Telomerase activation: A potential key modulator for human healthspan and longevity *

During the last 20 years, mounting evidences suggest that the progressive loss of telomeric repeats of chromosomes may function as an important timing mechanism during the aging process in various species. Numerous epidemiological studies show that shorter telomeres in humans are associated with many age related diseases such as cancer, cardiovascular diseases (atherosclerosis, hypertension, myocardial infarction), cognitive decline, diabetes and overall mortality.

Partial or complete loss of telomerase function dramatically accelerates aging in mice and it is associated with age-related disorders in humans. Thus, it has been hypothesized that the re-activation of telomerase may represent a promising mechanism to reverse or at least delay cellular senescence, potentially leading to healthspan extension.

Telomeres are specialized structures localized at very ends of eukaryotic chromosomes whose primary functions are to prevent a cell from sensing linear chromosome ends as breaks in the DNA. In vertebrates, telomeres are composed of tandem repeats of TTAGGG which together with specialized proteins, form a cap like structure thereby suppressing the activation of DNA damage response (DDR). However with every cell division cycle, telomeres progressively erode which eventually causes one or more telomeres to become dysfunctional and, as a result, initiate a permanent DDR. Telomere shortening thus has been proposed to function as a “mitotic clock” that measures how many times a cell has divided.

Because of this progressive and cell division dependent telomere erosion, telomeres length is frequently being used as a marker of somatic cells replicative history. In general telomeres length reflects the balance between additions and losses of TTAGGG repeats. While telomere loss is typically attributed to “the end replication problem” and it is clearly accelerated by many other factors, such as oxidative stress, replication stress and inflammation. Epidemiologists measured telomere length in cohort studies and investigated its association with demographics, behaviors, indicators of health, and other molecular markers. Based on these studies it has been suggested that measurement of telomere length in white blood cells (LTL) can be used as a surrogate marker for relative telomere length in many other tissues. LTL associations have only been found for age, gender, and race, whereas association to most other phenotypes, such as smoking, alcohol consumption, physical activity, diets, socioeconomic status and education, body mass index, lipid levels, markers of glucose metabolism, and blood pressure was inconsistent across studies. Thus, whether telomere length may be considered as a biomarker of aging and age related diseases is still not clear; however shorter telomeres have been found in many age-related diseases such as, diabetes, cardiovascular disorders, and neurodegenerative diseases, while its role in predicting longevity and lifespan is still contradictory. Interestingly, although mice have very long telomeres compared with humans, they have a much shorter maximal lifespan (5 years in mice) compared to us (the oldest confirmed recorded age for any human is 122 years). Thus telomere length per se does not predict lifespan, although it has been suggested that the telomere rate of telomere erosion does. Telomere shortening rates are apparently not constant but instead are influenced by a competing set of positive and negative regulators of telomere length. In the elderly (>60), telomere attrition is significantly associated with higher mortality rates, both from infectious and cardiovascular diseases. Indeed, more recently, based on studies in mice, it has been suggested that the rate of increase of short telomeres, rather than average telomere length, predicts longevity in mammals.

The first telomerase activator described is the small molecule TA-65, a chemical compound extracted from Astragalus membranaceus, capable in activating telomerase both in vitro and in vivo. TA-65 increases average telomere lengths and decreases the percentage of critically short telomeres as well as DNA damage foci both in vitro and importantly also in vivo. In fact, dietary supplementation of TA-65 in mice leads to an improvement of a number of health-span indicators such as glucose tolerance, osteoporosis and skin fitness, without significantly increasing the cancer incidence. Currently, only one human study is published demonstrating that aged healthy volunteers supplemented with TA-65 showed a better dynamics of immune system as well as an increase in several indicators of health. In fact, analysis of biomarkers of aging in subjects using TA-65 suggested a significant improvement in cardiovascular system, metabolism, and bone mineral density ( Harley et al., 2011). Of note, a novel compound, AGS-499, has recently been described and was demonstrated to delay the onset and progression of amyotrophic lateral sclerosis disease in mice and to protect human mesenchymal stem cells from oxidative stress by increasing telomerase. However, no study replicated these findings as of yet, and no longitudinal study is available investigating the potential lifespan extending properties of telomerase or negative effects of a telomerase activating drugs.

Telomerase is expressed at low levels in peripheral mononuclear cells (PBMC). Four small-scale intervention studies analyzing telomerase activity in PBMCs suggest that telomerase activity is responsive to lifestyle and diet change. In an uncontrolled study of intensive lifestyle modification in men affected by prostate cancer, with a program of low fat diet and increased physical activity, a 30% increase in PBMCs telomerase activity over 3 months, was observed. Again, in a stress reduction/mindful eating intervention for overweight women, telomerase activity increased up to 18%, although these data did not reach statistical significance. However, subjects showing the largest decreases in psychologic distress, cortisol, and glucose levels also displayed the greatest increases in telomerase activity. In another small study of dementia caregivers, it has been shown that brief daily meditation practices can lead to improved mental and cognitive functioning and lower levels of depressive symptoms, accompanied by an increase in telomerase activity. Finally, a 3-month trial linked meditation and positive psychological change with 30% higher telomerase activity compared the control group.

There are now striking new findings from two retrospective studies, showing the potential impact of telomerase activation for human health. The first study conducted in an aged population cohort, showed higher telomerase activity in subjects highly adhering to Mediterranean diet. The authors demonstrated that circulating telomerase activity correlated with longer telomeres length, corroborating a critical role for telomerase in regulating telomere maintenance in vivo. Stratifying subjects according to the Mediterranean diet score, participants with higher adherence to such a diet showed longer telomeres as well as higher telomerase activity. The effect of diet on telomeres length variability was mediated by telomerase activity levels independently of multiple confounding factors such as age, gender and smoking habit. Most importantly they demonstrated that telomerase activity was associated with a better healthy status among subjects, independently of age, gender, smoking habit, telomere length variability and diet. This is the first study revealing a direct correlation between telomere length and telomerase activity and identifying in this latter, rather than telomere length, the major determinant of a healthy status. The second study conducted in a population cohort with an average age of 64 years demonstrated that subjects under statin therapy had higher levels of telomerase activity, longer telomeres and slower telomere shortening rate compared with control group not taking this drug. The effect of statin on telomeres length was mediated by telomerase activity independently of age, gender and smoking habit. Moreover increasing telomerase activity with increasing age was also observed. Considering that in mice models and in cell culture systems telomerase preferentially acts on shorter telomeres, the authors discussed that slight increase in telomerase activity with advancing age might serve to repair shorter and dysfunctional telomeres. These results suggest that a primary function of human telomerase is to prevent telomere dysfunction in order to allow proliferation of cells with very short telomeres. The study not only identified statin a new potential modulator of telomerase activity but strongly demonstrate that increases in telomerase activity in the elderly is associated with a reduction of telomere attrition.

Life expectancy around the world is steadily increasing, as are the disabling age-associated diseases, such as diabetes and cognitive decline. Identification of pathways that regulate longevity is critical for development of strategies to increase lifespan and improve healthspan. Telomerase appears to be an ideal candidate for such interventions. Thus telomerase activation with chemical or natural activator, such as specific diets may lead to longer life expectancy and successful aging.

* Adapted from an article in Ageing Research Reviews, Vol. 15, 2014.

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