Since the days of Cleopatra and Ponce de León, if not before, people have been seeking the elusive Fountain of Youth. Until recently, such pursuits were the realm of quacks and charlatans. To be sure, there is no shortage of dubious promises and untested remedies to increase longevity that are available for the naïve or ill-informed. But recent scientific discoveries are bringing respectability to the field, unraveling the secrets of aging on a cellular level and looking for ways to slow it down.  It is, afterall, the workings of the cellular machinery that determines the overall health and functioning of the whole person.

Some critics object to the scientific quest for longevity believing it’s God’s will that we should die when our time comes. But in the past century, a clean water supply, antibiotics, vaccines and improved medical care have significantly boosted life expectancy in the United States—from 48 for men and 51 for women in 1900 to 75 for men and 80 for women today[1]. No one seems to take issue with that. Others express concern that keeping people alive longer will strain societal resources. But that thinking is misguided since the goal is to extend youth not to tack more years of sickness and infirmity to the end of life.

It has been abundantly clear for some time that a healthy lifestyle with regular exercise and a diet that includes lots of fruits, vegetables and whole grains can reduce your risk of chronic diseases and premature death. According to the World Health Organization, 80-90% of cardiovascular disease and nearly 40% of cancers, the two top killers of people worldwide, could be prevented with healthy lifestyle modifications. But is there an underlying biological process that can be exploited to improve, restore and prolong youthful vitality?

In 2009, the Nobel Prize in Medicine was awarded to Elizabeth Blackburn, a molecular scientist and two of her colleagues for their work in uncovering the role of telomeres and the enzyme telomerase in aging, cancer and chronic diseases. Telomeres are snippets of DNA at the ends of chromosomes that function, in part, like the plastic tips on the end of shoelaces, providing stability and protection to the genetic material. Telomerase is the enzyme responsible for rebuilding and maintaining telomeres. Most normal human adult cells do not have enough active telomerase to maintain telomere length indefinitely, and therefore undergo telomere attrition with age. In 1965 a geneticist named Leonard Hayflick discovered that most cells only divide about 80 times, then slow down and die; this has become known as the “Hayflick limit”[2]. Each time a cell divides, the telomere shortens until a critical length is reached, signaling cell senescence or cell death. This progressive telomere shortening is believed to represent a ‘molecular clock’ that underlies aging.[3] Scientific evidence also points to an important role for telomerase activity and telomere length in the causes of human disease. Many human diseases of different origins that are associated with aging, as well as late stages of cancer are characterized by the presence of short telomeres.[4] It then stands to reason that therapies directed at preserving telomere length may slow aging and retard the onset of age-related diseases.

Telomere length is currently the best measure of your actual biological age compared to chronological age. It is also an important barometer of your overall health. Obesity is closely associated with chronic diseases, several cancers and premature death. Obese adults were found to have shorter telomeres than their normal weight counterparts.[5] These findings support the notion that excess body fat may accelerate aging. Exercise, on the other hand, was found to upregulate telomerase activity, which may provide the underlying molecular mechanism for the beneficial effects of physical exercise.[6] Better cardiorespiratory fitness is associated with lower all-cause mortality, coronary heart disease and cardiovascular disease.[7] Similarly, combining the health benefits of regular exercise and a plant-based diet in a comprehensive lifestyle plan was shown to increase telomerase activity by nearly 30%, and resulted in improved telomere length maintenance.[8]

Cardiovascular disease is the number one cause of death worldwide including the United States. Risk factors for cardiovascular disease are well known. Three that cannot be changed are older age, male gender, and a family history of CVD. Other major risk factors include cigarette smoking, high cholesterol, high blood pressure, lack of exercise, diabetes, obesity, increased homocysteine and C-reactive protein levels, certain infections and inflammation, and several psychosocial factors which are all modifiable. Associations with shortened telomere length have been reported for hypertension[9], diabetes[10], insulin resistance[11], atheroclerosis[12], cigarette smoking[13], carotid intima medial thickness[14], vascular dementia[15] and mortality due to heart disease[16]. Another study demonstrated that the association of telomere shortening with cardiovascular disease mortality was independent of chronological age, clinical factors, CRP or echocardiographic findings[17]. If future studies can demonstrate that telomere shortening is a causal factor in the development of cardiovascular disease, not merely an association, it could open new avenues for the development of future preventive and therapeutic treatments[18].

As noted above, psychological stress is a risk factor for cardiovascular disease. Recent findings indicate that chronic psychological stress– both perceived stress and chronicity of stress- and mood disorders are associated with higher oxidative stress, lower telomerase activity, and reduced telomere length.[19] Women with the highest levels of perceived stress were found to have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women.[20]

Although most adult cells have an inactive telomerase enzyme, germ (immune system) cells, embryonic stem cells and adult stem cells, can express an active telomerase enzyme to facilitate rapid cellular replication[21]. Immune cells transiently stimulate telomerase activity in response to an antigen (foreign material or protein). As we age, we experience a decline in total lymphocytes and a reduced ability to respond to immune threats. Telomere shortening is one of the mechanisms that can limit the number of cell divisions, and therefore, impair immune function. Exposure of human lymphocytes to cortisol is associated with a significant reduction in telomerase activity. That finding provides a potential mechanism for stress-associated telomere length attrition. It suggests that strategies to enhance lymphocyte telomerase activity may provide beneficial effects on immune function in situations of chronic emotional stress.[22] The other class of cells that can activate their telomerase enzyme are cancer cells.

Years ago, this association between telomerase and cancer seemed to sprout the misunderstanding that somehow activating telomerase would cause a healthy cell to turn cancerous – directly confer upon it a genetic mutation resulting in cancer. That idea has effectively been put to rest. Telomerase does not cause growth deregulation, gene mutations (oncogenes) do. In fact, telomerase inhibition can be therapeutic in cancer patients, while controlled telomerase activation for degenerative diseases may actually reduce, rather than increase, the frequency of age-related cancers.[23] The legitimate worry that still circulates today is that telomerase expression, while not causing a healthy cell to turn cancerous directly, might provide a slightly longer lease on life for pre-cancerous cells that might otherwise hit the Hayflick limit earlier. Most of the available scientific evidence supports the opposite. That is, enhanced telomerase activity preserves telomere length as we age. That longer telomere length protects the chromosome from the very mutations necessary for cells to become cancerous. Otherwise you would expect the cells that have continually active telomerase (immune cells, and stem cells) to be the most common cell types for cancer; that is not the case. Further, the previously mentioned upregulation of telomerase associated with healthy lifestyles would similarly be expected to result in greater cancer risk but the opposite is true. Numerous studies link shortened telomere length to increased cancer risk.[24] [25] [26]

At then end of the day, advancing age (and its associated telomere shortening) is the biggest risk for cancer development.[27] [28] There is also evidence that whatever your age, having longer telomeres is associated with better health and vitality. Even among centenarians (100 year olds), those classified as healthy (being physically functionally independent without hypertension, heart failure, heart attacks, peripheral vascular disease, dementia, cancer, stroke, chronic obstructive lung disease and diabetes) had significantly longer telomeres than their unhealthy peers.[29]

It may soon be possible to reset your biological clock. A biotech company called Geron Corporation isolated two compounds, Astragaloside and Cycloastragenol, that have demonstrated an ability to activate telomerase and enhance the functional activity of immune cells. These are both naturally occurring substances isolated from the Astragalus plant, a Chinese herb used for its vitality enhancing and immune stimulating properties for centuries. It is not yet clear whether these highly concentrated plant extracts can rebuild telomeres or simply retard telomere attrition. We at Alternity Healthcare are hopeful and currently evaluating two products that promise to revolutionize the way we think about aging. Telomere lenght testing is available right now, and can provide a great reference point to see where you stand on a molecular level.

While the recommendations for living a healthy and vital life well into advanced age are things we have all heard before, the various associations with telomere length and telomerase activity provides mechanisms at the molecular cellular level to support the idea that, at least for the time being, healthy habits are the best way to put more life into your years.

[1] National Vital Statistics Reports. http://www.cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_09.pdf

[2] Hayflick L. “The limited in vitro lifetime of human diploid cell strains.” Experimental Cellular Research. 1965. 37 (3): 614-636.

[3] Blackburn, E. H. Switching and signaling at the telomere. Cell 106, 661–673 (2001).

[4] Shay, J. W. & Wright, W. E. Telomerase: a target for cancer therapeutics. Cancer Cell 2, 257–265 (2002).

[5] Kim S, Parks CG, et al. Obesity and weight gain in adulthood and telomere length. Cancer Epidemiol Biomarkers Prev. 2009 Mar; 18(3):816-20

[6] Wermer C, Furster T, et al. Physical Exercise Prevents Cellular Senescence in Circulating Leukocytes and in the Vessel Wall. Circulation. 2009 Nov 30.

[7] Kodama, S., et al. Cardiorespiratory Fitness as a Quantitative Predictor of All-Cause Mortality and Cardiovascular Events in Healthy Men and Women, JAMA. 2009;301(19):2024-2035.

[8] Ornish D, Lin J, et al. Increased telomerase activity and comprehensive lifestyle changes: a pilot study. Lancet Oncol. 2008;9(11): 1048-1057.

[9] Aviv A, Aviv H. Telomeres and essential hypertension. Am J Hypertens 1999;12:427-32.

[10] Jeanclos E, Krolweski A, et al. Shortened telomere length in white blood cells of patients with IDDM. Diabetes 1998;47:482-6.

[11] Gardner JP, Li S, Srinivasin SR, et al. Rise in insulin resistance is associated with escalated telomere attrition. Circulation 2005;111:2171-7.

[12] Samani NJ, Boutby, R, et al. Telomere shortening in atherosclerosis. Lancet 2001;358:472-3.

[13] Morla M, Busquet X, et al. Telomere shortening in smokers with and without COPD. Eur Respir J 2006; 27:525-528.

[14] O’Donnell CJ, Demisse S, Kimura M, et al. Leukocyte telomere length and carotid intima medial thickness: The Framingham heart Study. Arterioscler Thromb Vasc Biol 2008;28;1165-1171

[15] Von Zglinicki T, Serra V, et al. Short telomeres in patients with vascular dementia: an indicator of low antioxidantive capacity and a possible risk factor? Lab Invest 2000;80:1739-47.

[16] Cawthon RM, Smith KR, O’Brien E, et al. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet 2003;361:393-5.

[17] Farzenah-Far R, Cawthon R, et al. Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: Data from the Heart and Soul Study. Arterioscler Thromb Vasc Biol 2008;28;1379-1384.

[18] Huzen J, de Boer RA, van Veldhuisen DJ, et al. The emerging role of telomere biology in cardiovascular disease. Front Biosci. Jan2010;15:35-45.

[19] Simon NM, Smoller JW, McNamara KL, et al. Telomere shortening and mood disorders: preliminary support for a chronic stress model of accelerated aging. Biol Psychiatry 2006; 60:432-5

[20] Epel ES, Blackburn EH, Lin J, et al. Acelerated telomere shortening in response to life stress. Proc Natl Acad Sci USA. 7Dec2004; 101(49): 17312-5

[21] Gilson E, Londono-Vallejo A. Telomere Length Profiles in Humans. Cell Cycle 2007; 6:2486-2494.

[22] Choi J, Fauce S, Effros R. Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun. 2008 May; 22(4): 600-05

[23] Harley CB. Telomerase is not an oncogene. Oncogene (2002) 21, 494-502 DOI: 10.1038/sj/onc/1205076

[24] Wu X. Telomere length may be associated with risk of smoking related cancers. Journal of the National Cancer Institute 2003 95(16):1181

[25] Shen J, Gammon MD, et al. Telomere length, oxidative damage, antioxidants and breast cancer risk. Int J Cancer. 2009 Apr 1;124(7):1637-43

[26] Sullivan et al. “Telomere Length in the Colon Declines with Age: a Relation to Colorectal Cancer?” Cancer Epidemiology Biomarkers & Prevention. 2006. 15:573-577.

[27] National Institute on Aging. US National Institutes of Health. Cancer Incidence Rate by Age Group. http://www.nia.nih.gov/ResearchInformation/ConferencesAndMeetings/WorkshopReport/Figure1.htm

[28] Jiang H, Ju Z, Rudolph KL. Telomere shortening and ageing. Z Gerontol Geriat 40:314–324 (2007)

[29] Terry D, Nolan V, Anderson S, et al. Association of longer telomeres and better health in centenarians. Journal of Gerontology: Biological Sciences 2008 63A:8:809-812