Optimal Longevity Hinges on Telomeres

 

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,¹ telomeres 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.”² Telomerase 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.

 

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.⁶ What 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.

 

There are several techniques available to measure telomere length; however, the majority of these are reserved for the research setting due to the large quantity of genetic material required. The most commonly used technique in commercial laboratories is a real-time polymerase chain reaction (PCR)-based method. The results are reported as a relative ratio of telomere quantity divided by a reference gene quantity (T/S ratio). Typically telomere length is measured in leukocytes, as these cells offer the advantage of accessibility.

 

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 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.

 

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.

 

A systemic shortening of telomeres, as measured by lymphocytes, is associated with an increased risk of cancer. Lymphocytes are used to represent telomeres systemically due to their accessibility and predictive correlation with telomeres in cells throughout the body. In the case of malignancy, telomeres are shortened in lymphocytes at the same time that they are lengthened in malignant cells. The apparent paradoxical role of telomere shortening and activated telomerase is best clarified when one considers the chronology of these events. Shortened telomeres and the associated chromosomal instability is an initiating event in carcinogenesis.¹⁴ As mentioned, shortened telomeres predispose cells to chromosomal defects. Cellular defects activate p53-induced cell repair mechanisms. In cells with defective p53 (over 50% of all malignancies),¹⁵ the p53 is unable to activate cell repair or apoptosis. These damaged, often aneuploid cells are then able to develop into malignancy. The most common sites of malignancy (colon, breast, prostate, lung) are all highly proliferative epithelial tissues in which the high rate of cell divisions prematurely shortens telomeres.¹⁶

 

The clinical significance of telomere shortening and cancer was eloquently illustrated in a 10-year study published in the Journal of the American Medical Association, which demonstrated a direct correlation between shortened telomeres and both an increased risk of developing cancer and increased risk of dying from cancer—especially cancer of the lung, breast, prostate, and colon.¹⁷ Specifically, short telomere length at baseline was associated with a 3-fold increase in risk of cancer and a 2-fold increased risk of cancer mortality. In another analysis of patients with Hodgkin’s lymphoma, those individuals with shortened lymphocyte telomeres before treatment were at significantly higher risk of developing secondary cancers.¹⁸

 

Activated telomerase, on the other hand, while present in more than 90% of malignancies, does not occur until late in tumorigenesis.¹⁹ In fact, the activation of telomerase may be a response to the chromosomal instability in order to stabilize chromosomes and prevent further instability. Thus, when viewed chronologically, both shortened telomeres and subsequently activated telomerase contribute to the durability of malignancy.

 

Cardiovascular disease is highly linked to shortened telomere length. Underlying metabolic conditions that increase cardiovascular disease risk such as insulin resistance²⁰ and diabetes²¹ are both linked to shortened telomere length. The first clinical study that linked coronary artery disease (CAD) with telomere length (Samani et al, 2001) found that leukocyte telomere length in patients with CAD was significantly shorter than in controls.²² This has been confirmed in several studies since; however, a recent prospective study found that over a mean follow-up of 8.7 years, there was a nonlinear relationship between telomere length and the incidence of coronary heart disease (CHD).²³ While there was increased risk of CHD with shorter telomere length, after controlling for demographics, traditional risk factors, and cardiovascular inflammatory biomarkers (high sensitivity C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1), only the middle telomere length had significantly elevated risk (63%) for CHD (P=0.02), whereas the association between shortest telomeres and CHD incidence did not reach statistical significance. This confuses the outright association between telomeres and cardiovascular disease, but in this study, by controlling for inflammation, the effect of shortened telomeres may have diminished. It is possible that it is when telomeres shorten as a result of inflammation that the risk of subsequent disease is the most significant.

 

While the above study had a nonlinear association with overall CHD and telomere length, the association of shortened telomeres, again measured in circulating lymphocytes, with specific cardiovascular diseases is well evidenced. For instance, individuals with shortened telomeres are more likely to develop hypertension and atherosclerosis.²⁴ Children of parents with CAD have shorter telomeres compared to children of parents without CAD,²⁵ suggesting a genetic or epigenetic aspect to telomere shortening and providing a possible explanation of familial risk of CAD. Chronic heart failure is associated with telomere shortening as well. Individuals with chronic heart failure (CHF) have shorter telomere length than do healthy matched controls.²⁶ Finally, shortened telomeres are associated with reduced functionality of the heart as measured by ejection fraction.²⁷

 

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.

 

 

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.³⁵ In general, emotional distress, particularly when experienced as a child, impacts telomeres, and ultimately, genomic stability in adulthood.

 

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 currently 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,³⁸ multivitamin 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.

 

Telomere biodynamics offer 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.