RESUMO
MiRNAs, a class of non-coding RNA molecules, have emerged as critical modulators of telomere length and telomerase activity by finely tuning the expression of target genes (and not gene targets) within signaling pathways involved in telomere homeostasis. The primary objective of this systematic review was to compile and synthesize the existing body of knowledge on the role, association, and involvement of miRNAs in telomere length. Additionally, the review explored the regulation, function, and activation mechanism of the human telomerase reverse transcriptase (hTERT) gene and telomerase activity in tumor cells. A comprehensive analysis of 47 selected articles revealed 40 distinct miRNAs involved in these processes. These miRNAs were shown to exert their function, in both clinical cases and cell line models, either directly or indirectly, regulating hTERT and telomerase activity through distinct molecular mechanisms. The regulatory roles of these miRNAs significantly affected major cancer phenotypes, with outcomes largely dependent on the tissue type and the cellular actions within the tumor cells, whereby they functioned as oncogenes or tumor suppressors. These findings strongly support the pivotal role of miRNAs in modulating telomere length and telomerase activity, thereby contributing to the intricate and complex regulation of telomere homeostasis in tumor cells. Moreover, they emphasize the potential of targeting miRNAs and key regulatory genes as therapeutic strategies to disrupt cancer cell growth and promote senescence, offering promising avenues for novel cancer treatments.
Assuntos
Regulação Neoplásica da Expressão Gênica , MicroRNAs , Neoplasias , Telomerase , Homeostase do Telômero , Telômero , Humanos , Telomerase/genética , Telomerase/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Homeostase do Telômero/genética , Neoplasias/genética , Neoplasias/patologia , Neoplasias/metabolismo , Telômero/metabolismo , Telômero/genética , AnimaisRESUMO
BACKGROUND: The aging population prompts studying risk factors and markers to predict healthy aging. Telomere length is a promising candidate for assessing various age-related traits. AIM OF THE STUDY: To investigate the association between physical performance and telomere length. METHODS: We enrolled 323 older Mexican adults from the "Cohort of Obesity, Sarcopenia, and Frailty of Older Mexican Adults" affiliated with the Instituto Mexicano del Seguro Social and assessed their physical performance using the Short Physical Performance Battery, dividing participants into low (≤7) and high (>7) groups. Absolute telomere length was determined by qPCR, and individuals were classified into short (≤4.22 kb) and long (>4.22 kb) groups. We calculated the mean and adjusted mean, considering sex and age, among others, with 95% CI. We estimated the effect size between physical performance and telomere length using Cohen's d for unequal group sizes and calculated the odds ratio for physical performance based on telomere length. RESULTS: Participants with low physical performance had significantly shorter telomeres (mean 4.14.44.7 kb, adjusted mean 3.54.04.5 kb, p <0.001), while those with high physical performance exhibited longer telomeres (mean 5.55.75.9 kb, adjusted mean 4.75.35.8 kb, p <0.001), with a medium-to-high telomere length effect size (d = 0.762). The odds of low physical activity increased 2.13.66.1-fold per kb of telomere attrition (adjOR 1.73.36.3, p <0.001). CONCLUSION: Decreased physical function is associated with shorter telomere length. Absolute telomere length presents a promising biomarker for distinguishing between healthy and unhealthy aging, warranting further investigation.
Assuntos
Desempenho Físico Funcional , Telômero , Humanos , Masculino , Feminino , Idoso , México , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Envelhecimento/fisiologia , Envelhecimento/genética , Encurtamento do Telômero , Homeostase do Telômero , Fragilidade/genéticaRESUMO
BACKGROUND: Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies. METHODS AND RESULTS: Here we investigated the expression of RecQ (RECQL1, BLM, WRN, RECQL4, and RECQL5) and RTEL1 helicase genes in peripheral blood mononuclear cells (PBMCs) from human telomeropathy patients. The mRNA expression levels of all RecQ helicases, but not RTEL1, were significantly downregulated in patients' primary cells. Reduced RecQ expression was not attributable to cell proliferative exhaustion, as RecQ helicases were not attenuated in T cells exhausted in vitro. An additional fifteen genes involved in DNA damage repair and RecQ functional partners also were downregulated in the telomeropathy cells. CONCLUSION: These findings indicate that the expression of RecQ helicases and functional partners involved in DNA repair is downregulated in PBMCs of telomeropathy patients.
Assuntos
Leucócitos Mononucleares , RecQ Helicases , Adulto , Feminino , Humanos , Masculino , DNA Helicases/genética , DNA Helicases/metabolismo , Reparo do DNA/genética , Leucócitos Mononucleares/metabolismo , RecQ Helicases/genética , RecQ Helicases/metabolismo , Telômero/metabolismo , Telômero/genética , Homeostase do Telômero/genéticaRESUMO
ABSTRACT Introduction: Telomere length (TL) is a biomarker of cellular proliferative history. In healthy individuals, leukocyte TL shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the TL attrition, aging and sex. Methods: We evaluated the association between the TL, aging and sex in a cohort of 180 healthy subjects by quantile regression. The TL of nucleated blood cells was measured by fluorescent in situ hypridization (flow-FISH) in a cohort of 89 men, 81 women, and 10 umbilical cord samples. The results were validated by quantitative polymerase chain reaction (qPCR) and compared to a linear regression analysis. Results: By quantile regression, telomere dynamics slightly differed between sexes with aging: women had longer telomeres at birth and slower attrition rate than men until the sixth decade of life; after that, TL eroded faster and became shorter than that in men. These differences were not observed by linear regression analysis, as the overall telomere attrition rates in women and men were similar (42 pb per year, p < 0.0001 vs. 45 pb kb per year, p < 0.0001). Also, qPCR did not recapitulate flow-FISH findings, as the telomere dynamics by qPCR followed a linear model. Conclusion: The quantile regression analysis accurately reproduced a third-orderpolynomial TL attrition rate in both women and men, but it depended on the technique applied to measure TL. The Flow-FISH reproduced the expected telomere dynamics through life and, differently from the qPCR, was able to detect the subtle TL variations associated with sex and aging.
Assuntos
Humanos , Masculino , Feminino , Recém-Nascido , Lactente , Pré-Escolar , Criança , Adolescente , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Análise de Regressão , Telômero , Homeostase do Telômero , SexoRESUMO
The long noncoding RNA (lncRNA) telomeric repeat-containing RNA (TERRA) has been associated with telomeric homeostasis, telomerase recruitment, and the process of chromosome healing; nevertheless, the impact of this association has not been investigated during the carcinogenic process. Determining whether changes in TERRA expression are a cause or a consequence of cell transformation is a complex task because studies are usually carried out using either cancerous cells or tumor samples. To determine the role of this lncRNA in cellular aging and chromosome healing, we evaluated telomeric integrity and TERRA expression during the establishment of a clone of untransformed myeloid cells. We found that reduced expression of TERRA disturbed the telomeric homeostasis of certain loci, but the expression of the lncRNA was affected only when the methylation of subtelomeric bivalent chromatin domains was compromised. We conclude that the disruption in TERRA homeostasis is a consequence of cellular transformation and that changes in its expression profile can lead to telomeric and genomic instability.
Assuntos
RNA Longo não Codificante , Homeostase do Telômero , Cromatina/genética , Heterocromatina , Metilação , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Telômero/genética , Telômero/metabolismoRESUMO
It has been well-known that built environment features influence the risk of chronic diseases. However, the existing data of its relationship with telomere length, a biomarker of biological aging, is still limited, with no study available for Mexican Americans. This study investigates the relationship between several factors of the built environment with leukocyte telomere length among 5508 Mexican American adults enrolled in Mano-A-Mano, the Mexican American Cohort Study (MACS). Based on the quartile levels of telomere length, the study population was categorized into four groups, from the lowest (1st quartile) to the highest telomere length group (4th quartile). For individual built environment factors, their levels did not differ significantly across four groups. However, in the multinominal logistic regression analysis, increased Rundle's land use mixture (LUM) and Frank's LUM were found statistically significantly associated with increased odds of having high levels of telomere length (Rundle's LUM: 2nd quartile: Odds ratio (OR) 1.26, 95% Confidence interval (CI) 1.07, 1.48; 3rd quartile: OR 1.25, 95% CI 1.06, 1.46; 4th quartile: OR 1.19, 95% CI 1.01, 1.41; Frank's LUM: 2nd quartile: OR 1.34, 95% CI 1.02, 2.63; 3rd quartile: OR 1.55, 95% CI 1.04, 2.91; 4th quartile: OR 1.36, 95% CI 1.05, 2.72, respectively). The associations for Rundle's LUM remained significant after further adjusting other non-redundant built environment factors. Finally, in stratified analysis, we found the association between Rundle's LUM and telomere length was more evident among younger individuals (< 38 years old), women, and those with obesity, born in Mexico, having low levels of physical activity, and having low levels of acculturation than their relative counterparts. In summary, our results indicate that land use mixture may impact telomere length in leukocytes in Mexican Americans.
Assuntos
Ambiente Construído , Leucócitos , Americanos Mexicanos/genética , Modelos Teóricos , Telômero/genética , Adulto , Envelhecimento , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Homeostase do Telômero , Adulto JovemRESUMO
Background: Polycystic Ovary Syndrome (PCOS) often present metabolic disorders and hyperandrogenism (HA), facts that may influence the telomere length (TL). Aims: To compare the absolute TL (aTL) between women with PCOS and control women, and their association with the presence of obesity and HA parameters. Materials and methods: The PCOS group included 170 unrelated women outpatients and the control group, 64 unrelated donor women. Anthropometric, biochemical-clinical parameters and androgen profile were determined. The PCOS patients were divided accordingly to the presence of obesity and androgenic condition. The aTL was determined from peripheral blood leukocytes by Real Time quantitative PCR. Results: Women with PCOS exhibited a significantly longer aTL than controls after age adjustment (p=0.001). A stepwise multivariate linear regression in PCOS women, showed that WC (waist circumference) contributed negatively (b=-0.17) while testosterone levels contributed positively (b=7.24) to aTL. The non-Obese PCOS (noOB-PCOS) presented the longest aTL when compared to controls (p=0.001). Meanwhile, the aTL was significantly higher in the hyperandrogenic PCOS phenotype (HA-PCOS) than in the controls (p=0.001) and non hyperandrogenic PCOS phenotype (NHA-PCOS) (p=0.04). Interestingly, when considering obesity and HA parameters in PCOS, HA exerts the major effect over the aTL as non-obese HA exhibited the lengthiest aTL (23.9 ± 13.13 Kbp). Conversely, the obese NHA patients showed the shortest aTL (16.5 ± 10.59 Kbp). Conclusions: Whilst a shorter aTL could be related to the presence of obesity, a longer aTL would be associated with HA phenotype. These findings suggest a balance between the effect produced by the different metabolic and hormonal components, in PCOS women.
Assuntos
Hiperandrogenismo/genética , Obesidade/genética , Síndrome do Ovário Policístico/genética , Telômero/metabolismo , Adulto , Argentina/epidemiologia , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Hiperandrogenismo/complicações , Hiperandrogenismo/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/epidemiologia , Estudos Retrospectivos , Telômero/química , Homeostase do Telômero/fisiologia , Testosterona/sangueRESUMO
Chronic stress is related to the acceleration of telomere shortening. Recent work showed a correlation between chronic psychosocial stress and reduced telomere length in certain cells. The exposure of T lymphocytes to cortisol promoted a significant reduction in telomerase activity. Although stress can promote changes in telomere length, whether increased glucocorticoid concentrations alter telomere length in brain tissue cells is unclear. In addition to modulating the activity of the stress system, estrogen also influences telomere length. The objective of this study was to verify whether chronic exposure to glucocorticoids promotes changes in the telomere length of encephalic areas involved in the control of HPA axis activity and whether estrogen affects these changes. Wistar rats were ovariectomized and treated with estradiol cypionate [(50 or 100 µg/kg, subcutaneously)] or oil and 20 mg/kg corticosterone or vehicle (isotonic saline with 2% Tween 80, subcutaneously) for 28 days. On the day after the end of the hormonal treatment, the animals were euthanized for collection of blood, brain and pituitary gland samples. Estrogen modulated the activity of the HPA axis. CRH, AVP and POMC mRNA levels were reduced by estrogen. At least in doses and treatment time used, there was no correlation between effects of exposure to glucocorticoids and estrogen on telomere length in the brain areas of female rats. However, estrogen treatment reduced the telomere length in the central amygdala and dorsal hippocampus, but not in the PVN, indicating a variation of reaction of telomeres for estrogen in different brain areas.
Assuntos
Corticosterona/farmacologia , Estrogênios/farmacologia , Homeostase do Telômero/fisiologia , Hormônio Adrenocorticotrópico/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corticosterona/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Estrogênios/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Sistema Hipotálamo-Hipofisário/metabolismo , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Sistema Hipófise-Suprarrenal/metabolismo , Ratos , Estresse Fisiológico , Telômero/efeitos dos fármacos , Telômero/metabolismo , Telômero/fisiologia , Homeostase do Telômero/efeitos dos fármacosRESUMO
BACKGROUND: Hereditary hemochromatosis (HH) is a primary iron overload (IO) condition. Absolute telomere length (ATL) is a marker of cellular aging and DNA damage associated with chronic diseases and mortality. AIM: To evaluate the relationship between ATL and IO in patients with HH. METHODS: Cross-sectional study including 25 patients with HH: 8 with IO and 17 without IO (ferritin < 300 ng/ml) and 25 healthy controls. Inclusion criteria were: age > 18 years, male sex and HH diagnosis. Patients with diabetes or other endocrine and autoimmune diseases were excluded. ATL was measured by real-time PCR. RESULTS: HH patients with IO were older (P<0.001) and showed higher ferritin concentration (P<0.001). Patients with HH, disregarding the iron status, showed higher glucose and body mass index (BMI) than controls (both P<0.01). ATL was shorter in patients with IO than controls [with IO: 8 (6-14), without IO: 13 (9-20), and controls: 19 (15-25) kilobase pairs, P<0.01]; with a linear trend within groups (P for trend <0.01). Differences in ATL remained statistically significant after adjusting by age, BMI and glucose (P<0.05). DISCUSSION: Patients with IO featured shorter ATL while patients without IO showed only mild alterations vs. controls. Screening for IO is encouraged to prevent iron-associated cellular damage and early telomere attrition.
Assuntos
Hemocromatose/imunologia , Ferro/metabolismo , Leucócitos/imunologia , Homeostase do Telômero/imunologia , Telômero/metabolismo , Adulto , Idoso , Envelhecimento/imunologia , Estudos Transversais , Ferritinas/sangue , Hemocromatose/sangue , Hemocromatose/diagnóstico , Hemocromatose/genética , Proteína da Hemocromatose/genética , Humanos , Ferro/sangue , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , Estresse Oxidativo/imunologiaRESUMO
Telomere maintenance mechanisms (TMM) are used by cancer cells to avoid apoptosis, 85-90% reactivate telomerase, while 10-15% use the alternative lengthening of telomeres (ALT). Due to anti-telomerase-based treatments, some tumors switch from a telomerase-dependent mechanism to ALT; in fact, the co-existence between both mechanisms has been observed in some cancers. Although different elements in the ALT pathway are uncovered, some molecular mechanisms are still poorly understood. Therefore, with the aim to identify potential molecular markers for the study of ALT, we combined in silico approaches in a 411 telomere maintenance gene set. As a consequence, we conducted a genomic analysis of these genes in 31 Pan-Cancer Atlas studies from The Cancer Genome Atlas and found 325,936 genomic alterations; from which, we identified 20 genes highly mutated in the cancer studies. Finally, we made a protein-protein interaction network and enrichment analysis to observe the main pathways of these genes and discuss their role in ALT-related processes, like homologous recombination and homology directed repair. Overall, due to the lack of understanding of the molecular mechanisms of ALT cancers, we proposed a group of genes, which after ex vivo validations, could represent new potential therapeutic markers in the study of ALT.