An interesting report came to my attention relating to telomeres in pythons, and this set me off for the umpteenth time pursuing further research and thoughts about cell senescence, telomere lengths and telomerase. I share that all here.
First of all, about water pythons (Liasis fuscus), snakes that grow to about 2 meters in length. They are found in flood plains in Australia and New Guinea and are relatively long-lived. The just-released study report Short Telomeres in Hatchling Snakes: Erythrocyte Telomere Dynamics and Longevity in Tropical Pythons starts out with “In the present study we explore whether age- and sex-specific telomere dynamics affect life span in a long-lived snake, the water python (Liasis fuscus).” “– Erythrocyte TL (telomere length) was measured using the Telo TAGGG TL Assay Kit (Roche). In contrast to other vertebrates, TL of hatchling pythons was significantly shorter than that of older snakes. However, during their first year of life hatchling TL increased substantially. While TL of older snakes decreased with age, we did not observe any correlation between TL and age in cross-sectional sampling. In older snakes, female TL was longer than that of males. When using recapture as a proxy for survival, our results do not support that longer telomeres resulted in an increased water python survival/longevity.” – “In fish high telomerase activity has been observed in somatic cells exhibiting high proliferation rates. Hatchling pythons show similar high somatic cell proliferation rates. Thus, the increase in TL of this group may have been caused by increased telomerase activity. In older humans female TL is longer than that of males. This has been suggested to be caused by high estrogen levels that stimulate increased telomerase activity. Thus, high estrogen levels may also have caused the longer telomeres in female pythons. The lack of correlation between TL and age among old snakes and the fact that longer telomeres did not appear to affect python survival do not support that erythrocyte telomere dynamics has a major impact on water python longevity.”
OK. Taken at face value, the study says to forget about the Telomere shortening theory of aging at least as far as these snakes are concerned. What set me off thinking in the report, however, was the statement “However, other studies have demonstrated that TL does not affect survival among old humans. Furthermore, replicative senescence has been shown to be induced by changes in the protected status of the telomeres rather than the loss of TL.” This is the opposite of the party line believed by most people doing telomerase activation as an anti-aging measure. So I decided to pursue the author’s citations to check out these assertions.
The 2005 study Telomere length in white blood cells is not associated with morbidity or mortality in the oldest old: a population-based study which studied 598 participants concludes “Telomere length at baseline was not predictive for mortality (P > 0.40 for all-cause, cardiovascular causes, cancer or infectious diseases, Cox regression for gender-adjusted tertiles of telomere length) or for the incidence of dementia (P = 0.78). Longitudinally, telomere length was highly unstable in a large fraction of participants. We conclude that blood monocyte telomere length is not a predictive indicator for age-related morbidity and mortality at ages over 85 years, possibly because of a high degree of telomere length instability in this group.”
Another 2006 study No association between telomere length and survival among the elderly and oldest old looks at a different population and confirms the result. “Telomere length was measured as mean terminal restriction fragment length on blood cells from 812 persons, age 73 to 101 years, who participated in population-based surveys in 1997-1998. Among the participants were 652 twins. The participants were followed up through the Danish Civil Registration system until January 2005, at which time 412 (51%) were dead. RESULTS: Univariate Cox regression analyses revealed that longer telomeres were associated with better survival (hazard ratios = 0.89 [95% confidence interval = 0.76-1.04] per 1 kb in males and 0.79 [0.72-0.88] per 1 kb in females, respectively). However, including age in the analyses changed the estimates to 0.97 (0.83-1.14) and 0.93 (0.85-1.03), respectively.” — “CONCLUSION: This longitudinal study of the elderly and oldest old does not support the hypothesis that telomere length is a predictor for remaining lifespan once age is controlled for.”
A number of other recent studies also question the relationship of telomere lengths to mortality. “The question remains as to whether telomere dynamics is a determinant or merely a predictor of human biological age over and above chronological ageing. Although several reports have suggested a link between telomere attrition and ageing phenotypes and disorders, both reference values and a complete set of determinants are missing(ref).” What is happening to the Telomere shortening theory of aging? In all fairness there are a number of other studies that relate telomere shortening to a number of disease processes.
Another report cited in the python paper is the 2002 study Senescence Induced by Altered Telomere State, Not Telomere Loss which seems to be another attack on those pursuing longevity through telomerase activation. “Here, we report that overexpression of TRF2, a telomeric DNA binding protein, increased the rate of telomere shortening in primary cells without accelerating senescence. TRF2 reduced the senescence setpoint, defined as telomere length at senescence, from 7 to 4 kilobases. TRF2 protected critically short telomeres from fusion and repressed chromosome-end fusions in presenescent cultures, which explains the ability of TRF2 to delay senescence. Thus, replicative senescence is induced by a change in the protected status of shortened telomeres rather than by a complete loss of telomeric DNA.” Google shows this study is cited by 403 others.
Many of these studies deal with telomerase binding proteins and the very complex processes involved in telomere elongation. While there seems consensus on the importance of telomere states I am not at all clear that the simplistic conclusion of the title of this report is widely endorsed. Many publications express statements such as “loss of telomere integrity is a major trigger for the onset of premature senescence under mild chronic oxidative stress(ref).” Note that in my treatise I have expanded the 12th theory of aging to go beyond simple telomere shortening to read Telomere Shortening and Damage.
My own thoughts
1. Cell senescence is a bad thing and is postponed or avoided under healthy conditions even in cells that have replicated many times by cell signaling that either a) naturally activates telomerase at the last minute, or b) activates telomerase binding factors to delay senescence such as suggested above, or c) triggers apoptosis.
2. Loss of cells that have replicated many times due to healthy apoptosis need not affect health as long as there is a ready and able contingent of progenitor and stem cells to replace them (re the stem cell supply chain).
3. Telomerase activation by using exogenous telomerase activators may or may not work to extend telomeres of somatic cells, depending on telomere binding factor complexities. It may or may not work to thwart cell senescence. The complex natural mechanisms that control telomere lengths may work to subvert telomere extension for many classes of cells. Have you noticed that now, in year 2 of people striving to lengthen their telomeres via TA-2, astragaloside, etc. the almost complete absence of published reports of people that have demonstrably lengthened their telomeres?
4. Even if the average lengths of somatic cell telomeres can be increased by telomerase activation, this by itself may or may not have an effect on human longevity. (This statement could get me burned at the virtual stake in certain longevity circles, except for the following statement.)
5. Telomerase activation may nonetheless have a strong positive effect in supporting healthy operation of the stem cell supply chain and may therefore be worth doing despite its effects on telomere lengths. See the blog post Revisiting telomere shortening yet-again.
For reference purposes, a list of my previous writings related to telomerase can be found in this post .