RESUMEN
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Asunto(s)
Envejecimiento/inmunología , Envejecimiento/fisiología , Sistema Inmunológico/inmunología , Sistema Inmunológico/fisiología , Inmunosenescencia/inmunología , Inmunosenescencia/fisiología , Especificidad de Órganos/inmunología , Especificidad de Órganos/fisiología , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Animales , Daño del ADN/inmunología , Daño del ADN/fisiología , Reparación del ADN/inmunología , Reparación del ADN/fisiología , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Femenino , Envejecimiento Saludable/inmunología , Envejecimiento Saludable/fisiología , Homeostasis/inmunología , Homeostasis/fisiología , Sistema Inmunológico/efectos de los fármacos , Inmunosenescencia/efectos de los fármacos , Masculino , Ratones , Especificidad de Órganos/efectos de los fármacos , Rejuvenecimiento , Sirolimus/farmacología , Bazo/citología , Bazo/trasplanteRESUMEN
Targeted disruption of RIIß-protein kinase A (PKA) in mice leads to a lean phenotype, increased nocturnal locomotor activity, and activation of brown adipose tissue. Because RIIß is abundantly expressed in both white and brown adipose tissue as well as the brain, the contribution of neuronal vs. peripheral PKA to these phenotypes was investigated. We used a Cre-Lox strategy to reexpress RIIß in a tissue-specific manner in either adipocytes or neurons. Mice with adipocyte-specific RIIß reexpression remained hyperactive and lean, but pan-neuronal RIIß reexpression reversed both phenotypes. Selective RIIß reexpression in all striatal medium spiny neurons with Darpp32-Cre corrected the hyperlocomotor phenotype, but the mice remained lean. Further analysis revealed that RIIß reexpression in D2 dopamine receptor-expressing medium spiny neurons corrected the hyperlocomotor phenotype, which demonstrated that the lean phenotype in RIIß-PKA-deficient mice does not develop because of increased locomotor activity. To identify the neurons responsible for the lean phenotype, we used specific Cre-driver mice to reexpress RIIß in agouti-related peptide (AgRP)-, proopiomelanocortin (POMC)-, single-minded 1 (Sim1)-, or steroidogenic factor 1 (SF1)-expressing neurons in the hypothalamus, but observed no rescue of the lean phenotype. However, when RIIß was reexpressed in multiple regions of the hypothalamus and striatum driven by Rip2-Cre, or specifically in GABAergic neurons driven by Vgat-ires-Cre, both the hyperactive and lean phenotypes were completely corrected. Bilateral injection of adeno-associated virus1 (AAV1)-Cre directly into the hypothalamus caused reexpression of RIIß and partially reversed the lean phenotype. These data demonstrate that RIIß-PKA deficiency in a subset of hypothalamic GABAergic neurons leads to the lean phenotype.
Asunto(s)
Adiposidad/genética , Encéfalo/metabolismo , Subunidad RIIbeta de la Proteína Quinasa Dependiente de AMP Cíclico/metabolismo , Metabolismo Energético/fisiología , Homeostasis/fisiología , Locomoción/fisiología , Neuronas/metabolismo , Análisis de Varianza , Animales , Western Blotting , Peso Corporal/genética , Calorimetría Indirecta , Subunidad RIIbeta de la Proteína Quinasa Dependiente de AMP Cíclico/genética , Cartilla de ADN/genética , Ensayo de Inmunoadsorción Enzimática , Genotipo , Inmunohistoquímica , Integrasas/metabolismo , Leptina/sangre , Ratones , Ratones Noqueados , Neuronas/fisiología , Reacción en Cadena de la Polimerasa , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismoRESUMEN
Most yeast ribosomal protein genes are duplicated and their characterization has led to hypotheses regarding the existence of specialized ribosomes with different subunit composition or specifically-tailored functions. In yeast, ribosomal protein genes are generally duplicated and evidence has emerged that paralogs might have specific roles. Unlike yeast, most mammalian ribosomal proteins are thought to be encoded by a single gene copy, raising the possibility that heterogenous populations of ribosomes are unique to yeast. Here, we examine the roles of the mammalian Rpl22, finding that Rpl22(-/-) mice have only subtle phenotypes with no significant translation defects. We find that in the Rpl22(-/-) mouse there is a compensatory increase in Rpl22-like1 (Rpl22l1) expression and incorporation into ribosomes. Consistent with the hypothesis that either ribosomal protein can support translation, knockdown of Rpl22l1 impairs growth of cells lacking Rpl22. Mechanistically, Rpl22 regulates Rpl22l1 directly by binding to an internal hairpin structure and repressing its expression. We propose that ribosome specificity may exist in mammals, providing evidence that one ribosomal protein can influence composition of the ribosome by regulating its own paralog.
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Proteínas de Unión al ARN/genética , ARN/genética , Proteínas Ribosómicas/genética , Ribosomas/genética , Homología de Secuencia de Aminoácido , Secuencia de Aminoácidos , Animales , Regulación de la Expresión Génica , Ratones , Datos de Secuencia Molecular , Biosíntesis de Proteínas , ARN/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteínas Ribosómicas/metabolismo , Ribosomas/metabolismoRESUMEN
Whether mitochondrial mutations cause mammalian aging, or are merely correlated with it, is an area of intense debate. Here, we use a new, highly sensitive assay to redefine the relationship between mitochondrial mutations and age. We measured the in vivo rate of change of the mitochondrial genome at a single-base pair level in mice, and we demonstrate that the mutation frequency in mouse mitochondria is more than ten times lower than previously reported. Although we observed an 11-fold increase in mitochondrial point mutations with age, we report that a mitochondrial mutator mouse was able to sustain a 500-fold higher mutation burden than normal mice, without any obvious features of rapidly accelerated aging. Thus, our results strongly indicate that mitochondrial mutations do not limit the lifespan of wild-type mice.
Asunto(s)
Longevidad/genética , Mitocondrias/genética , Mutación Puntual/fisiología , Envejecimiento/genética , Animales , Células Cultivadas , ADN Polimerasa gamma , ADN Polimerasa Dirigida por ADN/genética , ADN Polimerasa Dirigida por ADN/metabolismo , Ratones , Ratones Transgénicos , Mitocondrias/enzimología , Mitocondrias/metabolismoRESUMEN
Oxidative DNA damage plays a role in disease development and the aging process. A prominent participant in orchestrating the repair of oxidative DNA damage, particularly single-strand breaks, is the scaffold protein XRCC1. A series of chronological and biological aging parameters in XRCC1 heterozygous (HZ) mice were examined. HZ and wild-type (WT) C57BL/6 mice exhibit a similar median lifespan of ~26 months and a nearly identical maximal life expectancy of ~37 months. However, a number of HZ animals (7 of 92) showed a propensity for abdominal organ rupture, which may stem from developmental abnormalities given the prominent role of XRCC1 in endoderm and mesoderm formation. For other end-points evaluated-weight, fat composition, blood chemistries, condition of major organs, tissues and relevant cell types, behavior, brain volume and function, and chromosome and telomere integrity-HZ mice exhibited by-and-large a normal phenotype. Treatment of animals with the alkylating agent azoxymethane resulted in both liver toxicity and an increased incidence of precancerous lesions in the colon of HZ mice. Our study indicates that XRCC1 haploinsufficiency in mammals has little effect on chronological longevity and many key biological markers of aging in the absence of environmental challenges, but may adversely affect normal animal development or increase disease susceptibility to a relevant genotoxic exposure.
Asunto(s)
Envejecimiento/genética , Proteínas de Unión al ADN/genética , Haploinsuficiencia , Alquilantes/toxicidad , Animales , Conducta Animal , Peso Corporal , Células de la Médula Ósea/efectos de los fármacos , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Supervivencia Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Susceptibilidad a Enfermedades , Femenino , Inestabilidad Genómica , Masculino , Ratones , Ratones Endogámicos C57BL , Mutágenos/toxicidad , Proteína 1 de Reparación por Escisión del Grupo de Complementación Cruzada de las Lesiones por Rayos XRESUMEN
The pathology of aging impacts multiple organ systems, including the kidney and skeletal and cardiac muscles. Long-term treatment with the mitochondrial-targeted peptide elamipretide has previously been shown to improve in vivo mitochondrial function in aged mice, which is associated with increased fatigue resistance and treadmill performance, improved cardiovascular diastolic function, and glomerular architecture of the kidney. However, elamipretide is a short tetrameric peptide that is not orally bioavailable, limiting its routes of administration. This study tested whether twice weekly intermittent injections of elamipretide could recapitulate the same functional improvements as continuous long-term infusion. We found that intermittent treatment with elamipretide for 8 months preserved exercise tolerance and left ventricular mass in mice with modest protection of diastolic function and skeletal muscle force production but did not affect kidney function as previously reported using continuous treatment.
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Tolerancia al Ejercicio , Oligopéptidos , Femenino , Animales , Ratones , Mitocondrias , EnvejecimientoRESUMEN
Regular exercise and physical activity provide many health benefits and are encouraged by medical professionals for the primary prevention of and adjuvant treatment of breast cancer Current consensus in the discipline of exercise oncology is that both regular physical activity and exercise training exert some protective effect against breast cancer risk, and may reduce morbidity in some advanced cases. While there is growing interest in the role of exercise and physical activity in breast cancer prevention, it is currently unclear how exercise may modulate tumor behavior. The tumor microenvironment is populated by stromal cells such as fibroblasts and adipocytes, as well as macrophages. Termed tumor-associated macrophages (TAMs), these immune cells are highly plastic and respond to different signals from the cancer microenvironment, causing them to either display tumor-promoting or tumor-suppressing phenotypes. Because of such plasticity, there has been considerable interest by immunologists to develop immunotherapies based on skewing the behavior of TAMs to become cancer-suppressive. Previous studies have indirectly shown the ability of exercise training to induce an anti-tumor effect of macrophages, although the studies did not address this in the tumor microenvironment. Nevertheless, this opens up the possibility that regular exercise training may exert a protective innate immune effect against breast cancer, potentially by inducing a cancer-suppressing phenotype of TAMs. This review will describe potential mechanisms through which exercise may modulate the behavior of TAMs.
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Neoplasias de la Mama/inmunología , Neoplasias de la Mama/prevención & control , Ejercicio Físico/fisiología , Macrófagos/inmunología , Microambiente Tumoral/inmunología , Femenino , Humanos , Inmunidad Innata , Macrófagos/patologíaRESUMEN
Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson's disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/-) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.
Asunto(s)
Metformina , NADH Deshidrogenasa , Animales , Complejo I de Transporte de Electrón/genética , Complejo I de Transporte de Electrón/metabolismo , Mamíferos/metabolismo , Metformina/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias/genética , Mitocondrias/metabolismo , NADH Deshidrogenasa/genética , NADH Deshidrogenasa/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Extreme longevity in humans has a strong genetic component, but whether this involves genetic variation in the same longevity pathways as found in model organisms is unclear. Using whole-exome sequences of a large cohort of Ashkenazi Jewish centenarians to examine enrichment for rare coding variants, we found most longevity-associated rare coding variants converge upon conserved insulin/insulin-like growth factor 1 signaling and AMP-activating protein kinase signaling pathways. Centenarians have a number of pathogenic rare coding variants similar to control individuals, suggesting that rare variants detected in the conserved longevity pathways are protective against age-related pathology. Indeed, we detected a pro-longevity effect of rare coding variants in the Wnt signaling pathway on individuals harboring the known common risk allele APOE4. The genetic component of extreme human longevity constitutes, at least in part, rare coding variants in pathways that protect against aging, including those that control longevity in model organisms.
Asunto(s)
Envejecimiento , Longevidad , Anciano de 80 o más Años , Humanos , Longevidad/genética , Envejecimiento/genética , Transducción de Señal , Centenarios , AlelosRESUMEN
BACKGROUND: Age is a major risk for cardiovascular diseases. Although mitochondrial reactive oxygen species have been proposed as one of the causes of aging, their role in cardiac aging remains unclear. We have previously shown that overexpression of catalase targeted to mitochondria (mCAT) prolongs murine median lifespan by 17% to 21%. METHODS AND RESULTS: We used echocardiography to study cardiac function in aging cohorts of wild-type and mCAT mice. Changes found in wild-type mice recapitulate human aging: age-dependent increases in left ventricular mass index and left atrial dimension, worsening of the myocardial performance index, and a decline in diastolic function. Cardiac aging in mice is accompanied by accumulation of mitochondrial protein oxidation, increased mitochondrial DNA mutations and deletions and mitochondrial biogenesis, increased ventricular fibrosis, enlarged myocardial fiber size, decreased cardiac SERCA2 protein, and activation of the calcineurin-nuclear factor of activated T-cell pathway. All of these age-related changes were significantly attenuated in mCAT mice. Analysis of survival of 130 mice demonstrated that echocardiographic cardiac aging risk scores were significant predictors of mortality. The estimated attributable risk to mortality for these 2 parameters was 55%. CONCLUSIONS: This study shows that cardiac aging in the mouse closely recapitulates human aging and demonstrates the critical role of mitochondrial reactive oxygen species in cardiac aging and the impact of cardiac aging on survival. These findings also support the potential application of mitochondrial antioxidants in reactive oxygen species-related cardiovascular diseases.
Asunto(s)
Envejecimiento/patología , Catalasa/fisiología , Mitocondrias Cardíacas/enzimología , Disfunción Ventricular Izquierda/prevención & control , Envejecimiento/metabolismo , Animales , Señalización del Calcio , Catalasa/biosíntesis , Catalasa/genética , ADN Mitocondrial/análisis , ADN Mitocondrial/genética , Diástole , Fibrosis , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias Cardíacas/química , Mitocondrias Cardíacas/fisiología , Modelos Cardiovasculares , Mutación , Miocitos Cardíacos/ultraestructura , Factores de Transcripción NFATC/análisis , Especificidad de Órganos , Estrés Oxidativo , Especies Reactivas de Oxígeno , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/fisiología , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/análisis , Ultrasonografía , Disfunción Ventricular Izquierda/diagnóstico por imagenRESUMEN
Mammalian DNA polymerase delta (Pol delta) is believed to replicate a large portion of the genome and to synthesize DNA in DNA repair and genetic recombination pathways. The effects of mutation in the polymerase domain of this essential enzyme are unknown. Here, we generated mice harboring an L604G or L604K substitution in highly conserved motif A in the polymerase active site of Pol delta. Homozygous Pold1(L604G/L604G) and Pold1(L604K/L604K) mice died in utero. However, heterozygous animals were viable and displayed no overall increase in disease incidence, indicative of efficient compensation for the defective mutant polymerase. The life spans of wild-type and heterozygous Pold1(+/L604G) mice did not differ, while that of Pold1(+/L604K) mice was reduced by 18%. Cultured embryonic fibroblasts from the heterozygous strains exhibited comparable increases in both spontaneous mutation rate and chromosome aberrations. We observed no significant increase in cancer incidence; however, Pold1(+/L604K) mice bearing histologically diagnosed tumors died at a younger median age than wild-type mice. Our results indicate that heterozygous mutation at L604 in the polymerase active site of DNA polymerase delta reduces life span, increases genomic instability, and accelerates tumorigenesis in an allele-specific manner, novel findings that have implications for human cancer.
Asunto(s)
Transformación Celular Neoplásica/genética , ADN Polimerasa III/química , ADN Polimerasa III/metabolismo , Inestabilidad Genómica , Mutación/genética , Neoplasias/enzimología , Neoplasias/genética , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Sitios de Unión , Células Cultivadas , Cromosomas de los Mamíferos/metabolismo , Daño del ADN , ADN Polimerasa III/genética , Embrión de Mamíferos/citología , Embrión de Mamíferos/enzimología , Fibroblastos/citología , Fibroblastos/enzimología , Heterocigoto , Histonas/metabolismo , Longevidad , Pérdida de Heterocigocidad , Ratones , Datos de Secuencia Molecular , Neoplasias/patología , Fenotipo , Fosforilación , Estructura Secundaria de Proteína , Análisis de SupervivenciaRESUMEN
Sleep deprivation is a potent stress factor that disrupts regulatory pathways in the brain resulting in cognitive dysfunction and increased risk of neurodegenerative disease with increasing age. Prevention of the adverse effects of sleep deprivation could be beneficial in older individuals by restoring healthy brain function. We report here on the ability of SS31, a mitochondrial specific peptide, to attenuate the negative neurological effects of short-term sleep deprivation in aging mice. C57BL/6 female mice, 20 months old, were subcutaneously injected with SS31 (3 mg/kg) or saline daily for four days. Sleep deprivation was 4 h daily for the last two days of SS31 treatment. Mice were immediately tested for learning ability followed by collection of brain and other tissues. In sleep deprived mice treated with SS31, learning impairment was prevented, brain mitochondrial ATP levels and synaptic plasticity regulatory proteins were restored, and reactive oxygen species (ROS) and inflammatory cytokines levels were decreased in the hippocampus. This observation suggests possible therapeutic benefits of SS31 for alleviating adverse neurological effects of short-term sleep loss.
RESUMEN
The idea that the degree of response to physical stress in early life can be used to measure health in later life is a novel approach to better define resilience to aging. To investigate this, middle-age (15 months) mice were stressed by vaccination with a commercial pneumococcal vaccine (Prevnar 13), and 30 days later separated into a high antibody response group and a low antibody response group using Elisa to detect IgG serum antibody levels. After 4 months, mice were evaluated for physiological performance and learning ability. The high antibody response group was able to stay on a rotating rod longer than the low antibody response group and were more quickly able to find the escape hole in a spatial navigation learning task. This observation suggests Prevnar 13 antibody response in midlife could be a useful stress test to predict healthy aging.
RESUMEN
Resilience to aging is a biological event that precedes age-related decline in physiological function and is defined as an organism's ability to respond to physical stress with increasing age. There is a need to identify factors that may predict resilience for enhancing and maintaining healthy aging. Older people often experience delayed wound healing beause of compromised tissue repair and immune response. Therefore preclincal models may be of value to investigate the relationship between cutaneous wound healing and resilience to aging. This brief report descibes an ear punch biopsy model of cutaneous wound healing in aging mice and shows that mice with biopsy ear wounds that heal more quickly have better cognition, increased strength and better running endurance later in life.
RESUMEN
An increase in the burden of senescent cells in tissues with age contributes to driving aging and the onset of age-related diseases. Genetic and pharmacologic elimination of senescent cells extends both health span and life span in mouse models. Heterochronic parabiosis in mice has been used to identify bloodborne, circulating pro- and anti-geronic factors able to drive or slow aging, respectively. However, whether factors in the circulation also regulate senescence is unknown. Here, we measured the expression of senescence and senescence-associated secretory phenotype (SASP) markers in multiple tissues from 4- to 18-month-old male mice that were either isochronically or heterochronically paired for 2 months. In heterochronic parabionts, the age-dependent increase in senescence and SASP marker expression was reduced in old mice exposed to a young environment, while senescence markers were concurrently increased in young heterochronic parabionts. These findings were supported by geropathology analysis using the Geropathology Grading Platform that showed a trend toward reduced hepatic lesions in old heterochronic parabionts. In summary, these results demonstrate that senescence is regulated in part by circulating geronic factors and suggest that one of the possible mediators of the rejuvenating effects with heterochronic parabiosis is through the reduction of the senescent cell burden.
Asunto(s)
Senescencia Celular , Parabiosis , Envejecimiento , Animales , Biomarcadores , Modelos Animales de Enfermedad , Masculino , RatonesRESUMEN
Ageing is the greatest risk factor for most common chronic human diseases, and it therefore is a logical target for developing interventions to prevent, mitigate or reverse multiple age-related morbidities. Over the past two decades, genetic and pharmacologic interventions targeting conserved pathways of growth and metabolism have consistently led to substantial extension of the lifespan and healthspan in model organisms as diverse as nematodes, flies and mice. Recent genetic analysis of long-lived individuals is revealing common and rare variants enriched in these same conserved pathways that significantly correlate with longevity. In this Perspective, we summarize recent insights into the genetics of extreme human longevity and propose the use of this rare phenotype to identify genetic variants as molecular targets for gaining insight into the physiology of healthy ageing and the development of new therapies to extend the human healthspan.
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Descubrimiento de Drogas , Genética , Envejecimiento Saludable/genética , Longevidad/genética , Envejecimiento/genética , Animales , HumanosRESUMEN
An insulin-like growth factor-1 receptor (IGF1R) variant in exon 6 (Arg-407-His) in Ashkenazi Jewish centenarians was previously found to be associated with reduced IGF1R activity. To further study this longevity associated IGF1R variant, we generated a novel mouse line carrying the R407H variant in exon 6 of the Igf1r gene by employing CRISPR/Cas9 genome editing technology. Here, we show that the Igf1r gene can be edited in mouse embryos by zygotic electroporation of Cas9 protein and a single-guide RNAs together with a single stranded oligonucleotide donor containing the desired key nucleotide changes at the Igf1r locus. Sequence analysis of F0 and F1 mice following targeted editing demonstrated the robustness of this approach in mice using CRISPR/Cas9 directed homologous recombination (HDR). Western blot analysis indicates that mice heterozygous for the variant have a significant decrease in IGF1R phosphorylation in various tissues, including skeletal muscle, compared to wildtype. In addition, depletion of IGF1R signaling specifically in skeletal muscle of progeroid Ercc1 -/Δ mice resulted in extended health span and median lifespan providing the rationale for long term lifespan studies in Igf1r hR407H variant mice. This mouse line will be a valuable genetic tool to help determine the impact of IGF1R signaling on aging and longevity. The CRISPR editing approach represents a prototype for generating additional longevity associated gene variant mouse lines to study relevance to human exceptional longevity.
RESUMEN
NF-κB is a transcription factor activated in response to inflammatory, genotoxic and oxidative stress and important for driving senescence and aging. Ataxia-telangiectasia mutated (ATM) kinase, a core component of DNA damage response signaling, activates NF-κB in response to genotoxic and oxidative stress via post-translational modifications. Here we demonstrate that ATM is activated in senescent cells in culture and murine tissues from Ercc1-deficient mouse models of accelerated aging, as well as naturally aged mice. Genetic and pharmacologic inhibition of ATM reduced activation of NF-κB and markers of senescence and the senescence-associated secretory phenotype (SASP) in senescent Ercc1-/- MEFs. Ercc1-/Δ mice heterozygous for Atm have reduced NF-κB activity and cellular senescence, improved function of muscle-derived stem/progenetor cells (MDSPCs) and extended healthspan with reduced age-related pathology especially age-related bone and intervertebral disc pathologies. In addition, treatment of Ercc1-/∆ mice with the ATM inhibitor KU-55933 suppressed markers of senescence and SASP. Taken together, these results demonstrate that the ATM kinase is a major mediator of DNA damage-induced, NF-κB-mediated cellular senescence, stem cell dysfunction and aging and thus represents a therapeutic target to slow the progression of aging.
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Envejecimiento/metabolismo , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Senescencia Celular/fisiología , Daño del ADN/fisiología , FN-kappa B/metabolismo , Células Madre/metabolismo , Animales , Células Cultivadas , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Canagliflozin (Cana) is an FDA-approved diabetes drug that protects against cardiovascular and kidney diseases. It also inhibits the sodium glucose transporter 2 by blocking renal reuptake and intestinal absorption of glucose. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing Cana at 180 ppm at 7 months of age until their death. Cana extended median survival of male mice by 14%. Cana also increased by 9% the age for 90th percentile survival, with parallel effects seen at each of 3 test sites. Neither the distribution of inferred cause of death nor incidental pathology findings at end-of-life necropsies were altered by Cana. Moreover, although no life span benefits were seen in female mice, Cana led to lower fasting glucose and improved glucose tolerance in both sexes, diminishing fat mass in females only. Therefore, the life span benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in male mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e., slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.
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Glucemia/análisis , Canagliflozina/farmacología , Intolerancia a la Glucosa/tratamiento farmacológico , Longevidad , Inhibidores del Cotransportador de Sodio-Glucosa 2/farmacología , Animales , Femenino , Intolerancia a la Glucosa/metabolismo , Intolerancia a la Glucosa/patología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Factores SexualesRESUMEN
Insulin resistance is a metabolic disorder that is highly prevalent in older populations. Mice expressing a truncated X-ray repair cross-complementing protein 1 (XRCC1tp) have normal repair of single-stranded breaks (SSBs) but are sensitive to alkylating agents. XRCC1tp mice thus provide a model to study perturbations in physiological function, such as metabolism, in the presence of normal DNA repair but attenuated XRCC1 activity. XRCC1tp male mice at six months of age fed a diet high in fat (lard) and sugar (sucrose) (HFSD) for three months showed a significant delay in glucose clearance, indicative of insulin resistance. These mice also had a decrease in respiratory exchange ratio, suggesting a change in the way fats and carbohydrates are used as a fuel source. Mechanisms for these observations are of interest, since there is a suggestion that XRCC1 is involved in glucoregulatory pathways, and XRCC1tp mice would provide an excellent model to pursue these studies in an age-related manner.