This searchable list includes the abstracts of all presentations given at a conference organised as part of the SENS series. We regret that the videos recorded at SENS3 and SENS4 are currently unavailable.
One basic quality of human life is that every time our cells divide the tips of our chromosomes get shorter. This shortening of telomeres may be the molecular clock of aging. Indeed, the shortening of telomeres has been shown to be the trigger that induces senescence of human cells grown in culture; whether this can be extrapolated to include human organismal aging itself is not yet known. The correlation between telomere length and age is very strong and shorter telomeres directly correspond to shorter human life expectancy, but "cause and effect" are still debated.
The inability to maintain telomere length in normal human cells lacking human telomerase (hTERT) activity results in cellular aging or replicative senescence. The identification of small molecules that induce telomerase activity in these normal cells may be useful for basic research aimed at studying telomerase regulation. Additionally, molecules found to induce hTERT expression, with high target selectivity, can possibly be used in therapeutic applications directed to alleviate or delay symptoms of aging. A high throughput screening (HTS) effort by Sierra Sciences L.L.C.
A Cell-Based, High Throughput Screening Assay to Identify Small Molecule Compounds that Derepress Endogenous hTERT Expression Using Toxic hTR Template Mutants
Human telomerase is the subject of intense research because of its critical function in cellular immortality via telomere length maintenance. Presence of telomerase activity is strongly associated with immortality of embryonic stem and cancer cells. The human telomerase complex is composed of the human Telomerase Reverse Transcriptase protein (hTERT) and the human Telomerase RNA (hTR). Expression of telomerase activity is controlled, mainly at the level of hTERT transcription. However, the specific mechanisms of repression or silencing of the hTERT promoter region remain unclear.
A Cell-Based, High Throughput Screen to Identify Small Molecule Compounds that Derepress the Telomerase Minimal Promoter in a Transient Luciferase Expression System
The presence of telomerase activity in human cells is strongly correlated to the expression of hTERT which is repressed in normal adult human cells. We are undertaking a screen for compounds that activate telomerase expression using a transient expression system similar to the one previously described by Won et al. The telomerase minimal promoter sequence was inserted into a promoter-reporter plasmid to drive expression of the luciferase coding sequence.
Telomeres are chromosomal caps that prevent genomic instability and protect chromosomal integrity. When cells divide, telomeres shorten due to the "end replication problem". Decreased telomere length is associated with cellular senescence (aging), as older cells show markedly shorter telomeres. A predominant hypothesis between telomere length and aging is that the relationship is causative rather than correlative, i.e. decreased telomere length causes aging, or at least several of the main symptoms of it.
Gene Expression Profiling of MRC5 Lung Fibroblasts Treated with TA-65 and C0057684 using DNA Microarrays
The majority of cancer cell lines and human embryonic stem cells express the catalytic subunit of telomerase reverse transcriptase (hTERT), which maintains chromosomal ends through the addition of telomeric repeats. In normal somatic cells, telomerase transcription is repressed and the erosion of telomeres limits replicative lifespan and leads to cellular senescence. Transient pharmacologic activation of hTERT has the potential to delay senescence and extend human lifespan. TA-65, a natural compound derived from the Chinese herb Astragalus and licensed to T.A.
Telomerase is a specialized ribonucleoprotein complex, consisting of a telomerase reverse transcriptase protein component (hTERT) and an RNA component (hTR), which adds telomeric TTAGGG repeats at the chromosome tips. Telomerase is expressed in stem cells, germ cells, cancer cells and some rapidly proliferating cells while being undetectable in most somatic cells. The lack of telomerase expression in normal somatic cells leads to cellular aging and senescence due to telomere shortening.
The long term goal of Sierra Sciences LLC is to find a compound that induces telomerase activity for basic research purposes as well as anti-aging therapeutic applications. As a result of our cell-based high throughput screening effort utilizing a transient hTERT minimal promoter and luciferase reporter expression system, 929 compounds from a diversified small molecule library of over 123,840 compounds were found to induce luciferase expression. Cells treated with the active compounds from our primary screen are being examined for hTERT mRNA expression through real-time RT-PCR.
Telomerase is of significant interest to many scientists for its ability to immortalize cells, usually expressed in most tumor cells and human embryonic stem cells, but it is silenced in normal differentiated cells. Cancer researchers are focused on the inhibition of telomerase activity in cancer cells for therapeutic purposes while anti-aging enthusiasts are interested in de-repressing telomerase expression. Induction of telomerase activity could contribute to maintaining telomere length and elongation of telomeres in normal somatic cells thus possibly extending replicative life span.