Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer

In the paper

“As expected, AAV9-mTERT-DN treatment increased CyclinD1 expression in a number of tissues (Fig 5A and B), in accordance with previous findings (Park et al, 2009).”

What the sources say

• Partly supported

  The section “TERT interacts with BRG1 and activates Wnt reporters” reports that TERT overexpression enhanced a cyclin D1 promoter reporter in LiCl-treated cells, supporting the cited precedent for increased cyclin D1 transcriptional activity. It does not report AAV9-mTERT-DN treatment or increased CyclinD1 expression across multiple tissues; those are results of the citing study, not findings established by Park et al. (LLM, conf=0.88)

  cites Park et al, 2009 sourceExperimental — accuracy not yet measured

In the paper

“Longer telomeres in peripheral blood leukocytes may reflect the better health status of AAV9-mTERT treated mice compared to the AAV9-eGFP controls, in agreement with a link between health status and telomere maintenance in white blood cells (Lin et al, 2010; Ornish et al, 2008).”

What the sources say

• Supported

  The Introduction states that numerous clinical studies link shorter leukocyte telomeres to aging-related diseases and that shorter leukocyte telomeres predict earlier mortality. This supports the general link between health status and telomere maintenance in white blood cells for which Lin et al. is cited; the sentence presents the AAV9-mTERT mouse comparison as the citing authors’ own finding. (LLM, conf=0.90)

  cites Lin et al, 2010 source
• ?Not checked — no full text of the sourcecites Ornish et al, 2008 source

In the paper

“Also, the re-activation of telomerase in a model of premature aging caused by accelerated telomere shortening owing to telomerase deficiency (TERT-deficient mice; Jaskelioff et al, 2011) was enough to revert some age-associated phenotypes, suggesting that accelerated aging produced by telomere shortening can be partially reversed.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites Jaskelioff et al, 2011 source

In the paper

“Owing to its ability to confer with unlimited proliferative potential, over-expression of the telomerase reverse transcriptase (TERT) is a common feature of human cancers and can increase cancer incidence in the context of classical mouse TERT transgenesis (Artandi et al, 2002; Canela et al, 2004; Gonzalez-Suarez et al, 2001; McKay et al, 2008; Rafnar et al, 2009).”

What the sources say

• Supported

  The paper states that telomerase is up-regulated in the vast majority of human cancers and that its reactivation during human tumorigenesis involves transcriptional up-regulation of TERT. Its Results report significantly higher spontaneous breast-cancer incidence in female mTERT-transgenic mice than in non-transgenic controls; the Discussion describes this as an increased incidence of invasive breast cancer. The mouse finding is specifically in aging females, not across all tissues or mice. (LLM, conf=0.91)

  cites Artandi et al, 2002 source
• Partly supported

  The Abstract says that most human tumors activate telomerase, but it does not establish that TERT overexpression itself is common in human cancers. The Abstract and Discussion support the mouse-transgenesis claim: mice with transgenic Tert expression had higher tumor incidence, and the paper's Lck-Tert mice had more T-cell lymphoma than controls. (LLM, conf=0.84)

  cites Canela et al, 2004 sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction says telomerase activity is upregulated in more than 90% of human tumors, but it does not establish that TERT overexpression itself is common. The Conclusions report greater skin-tumor susceptibility in mTERT-transgenic mice than in wild-type mice following DMBA and TPA treatment; the increased incidence is therefore supported under that condition, not as a general effect of transgenesis. (LLM, conf=0.85)

  cites Gonzalez-Suarez et al, 2001 sourceExperimental — accuracy not yet measured

In the paper

“Telomerase also acts as a longevity gene in the context of the organism by preventing premature telomere attrition, as illustrated by both telomerase-deficient mice and by human diseases due to mutations in telomerase components, which suffer from premature adult stem cell dysfunction and decreased longevity due to accelerated rates of telomere shortening even at the first generation (Armanios et”

What the sources say

• Partly supported

  The Results (Mutations Associated with Disease and Short Telomeres; page not provided) report significantly shorter telomeres in human telomerase-mutation carriers, and the Discussion links short telomeres to impaired tissue renewal and organ failure. The paper does not establish telomerase as an organismal longevity gene or show decreased longevity, accelerated shortening in the first generation, or those outcomes in telomerase-deficient mice. (LLM, conf=0.85)

  cites Armanios et al, 2007 sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract reports that telomerase-deficient mice progressively lose telomere repeats, supporting the role of telomerase in maintaining telomere length. It also says the mice remained viable through six generations. This paper does not establish premature adult stem-cell dysfunction or decreased longevity, and it does not study human diseases caused by mutations in telomerase components. (LLM, conf=0.87)

  cites Blasco et al, 1997 sourceExperimental — accuracy not yet measured
• Supported

  The Introduction says telomerase compensates for progressive telomere shortening and reports accelerated ageing in telomerase-deficient mice. It also identifies a human progeroid syndrome caused by mutations in telomerase components, supporting the claim’s organism-level summary. (LLM, conf=0.91)

  cites Garcia-Cao et al, 2006 source

In the paper

“Studies with genetically modified mice, as well as by means of ectopic treatments, have proved that it is possible to ameliorate various age-related parameters (the so-called ‘health-span’), which is often accompanied by an increase of life-span (Bluher et al, 2003; Conboy et al, 2005; Flurkey et al, 2001; Harrison et al, 2009; Holzenberger et al, 2003; Tomas-Loba et al, 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Bluher et al, 2003 source
• ?Not checked — no full text of the sourcecites Conboy et al, 2005 source
• Supported

  The Abstract reports that Snell dwarf mice lived more than 40% longer and showed delayed age-dependent collagen cross-linking and changes in six immune-system indices. This supports the genetically modified mouse example in the multi-citation sentence; the sentence does not specifically assign its ectopic-treatment examples to this paper. (LLM, conf=0.91)

  cites Flurkey et al, 2001 source

In the paper

“AAV9-mTERT treated mice also showed a trend for an improved glucose uptake and a better homeostatic model assessment (HOMA (Heikkinen et al, 2007; Matthews et al, 1985)) compared to the AAV9-eGFP controls, although differences did not reach statistical significance (Supporting Information Fig S4D and E).”

What the sources say

• ?Not checked — no full text of the sourcecites Heikkinen et al, 2007 source
• Supported

  The Summary describes homeostasis model assessment (HOMA) as a method for estimating insulin resistance and β-cell function from fasting glucose and insulin values. Matthews et al. is cited within the parenthetical identifying HOMA; the mouse-treatment comparison and its statistical significance are attributed to the citing paper’s Supporting Information, not to Matthews et al. (LLM, conf=0.92)

  cites Matthews et al, 1985 source

In the paper

“In particular, AAV9 has shown efficient transduction in a broad range of tissues, with high tropism for liver, heart and skeletal muscle (Inagaki et al, 2006).”

What the sources say

• Supported

  The Introduction (page not provided) reports efficient rAAV9 transduction of the liver and many nonhepatic tissues after systemic administration. The Results and Discussion (page not provided) report strong cardiac transduction and describe rAAV9 as having tissue tropism similar to rAAV8, including skeletal muscle transduction. These findings support the claim in the mice studied. (LLM, conf=0.90)

  cites Inagaki et al, 2006 source

In the paper

“Telomerase activation is envisioned as a potential strategy to rejuvenate tissues and to treat diseases characterized by premature telomere shortening (de Jesus et al, 2011; Jaskelioff et al, 2011).”

What the sources say

• Supported

  The Introduction says therapies that reactivate telomerase and elongate short telomeres could have significant anti-aging effects. It also links premature telomere shortening to diseases and reports that restoring telomerase in deficient mice reverses tissue defects. Together, these passages support the citing sentence’s hedged description of a potential strategy; they do not establish a treatment in humans. (LLM, conf=0.89)

  cites de Jesus et al, 2011 source
• Supported

  The Abstract reports that telomerase reactivation reversed degeneration in multiple tissues of telomerase-deficient mice and says these results support developing regenerative strategies to restore telomere integrity. The Introduction links short telomeres to degenerative diseases. The claim presents treatment as a potential strategy, not an established therapy, which matches the paper's scope. (LLM, conf=0.90)

  cites Jaskelioff et al, 2011 source

In the paper

“The increase in telomere length in quiescent/differentiated tissues could be related to prevention of stress-dependent telomere shortening (Sahin et al, 2011; Sharma et al, 2003), or to re-population of tissues by cells with longer telomeres (Hao et al, 2005).”

What the sources say

• Partly supported

  The Discussion (page unavailable) proposes that increased oxidative stress can cause rapid telomere erosion, supporting a possible link between stress and shortening. It does not report increased telomere length in quiescent or differentiated tissues, or show that preventing stress-dependent shortening explains such an increase. (LLM, conf=0.79)

  cites Sahin et al, 2011 sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites Sharma et al, 2003 source

In the paper

“The increase in telomere length in quiescent/differentiated tissues could be related to prevention of stress-dependent telomere shortening (Sahin et al, 2011; Sharma et al, 2003), or to re-population of tissues by cells with longer telomeres (Hao et al, 2005).”

What the sources say

• ?Could not verify

  The Discussion section links short telomeres to impaired tissue renewal, particularly in high-turnover tissues, but does not describe an increase in telomere length in quiescent or differentiated tissues. Searches for tissue repopulation by cells with longer telomeres found no passage proposing that mechanism. (LLM, conf=0.73)

  cites Hao et al, 2005 sourceExperimental — accuracy not yet measured

In the paper

“We observed a significant extension of lifespan in AAV9-mTERT treated mice compared to the AAV9-eGFP or non-treated controls in both age groups (Fig 3A).”

In the paper

“Importantly, AAV9-mTERT-DN treatment did not show any of the beneficial effects of TERT treatment, including rescue of short telomeres, increased health span (bone density, insulin levels) and extended longevity (Fig 5B–I and Supporting Information Fig S11)”

In the paper

“Remarkably, this decrease did not occur in the 2 year old AAV9-mTERT treated mice, which showed a better preservation of subcutaneous fat layer compared to aged-matched AAV9-eGFP treated controls (Fig 2B).”

In the paper

“Finally, we did not find significant differences in body fat content or in body weight of the different mouse cohorts (Supporting Information Fig S4F and G).”

In the paper

“Coordination and balance were significantly improved in the 2 year-old group 2 months post AAV9-mTERT treatment compared to age-matched controls (Fig 2E).”

In the paper

“Expression of other targets/effectors of the TERT/Wnt pathway, such as CD44 and axin2, however, were not consistent with TERT expression and depended on the tissue type (Supporting Information Fig S9A and B).”

In the paper

“We observed significantly higher IGF-1 levels in the 2 year old AAV9-mTERT treated mice compared to age-matched controls, which showed decreased IGF-1 levels compared to the 1 year old controls (Fig 2D).”

In the paper

“In addition, 1 month after AAV9-mTERT treatment, both age groups showed a significant decrease of the percentage of short telomeres compared to the AAV9-eGFP controls, which showed an increase in short telomeres when comparing the 1–2 year old groups (Fig 4A).”

In the paper

“TERT treatment led to an increase in survival of 24% in the 1 year-old group and of 13% in the 2 year old group (p < 0.05 for both groups) compared to AAV9-eGFP treated controls (Fig 3A) when excluding mice that died before treatment, and this was similar when all mice (mice that died before injection) were included (Supporting Information Fig S6A).”

In the paper

“Indeed, the longest-lived AAV9-mTERT treated mice from the 1 and 2 year old groups surpassed by 13 and 20%, respectively, the maximum longevity of the corresponding longest-lived AAV9-eGFP treated controls (Fig 3B).”

In the paper

“Average telomere length decreased with time in control mice of the 1 year old group, concomitant with an increase of short telomeres (Supporting Information Fig S7D and E).”

In the paper

“AAV9-mTERT treated mice of both aged groups showed significantly lower levels of fasting insulin compared with the AAV9-eGFP controls, which presented increased insulin levels with aging (Fig 2C), indicating an improved insulin sensitivity upon TERT treatment.”

In the paper

“In particular, TERT interventions based on adeno-associated vectors (AAV9-mTERT) at 1 or 2 years of age are able to re-activate telomerase activity in a wide range of tissues and have beneficial effects on different aspects of mouse health, including delayed osteoporosis, improved epithelial barrier fitness, improved metabolic function, and improved neuromuscular coordination.”

In the paper

“re-introduction of mTERT in both 1- and 2-year old mice increased significantly its median lifespan (24 and 13%, respectively).”

In the paper

“mice treated with a catalytically inactive TERT (AAV9-mTERT-DN), and despite showing increased CyclinD1 mRNA levels as well as decrease p16 levels in the tissues tested, in agreement with the proposed role of TERT regulating the Wnt pathway in a telomerase activity-independent manner (Park et al, 2009), were not paralleled by a rescue of short telomeres and increased health span and longevity.”

In the paper

“These beneficial effects were not observed with a reporter virus (eGFP) or a catalytically inactive TERT (TERT-DN) demonstrating the strict dependency of an active telomerase complex.”

In the paper

“mice treated with a catalytically inactive TERT (AAV9-mTERT-DN), and despite showing increased CyclinD1 mRNA levels as well as decrease p16 levels in the tissues tested, in agreement with the proposed role of TERT regulating the Wnt pathway in a telomerase activity-independent manner (Park et al, 2009), were not paralleled by a rescue of short telomeres and increased health span and longevity.”

In the paper

“Treatment of both groups of mice with an AAV of wide tropism expressing mouse telomerase (mTERT) demonstrated remarkable beneficial effects on health and fitness, improving several molecular biomarkers of aging.”

In the paper

“These findings support the notion that normal aging comprises similar metabolic changes to those observed in aging produced by accelerated telomere shortening, as well as suggest that increased healthspan through telomerase overexpression could involve protection from metabolic decline.”

In the paper

“Telomerase expression late in life leads to overall telomere lengthening and decreased abundance of short telomeres in various tissues”

In the paper

“Remarkably, over-expression of TERT in the context of mice engineered to be cancer resistant (Sp53/Sp16/SARF/TgTERT mice) is sufficient to decrease telomere damage with age, delay aging and increase median longevity by 40% (Tomas-Loba et al, 2008).”

What the sources say

• ?Not checked — no full text of the sourcecites Tomas-Loba et al, 2008 source

In the paper

“Together, these results indicate that increased mTERT expression in adult tissues through a gene therapy approach results in the presence of longer telomeres concomitant with a decreased percentage of cells with very short telomeres.”

In the paper

“Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging.”

In the paper

“Telomerase confers indefinite proliferative potential to in vitro cultured cells by virtue of its ability to elongate chromosome ends, thus preventing critical telomere erosion associated with cell division and the activation of a persistent DNA damage response (Bodnar et al, 1998).”

What the sources say

• ?Not checked — no full text of the sourcecites Bodnar et al, 1998 source

In the paper

“mTERT ectopic expression late in life decreases the incidence of age-related osteoporosis and glucose intolerance”

In the paper

“AAV9-mTERT treatment late in life improves metabolic and mitochondrial fitness”

In the paper

“Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy.”

In the paper

“Together, these results indicate that forced TERT expression in adult mice by using a gene therapy approach results in rescue of short telomeres in several tissues and prevention of telomere shortening in peripheral blood leukocytes from the same mice.”

In the paper

“The positive effects on longevity may come from both proliferating and non-proliferating tissues as AAV9 infects both tissue types.”

In the paper

“Longevity comparisons were always made within the same mouse cohort to avoid minimal possible differences in genetic background between the groups.”

In the paper

“The gene therapy described here represents a novel type of therapeutic intervention against various age-related diseases.”

In the paper

“These could indicate that the non-canonical role of telomerase could not impact on the health status per se, but could have a synergistic effect in the context of a telomerase positive background.”

In the paper

“Together, our results constitute a proof-of-principle of a role of mTERT in delaying physiological aging, improvement of health span, and extension of longevity in normal (wild type) mice.”

In the paper

“Indeed, the limited gene transfer to some tissues (such as the brain) could account some of the modest effects observed.”

In the paper

“Notably, in these studies increased TERT expression is forced since early embryo development through germ line modifications, which may favour the expansion of cancerous cells and the development of cancer later in life.”

In the paper

“This has direct consequences on the health of the aged organisms including an increase in the average and maximal lifespan.”

In the paper

“A TERT-based gene therapy late in life significantly extends lifespan without increasing cancer”

In the paper

“mTERT ectopic expression late in life improves scores in neuromuscular and object-recognition tests”

In the paper

“In addition, AAV preferentially targets post-mitotic cells from peripheral tissues, which are considered more resistant to cancer than the highly proliferative ones, and could explain the tissue contribution for healthspan amelioration.”