Understanding why and how we age has been one of the most fundamental questions hunting scientists for decades. Now, for the first time, in a study published in the open access journal PLoS Genetics, Miguel Godinho Ferreira, group leader at Instituto Gulbenkian de Ciência (IGC, Portugal), and his research team found that certain organs, such as the gut, start to age before other tissues because its cells have a "timekeeper" with a faster pace. Scientists found that monitoring the pace of these timekeepers can be a good indicator for the aging of the whole organism since the appearance of local age-related lesions anticipates the onset of age-associated diseases, such as cancer.
Telomeres, the molecular timekeepers of our cells, are protective structures located at the ends of chromosomes that ensure that there is no loss of genetic material at the chromosome tips during division. To keep a normal size, telomeres need to be elongated by the enzyme telomerase. However, most cells in our body turn off this enzyme from the time we are born and consequently telomeres shorten in response to the continuous cell divisions. Because the telomere protective function fades away as we grow older, the balance between the rate of proliferation of a tissue and the availability of telomerase is expected to dictate the pace at which telomeres shorten. "We used the zebrafish, an organism with human-like telomeres, to test whether more proliferative organs decline faster than less proliferative organs during the natural aging and lifetime of an individual", explains Miguel Godinho Ferreira.
Through a series of meticulous histopathology analysis, cell biology and biochemical experiments, researchers measured the length of telomeres in different tissues such as the gut, testis, blood, muscle and kidney at different time points, from the larval stage to adulthood and very old age. "Our results showed that, in normal aging, only specific tissues have telomeres that shorten to critical lengths. Surprisingly, though, this was not entirely dependent on the tissue proliferation rate. The gut, for example, which is a highly proliferative tissue, does accumulate shorter telomeres. However, the same does not happen to the blood, also a highly proliferative tissue that maintains some telomerase activity. Also, the muscle, a low proliferative tissue has telomeres with the same size as the gut, likely due to exposure to intrinsic DNA damaging agents", explains Madalena Carneiro, first author of the study. "It is the net pace of the tissue timekeeper that is faster in the gut. This means that the telomeres shorten faster in the gut and, as consequently, it ages before other organs. And this does not rely merely on the proliferative rate of the organ", adds Miguel Godinho Ferreira.
The researchers also showed that short telomeres accumulate DNA damage and block cell proliferation to some extent, demonstrating that tissues with shorter telomeres anticipate the cellular markers of aging. "These results are very similar to the ones obtained in zebrafish that lack the enzyme telomerase and therefore start to have these features earlier in life, further indicating that the pace of telomere shortening is a good indicator for local and, possibly, systemic aging", explains Madalena Carneiro.
Miguel Godinho Ferreira reinforces the importance of this work: "We believe this constitutes a breakthrough in our understanding of how short telomeres impact aging. We have now identified key tissues where telomere shortening becomes truly limiting for organ function in old age. Our next experiments will clarify if, by timely expressing telomerase in these specific organs, we may avert tissue dysfunction and revert the incidence of old age diseases, namely cancer".
This study was carried out at the IGC and was funded by Fundação para a Ciência e a Tecnologia (Portugal) and Howard Hughes Medical Institute (USA).