chronic diseases are marked by inflammation, which involves an increased production of inflammatory cytokines, many of which increase cell proliferation.

Since it is normal for the telomere to shorten with each cell division, increased cell proliferation would clip the telomeres at a more rapid rate than would occur normally. In this manner, chronic inflammation may result in increasingly unstable chromosomes, creating cells prone to aneuploidy and early senescence.

Measuring Telomeres

Telomere length in leukocytes has been shown to be consistently higher in childhood, somewhat shorter in adulthood, and significantly shorter at advanced age.8  This provides a backdrop of average ranges based on normal biological aging against which an individual’s telomere length test can be compared. Again, shortened telomere length portends greater risk of chronic degenerative diseases. However, the interpretation of telomere testing is not straightforward. Leukocyte telomere length is affected by immune activity, which means that leukocyte telomere length is actually reflective of systemic inflammation in addition to biological aging. Differences in telomere length exist between ethnicities—for instance African Americans generally have longer telomeres than white Americans—and between genders (women tend to have longer telomeres than men).9  Reference ranges based on age, gender, and ethnicity have yet to be reliably determined, confounding the utility of telomere length testing.

Telomerase
Telomerase is an enzyme, a complex of RNA and protein components that preserves telomere length or elongates it. Telomerase expression is high during embryonic development and is regularly expressed in other highly proliferative cells such as lymphocytes, skin keratinocytes, stem cells, and malignant cells.10  Of note, malignant cells can also elongate their telomeres via a telomerase-independent path involving a recombination mechanism.11  This makes malignant cells the exception to the rule regarding telomerase activation and restoration. Stem cells, on the other hand, normally have constitutively expressed telomerase granting them the ability to serve as replacements for senescent and apoptotic cells. In nonmalignant differentiated cells, telomerase activity is modifiable and affected by a variety of environmental factors. In this way, telomerase activity may represent one of the most important ways in which lifestyle is translated to illness or health and, ultimately, longevity.

Longevity

The link between telomere length and lifespan is an emerging picture. Most of the research in this area has been conducted on rodents. In rodents, longer telomere lengths do not confer additional lifespan. However, shortened telomeres, not the average telomere length overall, appear to have a tight correlation with a shortened lifespan.12  This suggests that there is some redundancy in telomeres, and abnormal and pervasive shortening of telomeres has the most significant effect on curtailing longevity. Once telomeres shrink to a certain length, chromosomal instability, apoptosis, and ultimately senescence will occur.13  On average, over a normal human lifespan, this point of deficient length consistent with chromosomal instability, is reached after 50 cell population doublings. While this poses a finite limit to lifespan, it also implies that any condition that induces faster cell replication will contribute to early senescence and premature death.

One of the most prevalent conditions that increases cell replication is inflammation. Due to the cytokine environment attendant to inflammation, the rate of cell division increases under conditions of inflammation and oxidative stress. This ultimately leads to prematurely shortened telomeres and early senescence.

Factors that Shorten Telomeres

A variety of factors are known to prematurely shorten telomeres. Perhaps most influential is oxidative stress. This has been aptly demonstrated in smokers who have an increased oxidative burden and decreased telomere lengths.28  Oxidative stress causes single-strand breaks in telomeres and subsequent shortening.29  Another demonstration of the effect of oxidative stress on telomere length comes from a study of 4,117 female participants in the Nurses’ Health Study.30  This study found that women under the age of 50 and those who slept less than 6 hours per night had significantly shorter telomeres than women who slept at least 9 hours. Shortened sleep is associated with decreased melatonin, a critical antioxidant. Thus, one consequence of shortened sleep duration is the reduced antioxidant effects of melatonin, thereby increasing the oxidative damage to telomeres.

In a sense, telomeres are genomic scribes, recording and reacting to the various insults that we accumulate over our lifetime.

Inflammation, another consequence of sleep deprivation, is also correlated with shortened telomeres. One characteristic of inflamed tissue is stimulation of cell proliferation, and this increased cell turnover would necessarily shorten telomeres.31 If sufficiently widespread, the resulting chromosomal instability leaves the tissue vulnerable to the dysfunction. This may be one of the underlying links between chronic inflammation and chronic diseases, such as cardiovascular disease and cancer.

Psychological stress also impacts telomeres. Adverse childhood events correlate with shortened telomeres in adulthood with the greater number of adverse events directly proportional to the degree of telomere shortening.32  Depressive symptoms in young adults are longitudinally associated with shorter telomeres.33  There is even some suggestion that telomere length is socially patterned in that a history of childhood socioeconomic hardship is correlated with shorter telomere length in young adults.34

The fact that various forms of stress during childhood are associated with shortened telomeres suggests childhood as a particularly sensitive time for telomere reduction.

Stress in adulthood is impactful to telomere length as well. Marital status, as an indicator of social support and connectedness, is correlated with telomere length. Unmarried individuals have shorter telomeres than their age-, gender-, and ethnicity-matched married counterparts.35In general, emotional distress, particularly when experienced as a child, impacts telomeres, and ultimately, genomic stability in adulthood.

Factors that Activate Telomerase, Thereby Lengthening Telomeres

A number of factors appear to increase telomerase activity, thereby preserving telomere length. In general, a healthy lifestyle is associated with longer telomeres and increased telomerase. A pivotal pilot study of 30 men with low-risk prostate cancer by Dean Ornish and colleagues assessed telomerase activity at baseline and after 3 months of a comprehensive lifestyle change program.36

The lifestyle program consisted of a low-fat (10% of calories from fat), whole-foods, plant-based diet high in fruits, vegetables, unrefined grains, and legumes and low in refined carbohydrates; moderate aerobic exercise (walking 30 min/day, 6 days/week); stress management (gentle yoga-based stretching, breathing, meditation, imagery, and progressive relaxation techniques 60 min/day, 6 days/week), and a 1-h group support session once per week. The diet was supplemented with soy (one daily serving of tofu plus 58 g of a fortified soy protein powdered beverage), fish oil (3 g daily), vitamin E (100 IU daily), selenium (200 mcg daily), and vitamin C (2 g daily). Telomerase activity increased 29.84% during the course of the 3-month intervention; however, because of the relatively small number of patients, these findings are preliminary.

A subsequent cross-sectional analysis of 5,862 women in the Nurses’ Health Study also assessed the relationship between healthy lifestyles and leukocyte telomere length.37  The 5 areas of lifestyle that were defined as healthy low-risk lifestyle practices were: not smoking, maintenance of a healthy body weight (BMI 18.5–24.9 kg/m2), regular moderate or vigorous physical activities (>150 minutes/week), moderate alcohol intake (1 drink/week to <2 drinks/day), and eating a healthy diet (higher intakes of vegetables, fruit, nuts, soy, cereal fiber, chicken, and fish with low consumption of red meat and trans and saturated fat). While none of the individual low-risk factors was associated with telomere length, there was a combined effect such that, for instance, women with all 5 lifestyle practices had 31.2% increased telomere length; women with 4 of the practices had 22.6% longer telomeres.

Other studies have found an association between individual lifestyle practices and telomere length. Exercise—specifically moderate- to vigorous-intensity exercise (>2.5 hours per week)—is associated with increased telomere length. Various nutritional factors have been associated with increased telomere length. High vegetable intake, specifically carotene-rich foods,38multivitamin use,39 and fiber40 have each been associated with longer telomeres. Hormones also affect telomerase. Estrogen results in increasing telomerase activity, lengthening the telomere.41 While this may explain why women live, on average, longer than men, this also has worrisome implications for estrogen receptor positive cancers and may influence one way in which these cancers gain their immortal characteristics.

Conclusion
Telomere biodynamics offers valuable insight into deciphering the influence of environment upon genetic expression and biological health. In a sense, telomeres are genomic scribes, recording and reacting to the various insults that we accumulate over our lifetime. In younger adults, telomere length is an eerily accurate record of social, psychological, and oxidative injury sustained as children and adolescents. In older adults, telomere length becomes the genomic seer, forecasting the likelihood of premature demise into chronic disease and death. And, like any good scribe or seer will attest, their recounting and predictions can be swayed by certain influences. Similarly, telomere shortening is not cast in stone, but is, in fact, a modifiable phenomenon, most dramatically by the manner in which we live our lives. Stress and mood, sleep, diet and activity are foundational strategies for living well, in part, for the direct genomic stabilization that they induce by upregulating telomerase. In fact, the dynamics of telomeres provides eloquent evidence of how whole person, lifestyle-based health optimization powerfully translates into healthy longevity.

References

  1. Muller HJ. The remaking of chromosomes. Collecting Net. 1938;13:15.
  2. Greider CW, Blackburn EH. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts.Cell. 1985;43(2):405–413
  3. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts.Nature.1990;345(6274):458–460.
  4. O’Donovan A, Tomiyama A, Lin J, et al. Stress appraisals and cellular aging: A key role for anticipatory threat in the relationship between psychological stress and telomere length. Brain Behav Immun. 2012; 26(4):573-579.
  5. Epel ES, Lin J, Wilhelm FH, et al. Cell aging in relation to stress arousal and cardiovascular disease risk factors.Psychoneuroendocrinology. 2006; 31(3):277-287.
  6. Oeseburg H, de Boer RA, van Gilst WH, van der Harst P. Telomere biology in healthy aging and disease. Pflugers Arch. 2010;459(2):259-268.
  7. Steffens JP, Masi S, D’Aiuto F, Spolidorio LC. Telomere length and its relationship with chronic diseases – New perspectives for periodontal research. Arch Oral Biol. 2012;S0003-9969(12)00330-5.
  8. Aubert G, Lansdorp PM. Telomeres and aging. Physiol Rev. 2008;88(2):557–579.
  9. Hunt SC, Chen W, Gardner JP, et al. Leukocyte telomeres are longer in African Americans than in whites: The National Heart, Lung, and Blood Institute Family Heart Study and the Bogalusa Heart Study. Aging Cell. 2008;7(4):451–458
  10. Bischoff DS, Makhijani NS, Yamaguchi DT. Constitutive expression of human telomerase enhances the proliferation potential of human mesenchymal stem cells. Biores Open Access. 2012;1(6):273-279.
  11. Bryan TM, Reddel RR. Telomere dynamics and telomerase activity in in vitro immortalised human cells. Eur J Cancer.1997;33(5):767–773.
  12. Hemann MT, Strong MA, Hao LY, Greider CW. The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell. 2001;107(1):67–7
  13. Kurz DJ, Decary S, Hong Y, Trivier E, Akhmedov A, Erusalimsky JD. Chronic oxidative stress compromises telomere integrity and accelerates the onset of senescence in human endothelial cells. J Cell Sci. 2004;117:2417–2426.
  14. Günes C, Rudolph KL. The role of telomeres in stem cells and cancer. Cell. 2013;152(3):390-393.
  15. Fukasawa K. P53, cyclin-dependent kinase and abnormal amplification of centrosomes. Biochim Biophys Acta.2008;1786(1):15-23.
  16. Batista LF, Artandi SE. Telomere uncapping, chromosomes, and carcinomas. Cancer Cell. 2009;15(6):455-457.
  17. Willeit P, Willeit J, Mayr A, et al. Telomere length and risk of incident cancer and cancer mortality. JAMA. 2010;304(1):69-75.
  18. M’kacher R, Bennaceur-Griscelli A, Girinsky T, et al. Telomere shortening and associated chromosomal instability in peripheral blood lymphocytes of patients with Hodgkin’s lymphoma prior to any treatment are predictive of second cancers. Int J Radiat Oncol Biol Phys. 2007;68(2):465-471.
  19. Hackett J. and Greider C. Balancing instability: dual roles for telomerase and telomere dysfunction in tumorigenesis.Oncogene. 2002;21(4):619-626
  20. Demissie S, Levy D, Benjamin EJ, et al. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell. 2006;5(4):325–330.
  21. Sampson MJ, Winterbone MS, Hughes JC, Dozio N, Hughes DA. Monocyte telomere shortening and oxidative DNA damage in type 2 diabetes. Diabetes Care. 29(2):283–289.
  22. Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH. Telomere shortening in atherosclerosis. Lancet.2001;358(9280):472–473.
  23. Ye S, Shaffer JA, Kang MS, et al. Relation between leukocyte telomere length and incident coronary heart disease events (from the 1995 Canadian Nova Scotia Health Survey). Am J Cardiol. 2013;111(7):962-967.
  24. Yang Z, Huang X, Jiang H, et al. Short telomeres and prognosis of hypertension in a Chinese population.Hypertension. 2009;53(4): 639–645.
  25. Samani NJ, Boultby R, Butler R, Thompson JR, Goodall AH. Telomere shortening in atherosclerosis. Lancet.2001;358(9280):472–473.
  26. Chimenti C, Kajstura J, Torella D, et al. Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res. 2003;93(7):604–613
  27. Starr JM, McGurn B, Harris SE, Whalley LJ, Deary IJ, Shiels PG. Association between telomere length and heart disease in a narrow age cohort of older people. Exp Gerontol. 2007;42(6):571–573.
  28. Morlá M, Busquets X, Pons J, Sauleda J, MacNee W, Agusti AG. Telomere shortening in smokers with and without COPD. Eur Respir J. 2006;27(3):525–528.
  29. von Zglinicki T, Pilger R, Sitte N. Accumulation of single-strand breaks is the major cause of telomere shortening in human fibroblasts. Free Radic Biol Med. 2000;28:64–74.
  30. Liang G, Schernhammer E, Qi L, Gao X, De Vivo I, Han J. Associations between rotating night shifts, sleep duration, and telomere length in women. PLoS One. 2011;6(8):e23462.
  31. Demissie S, Levy D, Benjamin EJ, et al. Insulin resistance, oxidative stress, hypertension, and leukocyte telomere length in men from the Framingham Heart Study. Aging Cell. 2006;5(4):325–330.
  32. Kiecolt-Glaser JK, Gouin JP, Weng NP, Malarkey WB, Beversdorf DQ, Glaser R. Childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation. Psychosom Med. 2011;73(1):16-22.
  33. Phillips AC, Robertson T, Carroll D, et al. Do symptoms of depression predict telomere length? Evidence from the west of Scotland twenty-07 study. Psychosom Med. 2013;75(3)288-296.
  34. Robertson T, Batty GD, Der G, et al. Is telomere length socially patterned? Evidence from the west of Scotland twenty-07 study. PLoS One. 2012;7(7):e41805.
  35. Mainous AG 3rd, Everett CJ, Diaz VA, et al. Leukocyte telomere length and marital status among middle-aged adults.Age Ageing. 2011;40(1):73-78.
  36. Ornish D, Lin J, Daubenmier J, et al. Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol. 2008;9(11):1048-1057.
  37. Sun Q, Shi L, Prescott J, et al. Healthy lifestyle and leukocyte telomere length in U.S. women. PLoS One. 2013;7(5):e38374.
  38. Marcon F, Siniscalchi E, Crebelli R, et al. Diet-related telomere shortening and chromosome stability. Mutagenesis. 2012;27(1): 49–57.
  39. Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H. Multivitamin use and telomere length in women. Am J Clin Nutr. 2009;89(6):1857-1863.
  40. Cassidy A, De Vivo I, Liu Y, et al. Associations between diet, lifestyle factors, and telomere length in women. Am J Clin Nutr. 2010;91(5):1273-1280.
  41. Kyo S, Takakura M, Kanaya T, Zhuo W, Fujimoto K, Nishio Y, Orimo A, and Inoue M. Estrogen activates telomerase.Cancer Res. 1999;59(23):5917-1521.