Gene therapy with the <scp>TRF</scp>1 telomere gene rescues decreased <scp>TRF</scp>1 levels with aging and prolongs mouse health span

Derevyanko, Aksinya; Whittemore, Kurt; Schneider, Ralph P.; Jiménez, Verónica; Bosch, Fátima; Blasco, Marı́a A.

doi:10.1111/acel.12677

Cited by 37 publications

(20 citation statements)

References 82 publications

(116 reference statements)

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“…In our study, gene expression analyses of YMSCs versus OMSCs revealed that TPP1 was likely to be involved in the process of aging ( Supplementary Figure 2A). Numerous studies have found that the levels of shelterin proteins that directly interact with TPP1, such as TRF1 and POT1, are decreased in aging (Derevyanko et al, 2017;Hosokawa et al, 2017). In the present study, the key role of TPP1 in enhancing therapeutic properties of OMSCs was demonstrated.…”

Section: Discussionsupporting

confidence: 55%

TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway

Zeng

Cheng

et al. 2020

Front. Cell Dev. Biol.

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Background: Poor cell survival after transplantation restricts the therapeutic potential of mesenchymal stem cell (MSC) transplantation into infarcted hearts, particularly in older individuals. TPP1, a component of the shelterin complex that is involved in telomere protection, is highly expressed in young MSCs but declines in aged ones. Here, we explore whether TPP1 overexpression in aged mouse MSCs improves cell viability in vivo and in vitro. Methods: Aged mouse MSCs overexpressing TPP1 were injected into the peri-infarct area of the mouse heart after left anterior descending coronary artery ligation. In parallel, to evaluate cellular-level effects, H 2 O 2 was applied to MSCs in vitro to mimic the microenvironment of myocardial injury. Results: In vivo, the transplantation of aged MSCs overexpressing TPP1 resulted in improved cell survival, enhanced cardiac function, and reduced fibrosis compared to unmodified aged MSCs. In vitro, TPP1 overexpression protected aged MSCs from H 2 O 2-induced apoptosis and enhanced DNA double-strand break (DSB) repair. In addition, the phosphorylation of AKT and the key DSB repair protein MRE11 were both significantly upregulated in aged MSCs that overexpressed TPP1. Conclusions: Our results reveal that TPP1 can enhance DNA repair through the AKT/MRE11 pathway, thereby improving the therapeutic effects of aged MSC transplantation and offering significant potential for the clinical application of autologous transplantation in aged patients.

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Section: Discussionsupporting

confidence: 55%

TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway

Zeng

Cheng

et al. 2020

Front. Cell Dev. Biol.

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“…Data were analyzed with Microsoft Excel (Microsoft). Telomere fluorescence values were converted into kilobases by external calibration with the CCRF-CEM (7.5 kb), L5178Y-S (10.2 kb), and L5178Y-R (79.7 kb) cell lines (43, 44).…”

Section: Methodsmentioning

confidence: 99%

Telomere shortening rate predicts species life span

Whittemore

Vera

Martínez‐Nevado³

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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295

219

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Telomere shortening to a critical length can trigger aging and shorter life spans in mice and humans by a mechanism that involves induction of a persistent DNA damage response at chromosome ends and loss of cellular viability. However, whether telomere length is a universal determinant of species longevity is not known. To determine whether telomere shortening can be a single parameter to predict species longevities, here we measured in parallel the telomere length of a wide variety of species (birds and mammals) with very different life spans and body sizes, including mouse (Mus musculus), goat (Capra hircus), Audouin’s gull (Larus audouinii), reindeer (Rangifer tarandus), griffon vulture (Gyps fulvus), bottlenose dolphin (Tursiops truncatus), American flamingo (Phoenicopterus ruber), and Sumatran elephant (Elephas maximus sumatranus). We found that the telomere shortening rate, but not the initial telomere length alone, is a powerful predictor of species life span. These results support the notion that critical telomere shortening and the consequent onset of telomeric DNA damage and cellular senescence are a general determinant of species life span.

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“…Thickness of the subcutaneous fat layer was measured as previously described 61 . Briefly, a total of 30 measurements were performed on 2 back sections of the skin for each mouse around 100 weeks old.…”

Section: Methodsmentioning

confidence: 99%

Mice with hyper-long telomeres show less metabolic aging and longer lifespans

2019

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Short telomeres trigger age-related pathologies and shorter lifespans in mice and humans. In the past, we generated mouse embryonic (ES) cells with longer telomeres than normal (hyper-long telomeres) in the absence of genetic manipulations, which contributed to all mouse tissues. To address whether hyper-long telomeres have deleterious effects, we generated mice in which 100% of their cells are derived from hyper-long telomere ES cells. We observe that these mice have longer telomeres and less DNA damage with aging. Hyper-long telomere mice are lean and show low cholesterol and LDL levels, as well as improved glucose and insulin tolerance. Hyper-long telomere mice also have less incidence of cancer and an increased longevity. These findings demonstrate that longer telomeres than normal in a given species are not deleterious but instead, show beneficial effects.

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Gene therapy with the TRF1 telomere gene rescues decreased TRF1 levels with aging and prolongs mouse health span

Cited by 37 publications

References 82 publications

TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway

TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway

Telomere shortening rate predicts species life span

Mice with hyper-long telomeres show less metabolic aging and longer lifespans

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