Maria Blasco heads the Telomeres & Telomerase Group at the Spanish National Cancer Center in Madrid. She and her group have produced a number of important papers over recent years contributing to our understanding of telomere/telomerase science. A November 2009 publication describes what I believe is a breakthrough result enhancing our understanding of both the Telomere Shortening and Damage and the Programmed Epigenomic Changes theories of aging and showing a way in which they fit together.
The publication, describes a new viewpoint on how telomere shortening contributes to aging. The “classical” viewpoint is that telomere shortening results from cell division and that after a certain number of divisions the telomeres start to become too-short for further cell division to take place reliably. At that point either apoptosis takes place and the cell dies, or the cell can become senescent, no longer reproducing but sending out noxious signals to neighboring cells. The new viewpoint suggested in the Blasco paper goes much further. It says that as telomeres become critically short, the gene expression in the cell changes so as to induce senescence and at the same time to affect the maintenance of epigenomic memory and nuclear organization, thereby contributing to organismal aging on the whole-animal level. Critically short telomeres deregulate epigenomic control and alter gene expression so as to create the changes we know as “aging.” Too-short telomeres is not just an issue of affected cells dying off or becoming senescent. After all, these can be replaced by differentiating stem cells. It is an issue of screwing up the body’s cellular control mechanisms in a way that creates aging.
In my mind, this is an important finding and provides all the more reason to pursue telomerase activation as an anti-aging strategy. I have stated before that telomerase activation may not make telomeres longer because of the complex feedback loops involved in telomere length regulation. The key point is that telomerase activation might keep telomere lengths from getting critically shorter, and that would be enough to stave off cell senescence and deregulation of the epigenome and, perhaps even, much of what we know as aging.
Going to a further level of detail, the new publication summarizes the results: “Using telomerase-deficient TRF2-overexpressing mice (K5TRF2/Terc_/_) as a model for accelerated aging, we show that telomere shortening is paralleled by a gradual deregulation of the mammalian transcriptome leading to cumulative changes in a defined set of genes, including up-regulation of the mTOR and Akt survival pathways and down-regulation of cell cycle and DNA repair pathways. — Collectively, these findings suggest that critically short telomeres activate a persistent DNA damage response that alters gene expression programs in a nonstochastic manner toward cell cycle arrest and activation of survival pathways, as well as impacts the maintenance of epigenetic memory and nuclear organization, thereby contributing to organismal aging.” We know that mTOR is involved in a number of disease and aging processes and that inhibition of mTOR confirms longevity. Introductions to mTOR signaling and its relationship to longevity can be found in my blog entries Longevity genes, mTOR and lifespan, More mTOR links to aging theories, and Viva mTOR! Caveat mTOR! As mentioned previously in this blog, the P13/Akt pathway is involved in cancer processes as well as cell survival and stem cell proliferation.
The paper states “Dysfunctional, critically short telomeres elicit a DNA damage response (DDR) that triggers senescence or apoptosis in mammalian cells, two processes that are associated with organismal aging (1–9).” This has been known for some time. “Mice with a targeted deletion of the RNA component of telomerase (Terc_/_) display accelerated telomere shortening, premature loss of tissue renewal, and decreased longevity (3, 7–9).” Again, this is not surprising. “DNA damage signals originating from critically short telomeres in these mice is in line with current models proposing a causative role for DNA damage in organismal aging (10–13. — Interestingly, epigenetic alterations at heterochromatic regions are proposed to lead to changes in gene expression associated with aging (14–16)..” Here is where the discussion starts to get interesting.
Going on, “In S. cerevisiae, induction of DNA double-strand breaks (DSBs) or cellular stress causes a dramatic redistribution of telomeric silentinformation regulator (Sir) proteins and yKU proteins (17–19), thus linking changes in telomere chromatin to global epigenetic alterations. “ This is interesting given the linkages of human Sir proteins to longevity. Stimulating Sir1 is why people take resveratrol. Disturbing these proteins is likely to contribute to “shortivity.” “Sir complex relocalization is known to alter the expression of stress response genes, survival factors, and ribosomal biogenesis (20, 21). In functional analogy to yeast, mammalian SIRT1 is redistributed upon induction of DNA damage, causing broad alterations in global gene expression (22). Collectively, these findings suggest that aging-related DNA damage drives gene expression alterations that could promote the development of aging pathologies. – The point is restated several times throughout the paper: “These findings suggest that progressive telomere shortening and the accumulation of dysfunctional telomeres with age may constitute a unique source of DNA damage, sufficient to induce global alterations in genome regulation.” – “Using a mouse model system, we provide evidence that progressive telomere shortening in stratified epithelia, such as the skin, is linked to global deregulation of the mammalian transcriptome and loss of maintenance of epigenetic silencing mechanisms, exemplified by the re-expression of an Xi-linked transgene.”
So, put simply, telomeric shortening at some point induces DNA damage which lets loose signaling which changes the epigenome disrupting epigenetic silencing and resulting in pro-aging global DNA expression.
From the viewpoint of the Programmed Epigenomic Changes theory of aging, the paper says that telomere shortening is at least one of the drivers of the epigenomic aging program. The paper goes into significantly more detail. For those of you who can read such technical material, I suggest you do. As for me, I popped my daily cycloastragenol telomerase-activator pill just a bit ago. It is late and I will soon be going to bed.