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Telomere dysfunction induces metabolic and mitochondrial compromise
Open accessAbstract
Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1β, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere–p53–PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.
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TL;DR
Telomere dysfunction in mice represses PGC-1α and PGC-1β through p53, impairing mitochondrial function and metabolism. This telomere–p53–PGC pathway links telomere attrition to cardiomyopathy, defective gluconeogenesis, and stem cell decline.
Key findings
- Transcriptomic profiling of haematopoietic stem cells, heart, and liver from G4 Tert−/− mice showed broad repression of the PGC-1α/β network, including oxidative phosphorylation, oxidative defence, gluconeogenesis, fatty acid/cholesterol synthesis, and β-oxidation genes; RT–qPCR and western blot confirmed lower PGC-1α/β and targets such as NRF-1, ERRα, PPARα, and TFAM.
- Mitochondrial consequences included reduced mitochondrial DNA content and density, lower complex I and IV activity, decreased state III respiration, reduced uncoupled respiration in G4 liver and heart (31% and 25%, respectively), lower ATP synthesis/content, and increased ROS/H2O2 production.
- G4 mice developed dilated cardiomyopathy by 15 months, showed a 30% drop in plasma glucose after 12 h fasting, and had impaired HSC reconstitution; adenoviral Tert partially restored PGC targets and raised glucose by 30% in vivo and 80% in cultured G4 hepatocytes, while adenoviral PGC-1α increased state III and IV respiration in G4 liver mitochondria by 3.1-fold and 3.2-fold.
- p53 deficiency restored PGC expression and mitochondrial DNA copy number; p53–ER activation repressed PGCs and reduced mitochondrial mass by 10–15%; p53 bound PGC-1α/β promoters and repressed reporters fivefold; p53 loss improved fractional shortening by 30% in a doxorubicin cardiomyopathy protocol.
Methods
- Used Tert−/− mice across WT, G1, and G4 generations, Terc−/− G2 mice, and p53−/− backgrounds; profiled HSCs, liver, and heart by microarray with SAM or fold-change analysis and Ingenuity pathway analysis, followed by RT–qPCR and western blot.
- Assessed mitochondrial and metabolic phenotypes via qPCR-based mtDNA quantification, HPLC ATP measurement, Seahorse XF24 and Clark electrode respiration, ROS and carbonylated protein assays, fasting glucose, hepatocyte gluconeogenesis, echocardiography, and competitive transplantation.
- Mechanistic tests included adenoviral Tert or PGC-1α delivery, p53–ER MEF activation, PGC promoter luciferase reporters, anti-p53 chromatin immunoprecipitation, and doxorubicin-induced cardiomyopathy.
Limitations
- No dedicated limitations section is present; the authors state that the relative contributions of DNA damage checkpoints versus metabolic/mitochondrial dysfunction require further study, and that p53-mediated PGC repression is context-dependent.
- Evidence comes from mouse genetic models and cell systems, with no human data; germline p53 deletion and adenoviral overexpression may introduce pleiotropic or context-specific effects.
- The ROS scavenger N-acetylcysteine did not rescue defective HSC repopulation, indicating increased ROS is not central to HSC failure, although its role in other phenotypes is not fully resolved.
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“This impaired mitochondrial ATP synthesis is associated with decreased total ATP content in G4 hearts and livers (Fig. 2d).”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction decreases mitochondrial mass and energy production
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“This Ad-PGC-1α impact was markedly more pronounced in G4 mice than in WT mice or hepatocytes.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction induces pathophysiologies classical for impaired PGC function
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“cultured G4 hepatocytes which show an 80% increase in glucose output relative to Ad-GFP controls”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction induces pathophysiologies classical for impaired PGC function
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“respiration uncoupled from ATP synthesis (induced by 2,4-dinitrophenol, DNP) was also reduced in G4 liver and heart mitochondria (31% and 25%, respectively)”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction decreases mitochondrial mass and energy production
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“Functionally, telomere dysfunction correlated with a marked decline in complex I and IV activity when assayed with either whole tissue lysates or isolated mitochondria from G1 and G4 heart and liver tissues”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction decreases mitochondrial mass and energy production
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“G4 mice also showed decreased blood triglyceride and cholesterol levels”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction represses PGC network and mitochondrial biogenesis
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“Additionally, complex II- and complex IV-dependent respiration was also decreased in G4 mitochondria”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction decreases mitochondrial mass and energy production
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“Telomere dysfunction transcriptomes showed strong enrichment for networks regulated by PGC-1α and PGC-1β including oxidative phosphorylation (OXPHOS), mitochondrial function, oxidative stress and gluconeogenesis”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction represses PGC network and mitochondrial biogenesis
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“while running endurance capacity was significantly reduced in G4 mice”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction represses PGC network and mitochondrial biogenesis
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“Ad-Tert had no effect on gluconeogenesis in WT mice”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction induces pathophysiologies classical for impaired PGC function
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“G4 mice also exhibited an inability to maintain plasma glucose levels under fasting conditions, experiencing a marked 30% drop at 12 h of fasting, yet maintained normal plasma glucose levels under fed conditions”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction induces pathophysiologies classical for impaired PGC function
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“In this model, progressive telomere shortening is associated with increasing atrophy and functional decline across proliferative organs (intestinal, haematopoietic) and equally profound impairment in relatively quiescent organs (liver and heart) that do not exhibit significant levels of apoptosis”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction represses PGC network and mitochondrial biogenesis
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“as well as reductions in PGC and targets, mitochondrial DNA content, complex I and IV activity, and ATP levels”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction decreases mitochondrial mass and energy production
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“Body composition analysis showed body weight reduction and striking decrease in fat mass with preserved lean mass, yet no differences in spontaneous activity or food intake were apparent”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction represses PGC network and mitochondrial biogenesis
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“this PGC-mitochondrial link is supported by Ad-PGC-1α-induced rescue of gluconeogenesis in vivo and in vitro in G4 hepatocytes”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction induces pathophysiologies classical for impaired PGC function
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“G4 Tert−/− mice exhibited these classical signs of impaired PGC function, including an age-progressive dilated cardiomyopathy with left ventricular wall thinning, increased left ventricular diameter, and reduced fractional shortening by 15 months of age”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction induces pathophysiologies classical for impaired PGC function
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“We documented reduced mitochondrial DNA content (Fig. 2a) and reduced mitochondrial density in G1 and G4 heart and liver”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction decreases mitochondrial mass and energy production
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“which aligned with increased ROS levels by FACS in HSCs and increased carbonylated proteins in liver homogenates”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction decreases mitochondrial mass and energy production
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“WT MEF or heart tissues of mice treated with the DNA damage agent doxorubicin showed increased p53 levels after 24 h and coincident binding of p53 to PGC-1α promoter and repression of PGC-1α levels”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > p53 directly represses PGC-1α and PGC-1β
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“anti-p53 chromatin-immunoprecipitation assays in G2 Terc−/− p53+/+, but not G2 Terc−/− p53−/−, MEFs demonstrated physical binding between p53 and (1) PGC-1α fragments containing p53 binding elements at −564 and −954, but not −2317, and (2) PGC1β fragments containing p53 binding elements at −1616 and −1030”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > p53 directly represses PGC-1α and PGC-1β
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“after 48 h of OHT treatment, G2 Terc−/− p53−/− p53–ER MEFs showed a 10–15% decrease in mitochondrial mass compared with no significant change in the OHT-treated G2 Terc−/− p53−/− controls”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > p53 directly represses PGC-1α and PGC-1β
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“Increasing dosage of p53 in either p53−/− or G2 p53−/− MEFs showed repressed PGC-1α and PGC-1β levels and increasing occupancy of p53 binding elements in PGC-1α and PGC-1β promoters”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > p53 directly represses PGC-1α and PGC-1β
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In the paper
“Taken together, these collective data establish that telomere-dysfunction-induced repression of the PGC network is associated with mitochondrial dysfunction as evidenced by compromised OXPHOS and respiration, decreased ATP generation capacity, and increased oxidative stress.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction decreases mitochondrial mass and energy production
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In the paper
“In summary, multiple levels of evidence establish telomere dysfunction-induced p53 represses PGC-1α and PGC-1β, thereby linking telomeres to mitochondrial biology, oxidative defence, and metabolism.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Discussion
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In the paper
“We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1β promoters, thereby forging a direct link between telomere and mitochondrial biology.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Abstract
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In the paper
“In the absence of telomerase, continued cell division results in telomere shortening, loss of ‘capping’ function, and p53 activation12-15.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Abstract
What the sources say
- Not checked yetcites [12] Hastie, N. D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990) source
- Not checked yetcites [13] Lee, H.-W. et al. Essential role of mouse telomerase in highly proliferative organs. Nature 392, 569–574 (1998) source
- Not checked yetcites [14] Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997) source
- Not checked yetcites [15] Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999) source
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We propose that this telomere–p53–PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Abstract
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In the paper
“We propose that telomere dysfunction-induced repression of the PGC network and consequent mitochondriopathy and metabolic changes, along with telomere-induced apoptotic and proliferative checkpoints, contributes to functional multi-system decline in the setting of telomere dysfunction.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Discussion
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In the paper
“p53 deficiency markedly attenuates the degenerative phenotypes associated with telomere dysfunction, whereas constitutively activated p53 accelerates ageing phenotypes15-18.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > p53 directly represses PGC-1α and PGC-1β
What the sources say
- Not checked yetcites [15] Chin, L. et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97, 527–538 (1999) source
- Not checked yetcites [16] Wong, K. K. et al. Telomere dysfunction and Atm deficiency compromises organ homeostasis and accelerates ageing. Nature 421, 643–648 (2003) source
- Not checked yetcites [17] Maier, B. et al. Modulation of mammalian life span by the short isoform of p53. Genes Dev. 18, 306–319 (2004) source
- Not checked yetcites [18] Tyner, S. D. et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415, 45–53 (2002) source
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In the paper
“The relevance of PGCs to age-related pathologies may stem from their regulation of mitochondrial biogenesis and control of metabolic processes (gluconeogenesis, fatty acid metabolism and β-oxidation), processes that relate to increased insulin resistance and diabetes in the aged9.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Abstract
What the sources say
- Not checked yetcites [9] Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC-1 family of transcription coactivators. Cell Metab. 1, 361–370 (2005) source
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In the paper
“prompted by studies linking impaired mitochondrial function to defective HSC maintenance27-29”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction induces pathophysiologies classical for impaired PGC function
What the sources say
- Not checked yetcites [27] Pannicke, U. et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nature Genet. 41, 101–105 (2008) source
- Not checked yetcites [28] Sankaran, V. G., Orkin, S. H. & Walkley, C. R. Rb intrinsically promotes erythropoiesis by coupling cell cycle exit with mitochondrial biogenesis. Genes Dev. 22, 463–475 (2008) source
- Not checked yetcites [29] Liu, J. et al. Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459, 387–392 (2009) source
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In the paper
“Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Abstract
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In the paper
“Previous work has established that repression of either or both co-activators (PGC-1α or PGC-1β) decreases mitochondrial biogenesis and function, elicits cardiomyopathy and impairs de novo glucose production23-25.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > Telomere dysfunction induces pathophysiologies classical for impaired PGC function
What the sources say
- Not checked yetcites [23] Arany, Z. et al. Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α. Proc. Natl Acad. Sci. USA 103, 10086–10091 (2006) source
- Not checked yetcites [24] Yoon, J. C. et al. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413, 131–138 (2001) source
- Not checked yetcites [25] Lai, L. et al. Transcriptional coactivators PGC-1α and PGC-lβ control overlapping programs required for perinatal maturation of the heart. Genes Dev. 22, 1948–1961 (2008) source
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In the paper
“qPCR-based mitochondrial quantification was performed with two different primer sets for genomic and mitochondrial loci.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > METHODS SUMMARY
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In the paper
“For chromatin immunoprecipitation, we followed the EZ-Chip protocol (Promega) using p53 specific antibody and control IgG.”
§ Telomere dysfunction induces metabolic and mitochondrial compromise > METHODS SUMMARY
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
N-acetylcysteine given from birth effectively scavenges reactive oxygen species in the haematopoietic stem cell compartments of G1 and G4 mice.
“G1 or G4 mice treated from birth with N-acetylcysteine, a ROS scavenger, did not rescue defective HSC repopulation in competitive transplantations”
The paper relies on this without support.
The G2 Terc−/− mice used have a degree of telomere dysfunction comparable to that of G4 Tert−/− mice.
“G2 Terc−/− liver and hearts (exhibiting comparable telomere dysfunction as G4 Tert−/− mice)”
The paper relies on this without support.
The transcriptomic network analyses used in this study were unbiased.
“These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta”
The paper relies on this without support.
The p53 binding elements identified in the PGC-1α and PGC-1β promoters are the functional sites through which p53 represses these genes.
“anti-p53 chromatin-immunoprecipitation assays in G2 Terc−/− p53+/+, but not G2 Terc−/− p53−/−, MEFs demonstrated physical binding between p53 and (1) PGC-1α fragments containing p53 binding elements at −564 and −954, but not −2317, and (2) PGC1β fragments containing p53 binding elements at −1616 and −1030”
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“TERC−/− mice present altered mitochondrial functions, including increased production of reactive oxygen species (ROS) from the electron transfer chain (ETC) (Passos et al., 2010; Sahin et al., 2011).”
From P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan (2016) · cites this paper as Sahin et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, other mutations in genes involved in ROS metabolism, such as SOD2 haploinsufficiency, do not cooperate with telomere dysfunction (Guachalla et al., 2009), and the treatment with N‐acetylcysteine does not rescue progeric phenotypes of late‐generation TERT‐deficient mice (Sahin et al., 2011).”
From P66SHC deletion improves fertility and progeric phenotype of late-generation TERC-deficient mice but not their short lifespan (2016) · cites this paper as Sahin et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing 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).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Sahin et al, 2011
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In mouse models of accelerated telomere shortening, critically short telomeres have been shown to repress PGC1‐α‐ and β‐mediated mitochondrial biogenesis (Sahin et al, 2011; Chang et al, 2016).”
From Length-independent telomere damage drives post-mitotic cardiomyocyte senescence (2019) · cites this paper as Sahin et al, 2011
The cited source says what the claim attributes to it.
In the citing paper
“Although the rates of stem cell replenishment are unlike to completely account for the telomere length differences observed, we cannot discard other roles of telomerase such as the rescue of telomere shortening through stress protection (Saretzki, 2009) or the recently association to mitochondrial protection in post mitotic tissues (Sahin et al, 2011).”
From Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer (2012) · cites this paper as Sahin et al, 2011
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“our sample sizes are similar to those reported in previous publications.15,24,86”
From TERT activation targets DNA methylation and multiple aging hallmarks (2024) · cites this paper as [24]
Experimental — accuracy not yet measuredIn the citing paper
“signaling downstream of short telomeres activates p53, which binds and represses PGC-1α and PGC-1β promoters leading to mitochondrial dysfunction (Sahin et al., 2011).”
From Telomeres and cell senescence—size matters not (2017) · cites this paper as Sahin et al., 2011
In the citing paper
“It is interesting that telomere dysfunction has been associated with changes in mitochondrial metabolism (93)”
From Causes, consequences, and reversal of immune system aging (2013) · cites this paper as [93]
In the citing paper
“more recently it has been recognized that telomere dysfunction causes prominent phenotypes in slow-turnover tissues97,99,100,103 (Table 2).”
From The telomere syndromes (2012) · cites this paper as [103]
In the citing paper
“The telomerase-knockout mouse has provided an important model for understanding telomere-mediated disease mechanisms because there is a remarkable convergence with human disease phenotypes (an overview is shown in Table 2)36,82,84,85,97,99–111.”
From The telomere syndromes (2012) · cites this paper as [103]
In the citing paper
“In these tissues, the metabolic dysfunction appears to be due to the effect of downregulation of PGC1α, which is a transcriptional co-activator that is important for mitochondrial biogenesis103.”
From The telomere syndromes (2012) · cites this paper as [103]
In the citing paper
“Shortened dysfunctional telomeres in other mouse cell types, such as cardiac myocytes and hepatocytes, have also been associated with decreased mitochondrial copy number and defective oxidative metabolism103.”
From The telomere syndromes (2012) · cites this paper as [103]
In the citing paper
“Recent findings correlate deficiency of TERT (and subsequent loss of telomeres) with deficiencies in mitochondrial function attributed to decreases in PGC-1α and PGC-1β expression and suppressed mitochondrial biogenesis (364).”
From Redox regulation of mitochondrial function (2012) · cites this paper as [364]
In the citing paper
“p53 activation was found to suppress expression of the PGC-1α and PGC-1β (364), thus linking telomeres to mitochondrial biogenesis.”
From Redox regulation of mitochondrial function (2012) · cites this paper as [364]
In the citing paper
“Cellular senescence is thought to further propagate nearby tissue aging through intracellular metabolic compromise (eg, mitochondrial dysfunction) (Sahin et al, 2011) and altered production of secretory factors that promote aging by increasing degradation of nearby tissue and sterile inflammation (Coppe et al, 2010a, b;Freund et al, 2010) (ie, senescence-associated secretory phenotype, SASP).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Sahin et al, 2011
In the citing paper
“For example, the tumor suppressor protein, p53, may be activated, which inhibits oxidative defense mechanisms (such as peroxisome proliferator-activated receptor-gamma coactivator [PGC] 1-α and β, promoting mitochondrial damage and senescence or apoptosis (Sahin et al., 2011) (Fig. 2).”
From Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging (2015) · cites this paper as Sahin et al., 2011
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Zhong, H., Hu, S., Yu, B., Jiang, S., Zhang, J., Luo, D., Yang, M.-W., Su, W., Shao, Y.-L., Deng, H.-L., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.21123 · Cited by 31
TRF1 as a major contributor for telomeres' shortening in the context of obesity
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The Contributions of Early Experience to Biological Development and Sensitivity to Context
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Self-citationTranscriptome-wide analyses indicate mitochondrial responses to particulate air pollution exposure
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Metadata
- Authors
- Sahin, E., Colla, S., Liesa, M., Moslehi, J., Müller, F. L., Guo, M., Cooper, M., Kotton, D., Fabian, A. J., Walkey, C., Maser, R. S., Tonon, G., Foerster, F., Xiong, R., Wang, Y. A., Shukla, S. A., Jaskelioff, M., Martin, E. S., Heffernan, T. P., Protopopov, A., Ivanova, E., Mahoney, J. E., Kost-Alimova, M., Perry, S. R., Bronson, R., Liao, R., Mulligan, R., Shirihai, O. S., Chin, L., & DePinho, R. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Harvard University (US)
- Boston University (US)
- Brigham and Women's Hospital (US)
- University of Massachusetts Chan Medical School (US)
- The University of Melbourne (AU)
- Corresponding author
- DePinho, Ronald A.
- ORCID
- Sahin, Ergün
- Colla, Simona
- Liesa, Marc
- Moslehi, Javid
- Müller, Florian L.
- Kotton, Darrell
- Walkey, Carl
- Tonon, Giovanni
- Foerster, Friedrich
- Wang, Y. Alan
- Shukla, Sachet A.
- Jaskelioff, Mariela
- Martin, Eric S.
- Heffernan, Timothy P.
- Protopopov, Alexei
- Ivanova, Elena
- Mahoney, John E.
- Bronson, Roderick
- Liao, Ronglih
- Shirihai, Orian S.
- DePinho, Ronald A.
- Venue
- Nature
- Published
- 2011-02-09
- Volume
- 470
- Issue
- 7334
- Pages
- 359-365
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3741661
- OpenAlex
- W2124098526
- Semantic Scholar
- 14115a60df726b2a29c3a0b4d83e9f284c2371bb
- Cited by
- 1,319
- References
- 49
- Citations by year
- 2026: 50 · 2025: 58 · 2024: 73 · 2023: 87 · 2022: 83 · 2021: 100 · 2020: 78 · 2019: 84 · 2018: 81 · 2017: 88 · 2016: 91 · 2015: 93 · 2014: 83 · 2013: 94 · 2012: 111
- FWCI
- 76.58
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-06-22)
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Funders
- National Cancer Institute (R01CA084628)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK035914, R01DK089185, U24DK59635, P30DK046200, U24DK059635, R01DK063356, R01DK056690, P30DK079638)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Keywords
- telomere dysfunction, p53, PGC-1α, PGC-1β, telomerase reverse transcriptase, telomerase RNA, mitochondrial biogenesis, mitochondrial dysfunction, gluconeogenesis, cardiomyopathy, reactive oxygen species, cellular senescence, hematopoietic stem cells, liver, heart, aging, transcriptional repression
- MeSH terms
- Adenosine Triphosphate, Aging, Animals, DNA, Mitochondrial, Doxorubicin, Gluconeogenesis, Hematopoietic Stem Cells, Liver, Mitochondria, Cardiomyopathies, Myocardium, RNA, Transcription Factors, Tumor Suppressor Protein p53, Telomere, Reactive Oxygen Species, Telomerase, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-06, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
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