Fight Aging!

Telomerase provides the primary mechanism by which cells lengthen their telomeres. In our species only stem cells and cancer cells do this, while in mice more types of cell use more telomerase. Telomere length determines the limit to cell divisions, a little of the length being lost each time a cell divides. Cells that can lengthen their telomeres can continue dividing indefinitely, and that is how stem cells can continually deliver a useful supply of daughter cells to support surrounding tissues. It is also how cancer grows. Cancer and regeneration are the two sides of the same coin of growth and regeneration, one controlled, the other uncontrolled. Thus, broadly speaking, there are two things that can be done with telomerase in medicine, and both projects, while in the comparatively early stages, have a fair number of research groups involved.

Firstly, blocking the ability of telomerase to lengthen telomeres is the larger part of the basis for a universal cancer therapy. Some 90% of cancers abuse telomerase in order to grow and spread. If that can be shut down, then the cancer will be halted in its tracks - any cancer. The challenge of cancer research is not that it is hard and expensive, but rather that most approaches to treating cancer are highly specific to just a few types out of the hundreds of forms of cancerous tissue. This is a poor strategy. Meaningful progress towards defeating cancer will require the development of therapies that can instead be applied to many, or for preference all cancers. Thus blocking telomere lengthening has the potential to completely change the economics of the field, making it feasible to bring an end to cancer within our lifetimes and within the present budget allocated to that goal.

Secondly, taking the opposite approach to increase the activity of telomerase may prove to be a way to enhance regeneration and tissue maintenance, and therefore compensate for the onset of aging and age-related degeneration. In animal studies the outcome of additional telomerase is somewhat analogous to the effects of stem cell therapies, in that cellular activity increases to produce greater healing than normally take place. This is of particular interest in the old, who suffer in part because stem cell activity declines with age, and frailty and organ failure encroaches as a result. Telomerase gene therapies have been used to extend life in mice, and have the secondary effect in that species of reducing cancer rates. This second item is a very interesting outcome, given the role of telomerase in cancer, and we might speculate that it occurs because of improved immune function - enough of a benefit there to counteract any increased cancer risk as old and damaged cells are given the opportunity to do more and divide more often. There is uncertainty as to whether the outcomes in mice reflect the balance of effects that would occur in humans, since mice have a very different balance of telomerase activity. Investigations are ongoing, and great deal remains to be explained.

Therapeutic Targeting of Telomerase

Telomere length and cell function can be preserved by the human reverse transcriptase telomerase (hTERT), which synthesizes the new telomeric DNA from a RNA template, but is normally restricted to cells needing a high proliferative capacity, such as stem cells. Consequently, telomerase-based therapies to elongate short telomeres are developed, some of which have successfully reached the stage I in clinical trials. Telomerase is also permissive for tumorigenesis and 90% of all malignant tumors use telomerase to obtain immortality. Thus, reversal of telomerase upregulation in tumor cells is a potential strategy to treat cancer.

Natural and small-molecule telomerase inhibitors, immunotherapeutic approaches, oligonucleotide inhibitors, and telomerase-directed gene therapy are useful treatment strategies. Telomerase is more widely expressed than any other tumor marker. The low expression in normal tissues, together with the longer telomeres in normal stem cells versus cancer cells, provides some degree of specificity with low risk of toxicity. However, long term telomerase inhibition may elicit negative effects in highly-proliferative cells which need telomerase for survival, and it may interfere with telomere-independent physiological functions. Moreover, only a few hTERT molecules are required to overcome senescence in cancer cells, and telomerase inhibition requires proliferating cells over a sufficient number of population doublings to induce tumor suppressive senescence. These limitations may explain the moderate success rates in many clinical studies.

Despite extensive studies, only one vaccine and one telomerase antagonist are routinely used in clinical work. For complete eradication of all subpopulations of cancer cells a simultaneous targeting of several mechanisms will likely be needed. Possible technical improvements have been proposed including the development of more specific inhibitors, methods to increase the efficacy of vaccination methods, and personalized approaches.

Telomerase activation and cell rejuvenation is successfully used in regenerative medicine for tissue engineering and reconstructive surgery. However, there are also a number of pitfalls in the treatment with telomerase activating procedures for the whole organism and for longer periods of time. Extended cell lifespan may accumulate rare genetic and epigenetic aberrations that can contribute to malignant transformation. Therefore, novel vector systems have been developed for a 'mild' integration of telomerase into the host genome and loss of the vector in rapidly-proliferating cells. It is currently unclear if this technique can also be used in human beings to treat chronic diseases, such as atherosclerosis.

It is important to note that therapies like telomerase enhancement or stem cell transplants do little to nothing to address a range of other issues that cause age-related disease. Age-related changes such as mitochondrial DNA damage, persistent cross-links, and the accumulation of other metabolic waste such as lipofuscin are not going to be meaningfully affected. Each of those individually probably causes enough harm to kill people. So while adjusting stem cells and regeneration can be beneficial, it does not repair these forms of underlying damage, and thus is limited in the degree to which it can turn back the clock. A good way to look at this is in terms of the stem cell therapies now becoming more widely available that address joint paint and dysfunction. They help many patients to a greater degree than any other form of therapy presently available. They do not and cannot remove liver spots or undo macular degeneration, or turn back stiffening of arteries and loss of elasticity of skin, all items driven by the forms of damage noted above. Rejuvenation will in the end require a complete toolkit.