The telomerase activator TA‐65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence

Abstract

SummaryHere, we show that a small-molecule activator of telomerase (TA-65) purified from the root of Astragalus membranaceus is capable of increasing average telomere length and decreasing the percentage of critically short telomeres and of DNA damage in haploinsufficient mouse embryonic fibroblasts (MEFs) that harbor critically short telomeres and a single copy of the telomerase RNA Terc gene (G3 Terc + ⁄ ) MEFs). Importantly, TA-65 does not cause telomere elongation or rescue DNA damage in similarly treated telomerase-deficient G3 Terc ) ⁄ ) littermateMEFs. These results indicate that TA-65 treatment results in telomerase-dependent elongation of short telomeres and rescue of associated DNA damage, thus demonstrating that TA-65 mechanism of action is through the telomerase pathway. In addition, we demonstrate that TA-65 is capable of increasing mouse telomerase reverse transcriptase levels in some mouse tissues and elongating critically short telomeres when supplemented as part of a standard diet in mice. Finally, TA-65 dietary supplementation in female mice leads to an improvement of certain health-span indicators including glucose tolerance, osteoporosis and skin fitness, without significantly increasing global cancer incidence.

Cycloastragenol Is a Potent Telomerase Activator in Neuronal Cells: Implications for Depression Management

“…Telomerase activators are proposed to increase the longevity of cells and are therefore actively being analyzed for antiaging strategies [47,48]. In accordance with our findings that CAG promotes the cellular functions of keratinocytes, the distinct telomerase-promoting activity of CAG has also been reported in human CD8+ T-lymphocytes; specifically, in its effects in enhancing their antiviral response against HIV [28].…”

<i>Withania somnifera</i> Root Extract Enhances Telomerase Activity in the Human HeLa Cell Line

“…Since aging promotes degenerative pathologies, screening for new drugs is a necessity to develop highly effective therapy for the enhancement of telomerase activity in order to avoid critically short telomere length leading to aging and age-related diseases. [8], the telomerase activator obtained from the Chinese medicine, can elongate short telomeres and increase health span of mice without increasing cancer incidence. Hence, we evaluated the enhancement of the telomerase activity, which is to maintain the telomere by adding the hexanucleotide repeats, by an ancient Ayurvedic herb Ashwagandha root extract (Figure 1).…”

“…Enhancing telomerase activity is one way to delay aging. A small molecule telomerase activator, TA-65, isolated from the root of the traditional Chinese medicine, Astragalus membranaceus in mice [8] can precisely do the same.…”

Microenvironmental Regulation of Telomerase Isoforms in Human Embryonic Stem Cells

“…Conversely, telomerase (TERT) overexpression extends telomeres, reduces DNA damage signaling and associated checkpoint responses, reactivates proliferation in quiescent cultures, and eliminates degenerative phenotypes across multiple organs [18][19][20]. Telomerase activation by transgenic [19,20] or pharmacological means [21] can reverse tissue degeneration and increase health span in aged mice. Together, these observations support the hypothesis that telomere length and telomerase activity are determinants for tissue homeostasis and regeneration.…”