In my last post I reviewed a paper that provided support for the use of leucocyte telomere length as a proxy for telomere length in the vasculature, concluding that adjustments for factors previously reported to impact on telomere length are critical in association studies. Of course there is always the possibility that some other, as yet unstudied, factor will play a pivotal role. So it is, perhaps, unsurprising that a recent paper, published by a group headed by Elizabeth Blackburn, points to telomerase as a major player.
Telomerase is the enzyme responsible for extending telomeres, but telomerase activity in peripheral blood mononuclear cells (PBMCs) is low, and until now it has never been examined in a longitudinal study. This pilot study, published in Lancet Oncology, examined the effect of three months of lifestyle changes on telomerase activity.
Increased telomerase activity and comprehensive lifestyle changes: a pilot study
BACKGROUND: Telomeres are protective DNA-protein complexes at the end of linear chromosomes that promote chromosomal stability. Telomere shortness in human beings is emerging as a prognostic marker of disease risk, progression, and premature mortality in many types of cancer, including breast, prostate, colorectal, bladder, head and neck, lung, and renal cell. Telomere shortening is counteracted by the cellular enzyme telomerase. Lifestyle factors known to promote cancer and cardiovascular disease might also adversely affect telomerase function. However, previous studies have not addressed whether improvements in nutrition and lifestyle are associated with increases in telomerase activity. We aimed to assess whether 3 months of intensive lifestyle changes increased telomerase activity in peripheral blood mononuclear cells (PBMC). METHODS: 30 men with biopsy-diagnosed low-risk prostate cancer were asked to make comprehensive lifestyle changes. The primary endpoint was telomerase enzymatic activity per viable cell, measured at baseline and after 3 months. 24 patients had sufficient PBMCs needed for longitudinal analysis. This study is registered on the ClinicalTrials.gov website, number NCT00739791. FINDINGS: PBMC telomerase activity expressed as natural logarithms increased from 2.00 (SD 0.44) to 2.22 (SD 0.49; p=0.031). Raw values of telomerase increased from 8.05 (SD 3.50) standard arbitrary units to 10.38 (SD 6.01) standard arbitrary units. The increases in telomerase activity were significantly associated with decreases in low-density lipoprotein (LDL) cholesterol (r=-0.36, p=0.041) and decreases in psychological distress (r=-0.35, p=0.047). INTERPRETATION: Comprehensive lifestyle changes significantly increase telomerase activity and consequently telomere maintenance capacity in human immune-system cells. Given this finding and the pilot nature of this study, we report these increases in telomerase activity as a significant association rather than inferring causation. Larger randomised controlled trials are warranted to confirm the findings of this study.
In summary, the study reports that 3 months of “comprehensive lifestyle modifications” resulted in increased telomerase activity in circulating PBMCs of 24 subjects with low-risk prostate cancer. The modifications included diet (low fat, low in refined carbs, lots of fruit and vegetables), exercise (30 minutes walking per day, 6 days per week), stress management (yoga, breathing, meditation, imagery, 60 minutes per day, 6 days per week) and supplements (tofu plus soy-powdered protein, fish oil, selenium, vitamin E and vitamin C).
Outcome measures included the standards for cardiovascular risk (blood pressure, lipid profile, body mass index (BMI), waist circumference and C-reactive protein). As one would expect with such drastic changes to diet and exercise in particular, the subjects experienced significant improvements in cardiovascular risk factors: both systolic and diastolic blood pressure decreased, as did BMI and waist circumference. Positive changes in lipid profile were also observed.
But perhaps the most critical part of the study focusses on the effect of “psychological functioning”; subjects were assessed using the “Impact of Event Scale, a well-validated measure of distress associated with a traumatic event.” In this study, the subjects had all previously been diagnosed with low-risk prostate cancer, and so a baseline of stress was assumed to be present. At the end of the 3-month lifestyle modification, “intrusive thoughts” were reduced significantly, presumably due to a combination of the improved diet, exercise and stress reduction techniques.
Upon detailed analysis of the data the authors report that the increased telomerase activity correlates with decreased LDL-cholesterol and decreased intrusive thoughts. Previous studies have demonstrated that both oxidised-LDL and cortisol impact on telomerase activity in vitro, providing potential mechanistic links for these observations.
The authors stress that this pilot study reports a significant association, but that they do not infer causation. However, the results raise another question relating to the use of telomere length in the circulating leucocytes as a proxy for other cells: does modification of telomerase activity in the leucocytes impact on their telomere length? The answer would appear to be “yes,” suggesting that “psychological functioning“ is another confounding variable when performing association studies of telomere length. My only concern is that the assessment of psychological functioning appears to be a very subjective variable; what is stressful to one person may not be to another.
Overall, the study clearly confirms the notion that a healthy diet and regular exercise is beneficial in terms of cardiovascular risk; the caveat is that if you suffer from “intrusive thoughts” as a result of worrying about your health, you may well undo all of your hard work…