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Introduction
The Nobel Prize for Medicine (2009) was awarded to E. H. Blackburn, C. W. Greider, and J. W. Szostak for scientific research on telomeres and their controlling enzyme, telomerase. Research into the biological significance of telomeres and telomerase has proceeded at a frenetic pace over the past couple of decades. This area of science remains embryonic, but it holds the promise of providing new frontiers and foundations for understanding the emergence of chronic disease, cancer, and aging. The purpose of this article is to highlight concepts that are most relevant to the introduction of a natural clinical protocol to support the structure and function of telomeres.

The Basics
Telomeres are DNA caps on linear chromosomes that function to prevent aberration or loss genetic of information during cell division.^1-4 These "protective regions" of DNA shorten with repeated cell division in somatic cells. The enzyme telomerase (a reverse transcriptase) acts to extend telomeres and reduce their attrition.

Shortened telomeres may reach a point where they cannot support normal division of chromosomes, resulting in cell senescence (replicative arrest) and abnormal chromosomal function. These changes can result in altered or loss of normal functions of genes, cancer propagation, immune dysfunction, aging of tissues, and the emergence of chronic disease.^5-12

If telomere shortening correlates with age and telomerase can sustain or lengthen telomere, then simple logic dictates that interventions to modulate the telomere/telomerase "duo" present a promising and novel strategy for anti-aging or disease prevention or treatment. While tampering with telomeres and telomerase enchant many scientists and clinicians, matters are not quite as simple as some individuals may have hitherto supposed. Leaders in telomere/telomerase include (by Internet reference) Geron, SpectraCell Laboratories, T. A. Sciences, Natural Clinician, and Sierra Sciences.

Observations on Telomere Tampering
Telomere length and telomerase expression appear to be linked in many but not all studied species of life.^1-10 While telomeres shorten with age, some people start with longer telomeres than others. Shortened telomeres tend to "push" a cell toward senescence prior to apoptosis (cell death), and this chain of events can be variably corrected in vitro and perhaps, safely, in vivo.

Telomerase activity may lengthen telomeres, but this enzyme is found to be expressed preferentially in cancer, certain germ cells, and stem cells (immortal cells). This leaves the unanswered question, will direct telomerase induction lead to cancer? We know relatively little about selective telomerase enhancers (see www.tasciences.com, www.geron.com). This selective approach for telomere support is an important target for pharmaceutical or nutraceutical development as the potential longevity-promoting properties of telomere support emerge.^1-10

Shortened telomeres exert a "telomere position effect" which alters genetic expressions at the cellular level. In this circumstance, DNA repair genes do not exert optimum function and those genes that promote cellular aging may emerge. The aging cell, with its shortened telomere, seems to lead to a circumstance that facilitates or favors mistakes. However, one must pause and think about the induction of cellular senescence with age as a potential defense mechanism against the occurrence of age-related cancer. Senescence and apoptosis serve both aging and disease-prevention options. The gene that regulates telomerase expression is "silenced" in healthy cells. "Switching on" or "switching off" this gene, to a variable degree, is possible by genetic manipulations and the administration of certain compounds.

Telomere loss or compromise is not consistently shown to be telomerase-dependent, and it may not always show a linear relationship with advancing years. For example, loss of telomere length is accelerated in childhood (up to the age of 20 years) and the elderly (greater than 65 years). While telomerase is not expressed in most somatic cells, some cells (expanding immunocytes, germ cells, and cancer cells) express high levels of telomerase. Does telomere shortening in laboratory tests of white blood cells (T-lymphocytes) mirror telomere shortening in other cell types? Further research is required.^1-17

Telomeres loss is associated with sedentary lifestyles, oxidative stress, cancer, insulin resistance, and chronic inflammatory disease … to name a few disorders, but some proportion of "chicken-and-egg" arguments prevail. To add to the conundrum, laboratory studies of germinal centers, which produce B cells (lymphocytes), show that telomere length that can increase, in spite of intense cell replication. Furthermore, some studies imply that telomere loss may not always exhibit a clear correlation with certain cells' history of replicative activity. These factors, and other concerns, may cast doubt on the sensitivity and specificity of some measures of telomere length as a reliable measurement of physiological age.^1-20

A general consensus has emerged that telomere length has reasonable clinical predictive value, but it is only one of several useful biomarkers of age; for example, immune function or the detection of immune senescence. That said, immune senescence seems to be closely related to telomere shortening. The presence of high numbers of certain T-lymphocytes (CD8 and CD28+) in elderly individuals is associated with blunted immune response, and this circumstance has been labeled as an "immune risk phenotypes" that is a predictor of all causes of mortality in the elite elderly >80 years of age.^10-13 Telomerase induction may be a solution to this "immune risk phenotype."

The telomere/telomerase literature is replete with promises of the potential benefit of targeted therapeutic interventions.^1-17 While no pharmaceutical is approved for telomere modulation, natural approaches are emerging with the use of specific dietary supplements (e.g., astragalus extracts; see www.tasciences.com). While this long-term safety or efficacy of nutraceutical interventions for telomere support remain unknown, the desirability of telomere retention or lengthening strategies is such that the use of safe and simple strategies to achieve this outcome seems to be a reasonable intervention.

I propose that this therapeutic approach with a natural protocol for "telomere support" can be applied with optimistic caution by health-care givers. I recommend patient monitoring and surveillance with this novel intervention strategy. However, the protocol that I suggest involves nutritional support and multipronged interventions using natural approaches that have an established precedent of safety. In the essence of any longitudinal safety or efficacy studies, outcome should be monitored on an individual basis by a caregiver.

Chemical Telomere Support
Several factors act to shorten telomere length, and some are amenable to corrections as shown in Table 1.

Table 1: Factors That Alter Telomere Length

                  Factor                                                       Comment

* Somewhat amenable to intervention^1-17

Telomere Support Protocol
Research data and clinical outcome observations permit the recommendation of a clinical protocol for telomere support (Table 2).^1-17 The existence of other "natural protocols" for telomere lengthening (e.g., the Patton Protocol; www.tasciences.com) may be superseded by a more comprehensive approach to telomere support and age management. This proposed protocol for the natural clinician is best summarized in line item statements:

• Initial telomere testing is recommended. The most available commercial telomere analysis in the US, at the time of writing, is provided by SpectraCell laboratories of Houston, Texas (www.spectracell.com). These laboratories provide a "telomere score," by measuring telomere length on T lymphocytes. The score is derived from comparisons of the measurement with results obtained from an American population within the same age range. This test is generally accepted as an efficient method to assess biological age (with certain reservations), and it can be interpreted with other biomarkers of aging; for example, cardiorespiratory functions, skin characteristics, eyes, renal function, immune function, and sexual functions. Interval telomere scores may be obtained on an annual basis, and biomarkers of aging can be monitored regularly by the caregiver.

• Lifestyle change. Many positive lifestyle changes may inhibit telomere shortening. These include optimum nutrition, weight control, stress reduction, withdrawal of substances of abuse (simple sugar, tobacco, alcohol, unnecessary prescription, over-the-counter, or illicit drugs) and the restoration of normal sleep patterns.

• Dietary supplements. A number of nutraceutical are associated with supporting telomere structure and function, including extracts of Gingko biloba, astragalus, Chinese ginger root, vitamin D, folic acid (and perhaps vitamin B12), nicotinamide, and omega-3 fatty acids (Table 2). Studies imply that multivitamin and/or antioxidant use may be associated with enhanced telomere length or interference with telomere shortening. Elevated levels of blood homocysteine should be addressed (folic acid, vitamin B12, etc.).

Table 2: An Emerging Evidence Base for Nutraceuticals That Support the Structure and Function of Telomeres

                  Nutraceutical                               Evidence Base for Use

Dietary supplementation is not a substitute for specific dietary guidelines in the quest for telomere support. In brief, the anti-aging, telomere-supporting diet should involve:

• Reductions in simple carbohydrate intake with increase in dietary fiber intake (to counter insulin resistance).
  
  
• Nutrient dense food selections that are low in calories. Calorie restriction enhances maximum and average lifespan and this process may be enhanced by the use of calorie restriction mimetic compounds.
  
  
• High antioxidant load in a diet rich in fruit and vegetables. Multivitamins taken in greens, berries, and fruit and vegetable mixes are a preferred form of general nutritional support. Phytonutrients are vitamin cofactors and provide an antioxidant food.
  
  
• Enrich sources of omega-3 fatty acids in active forms, such as cold-water fish.
  
  
• Decreased sources of saturated fat, hydrogenated oils, and trans fatty acids.
  
  
• Average balance protein intake with rotation among meat, dairy, vegetable, and fish protein sources (not greater than 1gm/kg of body weight per day, unless otherwise indicated).
  
  
• Intermittent short periods of fasting and methods for body detoxification (dietary and otherwise) may support telomere structure and function.
  
  
• Disease management. A clear association exists between common diseases (cancer and degenerative diseases) and shortening of telomere length; for example, cardiovascular disease (atherosclerosis), hypertension, insulin resistance (metabolic syndrome X), diabetes mellitus, and diseases associated with cognitive decline (dementia). Meticulous management of comorbid conditions is obligatory. Metabolic syndrome X and diabetes are classic disorders of premature aging.
  
  
• Miscellaneous factors. Every attempt should be made to tackle the following issues with appropriate medical interventions. Attempts to eliminate coronary heart disease and atherosclerosis risk factors must be applied; for example, reduce LDL (target <90 mg%>, reduce oxidized and dense particle size LDL, increase HDL. Control blood glucose (important in both established and prediabetes or metabolic syndrome X), control blood pressure, keep blood homocysteine in check, reduced chronic inflammation (monitor C-reactive protein, maintain HS-CRP <1).

Instituting an exercise program is obligatory, linked to levels of aerobic fitness (professional trainers recommended). Control of weight with holistic interventions of diet, exercise, behavior modification, and supplement adjuncts are mandatory. Interventions that support stem cell functions, increase nitric oxide signaling, improve mitochondrial function, detoxify the body, and optimize hormonal controls (e.g., bioidentical hormone therapy) may be valuable adjunctive approaches to telomere support.

Specific Nutraceutical Interventions
I propose a synergistic combination of herbs, botanicals, and nutrients for the nutritional support of telomere structure and function (compatible with guidelines of the US Dietary Supplement Health and Education Act, 1994). This nutraceutical approach is based on evidence of good scientific agreement in reviewed medical literature. It is not possible to provide a detailed overview of all nutritional agents that are putative agents for telomere support in this short article. Table 2 summarizes an evidence-based nutraceutical approach, within the limits of current research and knowledge in natural therapeutics.^18-31

A combined use of the natural agents is proposed as more versatile and powerful than the use of single agents alone in the nutritional support of telomeres. A consensus has not emerged on the best nutraceutical approach for telomere support, but the author proposes the use of combinations of natural agents that act on different aspects of the cascades of events that support telomere structure and function. This is a synergistic approach.

Much attention has been paid to the phenomenon of telomerase activation in therapeutics. Gingko biloba extracts, astragalus extracts (TA 65), and perhaps Chinese gingerroot have been proposed as botanical approaches that may activate telomerase. TA-65 is a specific activator of telomerase (www.tasciences.com, www.geron.com). In a clinical study, which remains somewhat incomplete in its reporting at the time of writing, the astragalus extract (TA-65) showed an ability to enhance immune function (a known consequence of the use of astragalus species) and improve certain biomarkers of aging. Improvements in eyesight, sexual function and cutaneous signs were noted but these benefits cannot be separated from the variable comprehensive care given during the administration of TA-65 (see www.tasciences.com).

The association of vitamin D, marine omega-3 fatty acids, and statins (HMG-CoA reductase inhibition) with positive effects on telomere-dependant senescence appears to be supported by credible scientific studies. "Statin effects" can be achieved in natural therapeutics by using red yeast rice which contains lovastatin. The nutritional cofactors folic acid and vitamin B12 are important for the maintenance for DNA integrity.

The value of antioxidants or multivitamin administration in telomere support is apparent in recent population studies, and N-acetylcysteine has been shown to block the nuclear loss of hTERT into cell cytoplasm. This latter action of N-acetylcysteine was shown in endothelial cells that take on early senescent properties when attacked by reactive oxygen species (oxidant molecules). Similar findings are apparent with the administration of alpha-tocopherol (vitamin E components), which has been shown to inhibit telomere shortening (with retention of telomerase enzyme activity) in endothelial cells that are present in the microvasculature of the brain.

I propose that an evidence-based natural protocol can be applied to support the structure and function of telomeres by telomerase-inducing and non-telomerase-dependent mechanisms that are not completely defined. In summary, this protocol (www.naturalclinician.com) involves: positive lifestyle change, nutritional support with combinations of dietary supplements to contribute to the healthy telomere structure and function, monitoring of clinical outcome.

Conclusion
In my educational columns on natural therapeutics, I have focused on three very important issues in anti-aging or regenerative medicine. These areas include stem cell support, the use of calorie restriction mimetics, and support for telomere structure and function (the "Anti-Aging Trilogy"). I believe that these three areas of longevity medicine interdigitate to create the most important and promising frontier for "turning back the clock" in the field of anti-aging medicine.

Notes

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8. Blasco MA, Gasser SM, Lingner J. Telomeres and telomerase. Genes Dev. 1999;13;2353-2359.
9. Hemann MT, Strong MA, Hao LY and Greider CW. (2001) The shortest telomere, not average telomere length, is critical for cell viability and chromosome stability. Cell;107:67-77.
10. de Lange T. Structure and variability of human-chromosome ends. Mol Cell Biol. 1990;10:518-527.
11. Kipling D and Cook HJ. (1990) Hypervariable ultra-long telomeres in mice. Nature  347:400-402.
12. Yamaguchi Y, Nozawa K, Savoysky E, Hayakawa N, Nimura Y, Yoshida S. Change in telomerase activity of rat organs during growth and aging. Exp Cell Res. 1998;242:120-127.
13. Slagboom PE, Droog S, Boomsma DI. Genetic determination of telomere size in humans: a twin study of three age groups. Am J Hum Genet. 1994;55:876-882.
14. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;345:458-460.
15. Kim NW, Piatyszek MA, Prowse KR, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994;266:2011-2015.
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17. Kyo S, Takakura M, Kanaya T, et al. Estrogen activates telomerase. Cancer Res. 1999;59:5917-5921.
18. Reviewed at Tasciences.Com; accessed February 6, 2010.
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20. Saretzki G, Von Zglinicki T. Replicative aging, telomeres, and oxidative stress. Ann NY Acad Sci. 2002;959:24-29.
21. Shen J et al. Telomere length, oxidative damage, antioxidants and breast cancer risk. Int J Cancer. 2009;124:1637-1643.
22. Richards JB et al. Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women. Am J Clin Nutr. 2007;86(5):1420-1425.
23. Cattaneo PL et al. Telomere length in peripheral blood mononuclear cells is associated with folate status in men. J Nutr. 2009;139(7):1273-1278.
24. Bull CF et al. Telomere length in lymphocytes of older south Australian men may be inversely associated with plasma homocysteine. Rejuvenation R. Sep. 28, 2009.
25. Kang HT Lee HI, Hwang ES. Nicotinamide extends replicative lifespan of human cells. Aging Cell. 2006;5:423-436.
26. Xu Q et al. Multivitamin use and telomere length in women. Am J Clin Nutr. 2009;89(6):1857-1863.
27. Tanaka Y, Moritoh Y, Miwa N. Age-dependent telomere-shortening is repressed by phosphorylated alpha-tocopherol together with cellular longevity and intracellular oxidative-stress reduction in human brain microvascular endotheliocytes. J Cell Biochem. 2007;102(3)689-703.
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30. Haendeler, op cit.
31. Spyridopolous I et al. Statins enhance migratory capacity by upregulation of the telomere repeat-binding factor TRF2 in endothelial progenitor cells. Circulation. 2004;110;3136-3142.
32. Xu D et al.; D X et al. J Cardiovasc Pharmacol. 2007;4-9;111-115.