Arguing for Telomerase Therapies to Treat Aging

At the high level, the arguments for deploying telomerase-based therapies to lengthen average telomere length in various tissues and cell populations as a treatment for aging have not changed much over the past decade. The data and details have evolved with progress in investigative research, but the digest of the views held by the faction who think this way remains this: that average telomere length is enough of a cause of issues in aging, as opposed to being a reflection of other processes with few secondary effects of its own, to merit addressing. My view of the state of research is still that average telomere length looks very much like a signature of aging, not a cause of aging. It is a measure of some combination of stem cell activity, meaning the pace of delivery of new cells with long telomeres, and rates of cell division, as telomeres shorten a bit every time a cell divides. Since stem cell activity declines with age, so too does average telomere length - and the problem here is the loss of tissue maintenance by stem cells, not the length of telomeres per se.

Researchers have demonstrated that telomerase therapy can extend life in mice, most likely by improving stem cell activity in old age, one of the many ways in which it is possible to force old stem cells do more work than they have evolved to undertake at that stage in life. This approach to treating issues of old age is heading in the direction of human medicine, at the usual glacial pace of later stage research moving through the regulatory pipeline, barring a few brave outliers. There are concerns about cancer risk, given that the present consensus is that loss of stem cell activity with age most likely serves to reduce cancer incidence, extending life at the cost of frailty. In mice telomerase therapy has not shown increased cancer rates, which is a challenge to the consensus view, but mice have very different telomere dynamics in comparison to we humans. In any case, this paper is authored by one of the more prominent groups involved in this work, arguing for more of a focus on the field of telomerase therapies to treat aging:

Telomerase is a DNA reverse transcriptase polymerase (telomerase reverse transcriptase, TERT) which uses an RNA template (telomerase RNA component, TERC) for de novo addition of telomeric DNA onto telomeres, thus compensating for the telomere erosion caused by cell divisions. Indeed, overexpression of telomerase is sufficient to counteract telomere attrition and to indefinitely extend the replicative lifespan of primary cells in culture in the absence of genomic instability, transforming them into cancerous cells. However, high telomerase expression is normally restricted to early stages of embryonic development (i.e. the blastocyst stage in mice and humans) and to pluripotent embryonic stem cells. Thus, adult mammalian tissues including adult stem cell compartments do not express sufficient amounts of telomerase to maintain telomere length throughout organismal lifespan. Consequently, telomere shortening occurs along with physiological aging in humans and mice and this process is proposed to underlie aging and age-associated diseases as well as organismal longevity.

During recent years, a number of molecular pathways have been identified as main molecular causes of aging, including telomere attrition, cellular senescence, genomic instability, stem cell exhaustion, mitochondrial dysfunction, and epigenetic alterations, among others. Interestingly, telomere attrition is considered a primary cause of aging, as it can trigger all the above-mentioned hallmarks of aging, although the degree to which it is a principal cause of aging is under active investigation. Critical telomere shortening elicits the induction of cellular senescence or the permanent inability of cells to further divide, which in turn has been proposed to be at the origin of different disease states. In addition, telomere attrition in the stem cell compartments results in the exhaustion of their tissue- and self-renewal capacity, thus also leading to age-related pathologies.

A substantial number of companies are now aiming to harness the knowledge that has been generated, unveiling the molecular mechanisms of aging in order to develop a new class of drugs to prevent and treat the major age-related diseases. In this regard, telomerase overexpression studies in mice have been proof of principle that just modifying a single hallmark of aging, i.e. telomere shortening, this was sufficient to delay not one but many different age-associated pathologies in mice, including cognitive decline. Indeed, the use of telomerase activation in delaying aging-associated conditions has spurred the interest of commercial enterprises. However, potential off-target effects of compounds that activate TERT at a transcriptional level should be a concern. Such off-target effects may be circumvented through direct delivery of TERT, such as by means of systemic gene therapy using non-integrative AAV vectors, which showed a significant delay of age-related pathologies in mice and increased longevity. However, it should be mentioned that strategies for telomerase activation, indirect or direct, have raised safety concerns due to the close correlation of most cancers and constitutive reactivation of endogenous telomerase. This highlights that, in addition to proof-of-concept studies in mice, the development of safe strategies for transient and controllable telomerase activation in humans should be a future goal.

In this regard, TERT gene therapy with AAVs is particularly attractive for TERT activation, since the non-integrative and replication-incompetent properties of AAVs allow for cell division-associated telomere elongation and subsequent loss of TERT expression as cells divide, thus restricting TERT expression to a few cell divisions. It is likely that the first clinical use of a TERT-based therapy, such as the TERT gene therapy approach developed by us, will be for the treatment of the human telomere syndromes, including aplastic anemia and pulmonary fibrosis. However, this requires the development of appropriate preclinical models and the subsequent clinical trials in humans. Given that physiological aging is provoked, at least in part, by telomere shortening, a TERT gene therapy may be used not only for the prevention and treatment of telomere syndromes but also for the treatment of multiple age-related diseases. In this regard, short telomeres have been extensively associated with a higher risk for cardiovascular disease. In support of a potential use of TERT activation in the treatment of age-related diseases, we demonstrated that TERT gene therapy can efficiently rescue mouse survival and heart scarring in a preclinical mouse model for heart failure upon induction of acute myocardial infarction. Collectively, experiments in cell and animal models provide proof of concept for the feasibility of telomerase activation approaches to counteract telomere shortening and its consequences. In particular, the successful use of telomerase gene therapy in animal models of aging and short telomere-related diseases paves the way for the development of therapeutic telomerase treatments in human aging and associated disease.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4815611/

Comments

Although the major function of telomerase is thought to be telomere elongation, accumulating evidence has suggested that it can modulate expression of various genes including target of Wnt/β-catenin and NFκB signaling which affect cancer progression and tumorigenesis. High throughput genomic and transcriptomic analysis has revealed that TERT can regulate expression of about 300 genes involved in cell cycle regulation, cellular signaling, and cell proliferation. For example, expression of catalytically inactive Tert in mouse model led to the activation of hair follicle stem cells and induction of hair growth; in human cancer cell lines, knocking down Tert resulted in RAPID decreases in cell proliferation and growth.
The fact that telomerase may participate in several other (sometimes quick) ways of cell regulation, besides de novo addition of telomeric DNA onto telomeres, should be considered when developing age therapies using TERT gene therapy.
http://cancerres.aacrjournals.org/content/74/6/1639.long

Posted by: Dmitry Dzhagarov at April 21st, 2016 2:31 PM

Didn't Liz Parrish get a gene therapy to increase telomerase activity?

Posted by: Dukenukemx at April 22nd, 2016 12:42 AM

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