A Mouse Lineage Expressing Telomerase Exhibits Extended Life Span
Telomeres are repeated DNA sequences at the ends of chromosomes. A little telomere length is lost with each cell division, a part of the machinery that limits the replication of somatic cells. Cells with very short telomeres become senescent or self-destruct. Stem cells and cancer cells employ telomerase to extend telomeres, evading the replication limit. The use of telomerase more broadly in the body has attracted attention, particularly given studies in mice demonstrating improved health and extended life span. One challenge here is that the telomere dynamics of mice are fairly different from those of humans, so it is unclear as to whether the benefits will be the same. In mice, it seems that any additional risk of cancer due to damaged cells being provided with telomerase is far outweighed by improvements to immune function and cancer suppression in later life. The only practical way to determine whether this is also true in humans is to attempt telomerase gene therapies and observe the results.
While previous research has demonstrated the therapeutic efficacy of telomerase reverse transcriptase (TERT) overexpression using adeno-associated virus and cytomegalovirus vectors to combat aging, the broader implications of TERT germline gene editing on the mammalian genome, proteomic composition, phenotypes, lifespan extension, and damage repair remain largely unexplored. In this study, we elucidate the functional properties of transgenic mice carrying the Tert transgene, guided by precise gene targeting into the Rosa26 locus via embryonic stem (ES) cells under the control of the elongation factor 1α (EF1α) promoter.
The Tert knock-in (TertKI) mice harboring the EF1α-Tert gene displayed elevated telomerase activity, elongated telomeres, and extended lifespan, with no spontaneous genotoxicity or carcinogenicity. The TertKI mice showed also enhanced wound healing, characterized by significantly increased expression of Fgf7, Vegf, and collagen. Additionally, TertKI mice exhibited robust resistance to the progression of colitis induced by dextran sodium sulfate (DSS), accompanied by reduced expression of disease-deteriorating genes. These findings foreshadow the potential of TertKI as an extraordinary rejuvenation force, promising not only longevity but also rejuvenation in skin and intestinal aging.