TRF1 Gene Therapy Improves Health Span in Mice
One of the research groups interested in telomerase gene therapy and its ability to lengthen mouse life span also works on a number of related items, such as the potential to shut down cancers by dramatically accelerating the erosion of telomeres in cancerous tissue, telomeres being the caps of repeated DNA sequences at the end of chromosomes. As is true elsewhere in biochemistry, here it is the case that a mechanism influential on aging is also important in cancer. Other approaches to cancer that involve telomeres include sabotaging the ability of telomerase to extend telomeres. This sort of thing can form the basis for a potential therapy that could in principle put a halt to all types of cancer. All cancers, without exception, depend on the abuse of either telomerase or alternative lengthening of telomeres (ALT) in order to keep telomeres long and thus keep replicating rampantly. Each cell division shortens telomeres a little, and when telomeres become too short, a cell self-destructs or becomes senescent, in either case ceasing to replicate. Thus without telomere lengthening, a cancer must inevitably wither away.
The method used to accelerate telomere length loss is a blockade of TRF1, a component of shelterin, which appears necessary to the operation of various processes that help to maintain telomere integrity. Given other work on telomeres and telomerase, it makes sense to ask whether turning this around to enhance levels of TRF1 and its activity will slow aging in mice, as is the case for the use of gene therapy to increase telomerase levels. Researchers here show that the enhanced TRF1 approach does extend the span of healthy life in mice, but doesn't have much of an effect on overall life span. I think that most of the commentary on telomerase gene therapies made in recent years probably also applies to this work, particularly with respect to whether or not the effect is mediated through increased stem cell activity, potential applications, expected degree of safety in humans, the sizable differences between mouse and human telomere dynamics, and so on.
Telomere shortening has been identified as one of the primary hallmarks of aging. Mammalian telomeres are structures at the end of linear chromosomes that consist of repeated DNA bound by an array of associated proteins known as shelterin, which prevent chromosome ends from being recognized as double-strand DNA breaks and from chromosome end-to-end fusions. Telomerase is a reverse transcriptase (TERT) that elongates telomeres de novo by adding telomeric repeats on chromosome ends using as template an RNA component (TERC), thus preventing telomere erosion. However, mammalian cells stop expressing telomerase in the majority of tissues after birth, leading to progressive telomere erosion throughout the lifespan of the organism. Telomere shortening has been demonstrated to be sufficient to trigger age-related pathologies and shorten lifespan in mice.
Telomerase reactivation has been envisioned as an strategy to maintain telomeres and therefore to increase the proliferative potential of tissues, both in the telomere syndromes and in age-related conditions. In addition to telomerase, the shelterin complex is also critical for the protection of telomeres. Shelterin consists of six proteins, of which TRF1 is one of the key components. In particular, deletion of TRF1 in mouse embryonic fibroblasts (MEFs) results in induction of senescence, as well as in chromosome fusions and multitelomeric signals (aberrant number of telomeric signals per chromosome end). Importantly, these effects of TRF1 abrogation are independent of telomere length, as TRF1 deletion uncaps telomeres independently of telomerase and cell division. In addition, conditional TRF1 abrogation in various mouse tissues has demonstrated the importance of TRF1 for tissue regeneration and tissue homeostasis. Indeed, high TRF1 levels mark stem cell compartments as well as pluripotent stem cells and are essential to induce and maintain pluripotency.
Given the importance of TRF1 for organismal viability and tissue homeostasis, here we set to address whether TRF1 levels vary with aging in vivo both in mouse and human tissues, as well as to study the potential therapeutic effects of TRF1 increased expression in delaying aging-associated pathologies in vivo. A previous work of our group showed that constitutive TRF1 overexpression acted as a negative regulator of telomere length, mediating telomere cleavage by XPF nuclease. To circumvent this undesired effect of TRF1 overexpression, here we induced moderate and transient TRF1 overexpression in adult (1 year of age) and old (2 years of age) mice using nonintegrative adeno-associated gene therapy vectors (AAV) that can transduce many different tissues but their expression is diluted as cells proliferate.
The results shown here demonstrate that TRF1 levels decrease with age both in mice and in humans. Furthermore, we demonstrate that transient TRF1 expression through the use of AAV9-TRF1 gene therapy in wild-type mice is able to improve mouse physiological health span as indicated by improvements in different markers of aging. AAV9-TRF1 gene therapy significantly prevented age-related decline in neuromuscular function, glucose tolerance, cognitive function, maintenance of subcutaneous fat, and chronic anemia. Interestingly, although AAV9-TRF1 treatment did not significantly affect median telomere length, we found a lower abundance of short telomeres and of telomere-associated DNA damage in some tissues.