A new study reported in the press this week looks at the relationship of exercise to expression of telomerase and telomere lengths in athletes and non-athletes. Other studies on the same topic have appeared in the last year or so. My purpose here is to review these studies in the context of some earlier studies. It is not just a simple matter of “the more and the harder the exercise, the better.”
The 12th theory of aging in my treatise Telomere Shortening and Damage forwards the hypothesis that longer telomere lengths are likely to be correlated with longer lifespans and that keeping one’s telomeres as long as possible through expression of telomerase is vital for health and longevity. I have devoted numerous blog entries to telomeres and telomerase, including most recently Timely telomerase tidbits, Breakthrough telomere research finding, and Telomere and telomerase writings. On the other hand, it is also well established that regular exercise is also strongly supportive of longevity(ref)(ref)(ref). The mechanisms through which exercise improves health and life expectancy hitherto appeared to be complex and unclear. The new research suggests that telomere extension may be a key mediator of the health and longevity benefits of regular exercise.
Sustained exercise can keep leukocytes younger
The latest study, an e-publication dated January 8 2010 from a University of Colarado group, is Leukocyte Telomere Length is Preserved with Aging in Endurance Exercise-Trained Adults and Related to Maximal Aerobic Capacity. “To determine if age-associated reductions in TL (telomere length) are related to habitual endurance exercise and maximal aerobic exercise capacity (maximal oxygen consumption, VO(2)max), we studied groups of young (18 – 32 years; n = 15, 7m) and older (55 – 72 years; n = 15, 9m) sedentary and young (n = 10, 7m) and older endurance exercise-trained (n = 17, 11m) healthy adults. Leukocyte TL (LTL) was shorter in the older (7059 +/- 141bp) vs. young (8407 +/- 218) sedentary adults (P < 0.01). LTL of the older endurance-trained adults (7992 +/- 169bp) was approximately 900bp greater than their sedentary peers (P < 0.01) and was not significantly different (P=0.12) from young exercise-trained adults (8579 +/- 413). — Our results indicate that LTL is preserved in healthy older adults who perform vigorous aerobic exercise and is positively related to maximal aerobic exercise capacity. This may represent a novel molecular mechanism underlying the “anti-aging” effects of maintaining high aerobic fitness.”
So, older folks who vigorously exercise keep up their leukocyte telomere lengths and folks who sit around watching TV instead do not. This message seems repeated in several other research reports. A 2009 study, this time from a German group, is: Beneficial Effects of Long-term Endurance Exercise on Leukocyte Telomere Biology. “This study examines telomere biology and senescence-associated factors in endurance athletes and matched controls without physical activity. –Methods: Leukocytes where isolated from the peripheral blood of professional young track & field athletes (n=32, age 20.4 years, running 73±5 km/week), aged athletes performing regular endurance training (n=25, age 51.1 years, running 80±8 km/week, 35 years training history) and two control groups of age-matched, physically inactive healthy volunteers (26 young and 21 aged subjects). –Results: Telomere repeat amplification protocols revealed an activation of leukocyte telomerase in young athletes to 256±19% and in elderly athletes to 182±11% compared to controls. Western blots showed an up-regulation of the telomere-capping protein TRF2 in young (179±1%) as well as in aged athletes (176±10%). FlowFISH assays and real-time PCR measurements of leukocyte telomere length showed no difference between young athletes and young controls. Sedentary elder controls exhibited a significant reduction of leukocyte telomere length (FF: 53±3%; PCR: 70±8%; vs. young controls). Importantly, there was a striking conservation of telomere length in aged athletes (FF: 88±4%; PCR: 84±7%; vs. young controls). Further analysis of telomere-associated proteins and cellular senescence regulators demonstrated an increase of TRF2, Ku70 and Ku80 mRNA and a reduced protein expression of Chk2, p16 and p53 in aged athletes compared to untrained elder controls.”
More or less the same story. Among the younger people exercise seems to have a strong effect on leukocyte telomerase expression but no effect on telomere lengths. But in the older folks, only those who exercised kept up most of their telomere lengths. Further, their cells showed markedly lower levels of senescence markers. As far as leukocytes are concerned, vigorous regular exercise definitely seems to keep them young.
A 2009 mouse and human study Physical Exercise Prevents Cellular Senescence in Circulating Leukocytes and in the Vessel Wall looks a bit further at the molecular dynamics of exercise and comes to a consistent conclusion. “Exercise upregulated telomerase activity in the thoracic aorta and in circulating mononuclear cells compared with sedentary controls, increased vascular expression of telomere repeat-binding factor 2 and Ku70, and reduced the expression of vascular apoptosis regulators such as cell-cycle–checkpoint kinase 2, p16, and p53. Mice preconditioned by voluntary running exhibited a marked reduction in lipopolysaccharide-induced aortic endothelial apoptosis. Transgenic mouse studies showed that endothelial nitric oxide synthase and telomerase reverse transcriptase synergize to confer endothelial stress resistance after physical activity. To test the significance of these data in humans, telomere biology in circulating leukocytes of young and middle-aged track and field athletes was analyzed. Peripheral blood leukocytes isolated from endurance athletes showed increased telomerase activity, expression of telomere-stabilizing proteins, and downregulation of cell-cycle inhibitors compared with untrained individuals. Long-term endurance training was associated with reduced leukocyte telomere erosion compared with untrained controls. — Conclusions— Physical activity regulates telomere-stabilizing proteins in mice and in humans and thereby protects from stress-induced vascular apoptosis.”
Watch out for your muscle satellite cells
There is a caution however, for more or harder exercise is not always better. And leukocytes are not the only relevant cells to consider. Earlier studies indicate that too strenuous or prolonged exercise can lead to serious depletion of telomerase in muscle satellite cells. Muscle satellite cells “are small mononuclear progenitor cells with virtually no cytoplasm found in mature muscle. They are found sandwiched between the basement membrane and sarcolemma (cell membrane) of individual muscle fibres, and can be difficult to distinguish from the sub-sarcolemmal nuclei of the fibres. Satellite cells are able to differentiate and fuse to augment existing muscle fibres and to form new fibres. These cells represent the oldest known adult stem cell niche, and are involved in the normal growth of muscle, as well as regeneration following injury or disease.”
Under conditions of hard exercise satellite cells can be forced into multiple rounds of duplication and differentiation leading to telomere shortening. The 2003 publication Athletes with exercise-associated fatigue have abnormally short muscle DNA telomeres tells the story. “Although the beneficial health effects of regular moderate exercise are well established, there is substantial evidence that the heavy training and racing carried out by endurance athletes can cause skeletal muscle damage. This damage is repaired by satellite cells that can undergo a finite number of cell divisions. — In this study, we have compared a marker of skeletal muscle regeneration of athletes with exercise-associated chronic fatigue, a condition labeled the “fatigued athlete myopathic syndrome” (FAMS), with healthy asymptomatic age- and mileage-matched control endurance athletes. — Three of the FAMS patients had extremely short telomeres (1.0 +/- 0.3 kb). The minimum TRF lengths of the remaining 10 symptomatic athletes (4.9 +/- 0.5 kb, P < 0.05) were also significantly shorter that those of the control athletes. CONCLUSION: These findings suggest that skeletal muscle from symptomatic athletes with FAMS show extensive regeneration which most probably results from more frequent bouts of satellite cell proliferation in response to recurrent training- and racing-induced muscle injury.”
The 2008 study The effects of regular strength training on telomere length in human skeletal muscle looked at power lifters and showed that long-term exercise is not necessarily associated with satellite cell telomere loss although lifting heavier loads mean more loss. “These results show for the first time that long-term training is not associated with an abnormal shortening of skeletal muscle telomere length. Although the minimum telomere length in PL (power lifters) remains within normal physiological ranges, a heavier load put on the muscles means a shorter minimum TRF length in skeletal muscle.”
The effect of exercise on telomeres in satellite cells is further reported in the 2009 publication The biology of satellite cells and telomeres in human skeletal muscle: effects of aging and physical activity. “New insights suggest that telomeres in skeletal muscle are dynamic structures under the influence of their environment. When satellite cells are heavily recruited for regenerative events as in the skeletal muscle of athletes, telomere length has been found to be either dramatically shortened or maintained and even longer than in non-trained individuals. This suggests the existence of mechanisms allowing the control of telomere length in vivo.” Whether satellite cell telomeres get shorter or longer or stay the same with exercise depend, among other matters, on the expression of telomerase in the satellite cells as a result of the exercise, and this in turn depends on several factors including physical condition of the person and the nature of the exercise.
Finally a late 2008 study report Relationship between physical activity level, telomere length, and telomerase activity looks at the results of exercise on telomeres in peripheral blood mononuclear cells (PBMCs). “A Peripheral Blood Mononuclear Cell (PBMC) is any blood cell having a round nucleus. For example: a lymphocyte, a monocyte or a macrophage. These blood cells are a critical component in the immune system to fight infection and adapt to intruders. The lymphocyte population consists of T cells (CD4 and CD8 positive ~75%), B cells and NK cells (~25% combined)(ref).” According to the report: “The purpose of this study was to examine the relationship of exercise energy expenditure (EEE) with both telomere length and telomerase activity in addition to accounting for hTERT C-1327T promoter genotype. — Sixty-nine (n = 34 males; n = 35 females) participants 50-70 yr were assessed for weekly EEE level using the Yale Physical Activity Survey. Lifetime consistency of EEE was also determined. Subjects were recruited across a large range of EEE levels and separated into quartiles: 0-990, 991-2340, 2341-3540, and >3541 kcal x wk(-1). Relative telomere length and telomerase activity were measured in peripheral blood mononuclear cells (PBMC). — CONCLUSION: These results indicate that moderate physical activity levels may provide a protective effect on PBMC telomere length compared with both low and high EEE levels.”
These studies leave me tentatively concluding:
· Regular mildly cardiovascular exercise is likely to protect telomere lengths with aging across the three cell categories studied.
· Vigorous aerobic exercise approaching “maximal aerobic exercise activity” may further serve to keep telomere lengths at youthful levels in leukocytes.
· However, excessively strenuous exercise such as lifting very heavy weights or leading to exercise-associated fatigue may lead to compromised telomere lengths in muscle and/or PBMC cells and be life-shortening.
So, I believe moderation should be the rule. See the suggestions for regular exercise in my treatise.