Rate of Telomere Shortening Correlates with Species Average Life Span

[barbara]

FightAging!
7-14-19

https://www.fightaging.org/archives/2019/07/rate-of-telomere-shortening-correlates-with-species-average-life-span/

Researchers here report on data showing a correlation between species life span and pace of telomere shortening. Telomeres are the repeated DNA sequences at the ends of chromosomes. A little is lost with each cell division, during replication of DNA, and cells with very short telomeres become senescent or self-destruct. This is how the vast majority of cells in the body are limited in their replicative capacity, in order to lower the risk of damaged cells becoming cancerous to an evolutionarily acceptable level. Not a personally acceptable level, of course.

With age, average telomere length tends to shorten in most species, and this is most likely a reflection of loss of stem cell function. Stem cells maintain long telomeres via use of telomerase, and thus the daughter somatic cells they provide to support surrounding tissue also have long telomeres. Given fewer such daughter cells, average telomere length diminishes, along with tissue function - but that loss of telomere length isn't the cause of loss of tissue function.

Nonetheless, telomerase gene therapy extends life in mice, most likely by inducing damaged cells to greater activity in tissue maintenance. Since the immune system is most likely improved as well, this treatment doesn't lead to a greater incidence of cancer, which would be the usual outcome of making damage cells do more work. This hypothesis on what takes place in telomerase gene therapy is still not a suggestion that telomere shortening is a cause of aging. In this view telomerase gene therapy is conceptually similar to stem cell therapies or signaling therapies that increase native cell activity without repairing the underlying damage that caused the decline. As noted in the publicity materials, this particular research group is generally in favor of the opposite viewpoint, that telomere shortening is an important causative mechanism of aging, rather than a largely downstream reflection of other issues.

Researchers discover that the rate of telomere shortening predicts species lifespan

After analyzing nine species of mammals and birds, researchers found a very clear relationship between the lifespan of these species and the shortening rate of their telomeres, the structures that protect the chromosomes and the genes they contain. The fit is better when using the average lifespan of the species - 79 years in the case of humans - rather than the maximum lifespan -the 122 documented years lived by the Frenchwoman Jeanne Calment.

Until now, however, no relationship had been found between telomere length and lifespan of each species. There are species with very long telomeres that are short-lived and vice versa. The researchers decided not to compare the absolute length of the telomeres, but rather their rate of shortening. It is the first large-scale study that compares this highly variable parameter between species: human telomeres lose on average about 70 base pairs - the building blocks of the genetic material - per year, whereas those of mice lose about 7,000 base pairs per year.

"This study confirms that telomeres play an important role in aging. There are people who are not convinced, and they say that for example mice live two years and have very long telomeres, while humans live much longer and have short telomeres; but we have shown that the important thing is not the initial length but the rate of shortening and this parameter predicts the longevity of a species with a high degree of precision."

Telomere shortening rate predicts species life span

Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin's gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus).

We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

 

[barbara]

Telomere Dynamics with Age are Very Different Between Mammalian Species

https://www.fightaging.org/archives/2019/07/telomere-dynamics-with-age-are-very-different-between-mammalian-species/

Telomeres are caps of repeated DNA sequences at the ends of chromosomes. They shorten with each cell division, a part of the mechanism that ensures somatic cells can only replicate a limited number of times. Telomerase acts to lengthen telomeres, and in humans telomerase is only active in stem cells. Thus our cells exist in a two-tier system, in which only tiny populations of privileged stem cells are permitted unrestricted replication, while the vast majority of somatic cells are limited. Matters are similar across all higher animals, and this state of affairs likely evolved because it keeps cancer to a low enough level, and pushed off far enough into late life, for allow for evolutionary success.

A lot of ink has been spilled on the topic of telomere length because, statistically across large populations, average telomere length and proportion of short telomeres tends to decrease with advancing age. Given that stem cell activity declines with age, this is most likely a reflection of a lower pace of creation of new somatic cells with long telomeres. The human data is complicated by the fact that telomere length is most commonly measured in immune cells from a blood sample, and is thus a very dynamic measure influenced by the day to day reactions of the immune system. In individuals, there isn't much anyone can do with measures of telomere length, given that it is so variable over time and between people of similar health and age: it is a terrible biomarker for any practical purpose.

Further, can we actually use anything that we learn about telomere dynamics in other species? It is well known that mouse telomere dynamics and telomerase expression are quite different from that of humans. This might make us suspect that positive results from telomerase gene therapies in mice, where life span is extended and health improved, without raising the risk of cancer, may not hold up in humans. There is no particular reason why increased cancer risk through putting damaged cells back to work will be balanced in the same way by improved tissue function and improved immune function, from species to species. The research and development community will find out in the years ahead by trying telomerase gene therapies in primates and then humans.

I feel that the open access paper here adds to doubts about the value that the research community can extract from a study of telomeres and telomerase in other mammalian species, though the researchers don't present it in that way. If various short and long lived mammals can have such a range of telomere dynamics, what are we supposed to make of the data resulting from animal studies of any therapeutic approach to targeting telomeres?

Telomeres and Longevity: A Cause or an Effect?

Since telomere dynamics were found to be better predictors of survival and mortality than chronological age in wild populations, many cross-sectional and longitudinal studies have been conducted on different organisms with variations in maximum life span investigating the relationship between chronologic age and telomere shortening. Yet, some studies have reported a lack of telomere shortening with age or even an increase in telomere length in organisms with exceptional longevity. Therefore, studying telomere dynamics in long-lived organisms is of particular importance since they may have developed mechanisms that actively postpone senescence and promote effective defenses against the deteriorating effects of aging processes.

The naked mole-rat (Hetercephallus glabers/NMR) and the blind mole-rat (Spalax ehrenbergi) are both considered excellent models for studying aging. They both exhibit extraordinary longevity with a maximum lifespan of approximately 30 years in NMRs (10 times longer than any other rodent of the same size) and 20 years in captivity for Spalax. They exhibit lifelong maintenance of superior anti-aging mechanisms leading to unchanged physiological functions and negligible senescence. Moreover, both of these mole-rats live in a presumably relatively stressful environment due to their subterranean lifestyle where they experience darkness, low oxygen and high carbon dioxide concentrations. Despite all these common features, NMRs and Spalax belong to different families; they are different in size and have different social lifestyles.

Whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence, and promote longevity is still an ongoing debate. In the current study, we aimed to investigate the relationship between telomere length and age in NMRs and Spalax. We tested blood telomeres in NMRs and three different tissues in Spalax and compared each one with a short-lived animal of their size.

While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR suggest an age buffering mechanism, while in Spalax tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.