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Abstract

The aging process occurs due to the decline of vital physiological functions and adaptability of the body, being influenced by genetics and lifestyle. With advances in genetics, biological aging can be calculated by telomere length. Telomeres are regions at the ends of chromosomes that play a role in the maintenance and integrity of DNA. With biological aging, telomere shortening occurs, causing cellular senescence. Several studies show that shorter telomeres are associated with acute and chronic diseases, stress, addictions, and intoxications. Even in the current COVID-19 pandemic, telomere shortening is proposed as a marker of severity in individuals infected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the other hand, healthy lifestyle habits increase telomere length and balance of various cellular functions, preventing diseases.
Journal of e Brazilian Medical Association
Volume 67, number 2, February, 2021
SECTIONS
EDITORIAL
163 Possible impact of adopting extreme hypofractionation
after FAST Forward trial publication
LETTER TO THE EDITOR
166 Focusing on thyroid nodules in suspense: 10-15 mm
with repeat cytology, Category III, the Bethesda
System for Reporting Thyroid Cytopathology, TBSRTC
AT BEDSIDE
168 Refractory celiac disease type 2: how to diagnose
and treat?
SHORT COMMUNICATIONS
173 Telomere length: biological marker of cellular
vitality, aging, and health-disease process
178 Ethical support to psychiatry residents: a report of a
Brazilian ethics consultation group
182 New papulovesicular rash in the course of COVID-19
signaling viral reactivation
ARTICLES
ORIGINAL ARTICLES
185 The effect of mutation status, pathological features
and tumor location on prognosis ın patients with
colorectal cancer
190 Dengzhan shengmai capsule combined with
donepezil hydrochloride in the treatment
of Alzheimer’s disease: preliminary findings,
randomized and controlled clinical trial
195 Abdominal ultrasound augments the medical
students’ ability to identify free intraabdominal fluid
200 Comparison of cardiovascular risk calculators in
patients with diabetes
207 Evaluation of serum ghrelin, nesfatin-1, irisin, and
vasoactive intestinal peptide levels in temporal lobe
epilepsy patients with and without drug resistance: a
cross-sectional study
213 Transcutaneous Electric Nerve Stimulation on
ischemic rest pain in inpatients: randomised trial
218 Quantitative evaluation of computed tomography
findings in patients with pulmonary embolism: the
link between D-Dimer level and thrombus volume
224 Lower LDL-cholesterol levels associated with
increased inflammatory burden in patients with
acute ST-segment elevation myocardial infarction
230 Parathyroid hormone levels after parathyroidectomy
for secondary hyperparathyroidism
235 Combined effects of nutritional status on long-term
mortality in patients with non-st segment elevation
myocardial infarction undergoing percutaneous
coronary intervention
243 Comparison of two endoscopic spine surgical
techniques
248 Prediction of impacts on liver enzymes from the
exposure of low-dose medical radiations through
artificial intelligence algorithms
260 Anxiety in candidates for radical prostatectomy in a
university hospital
265 Immunohistochemical and clinicopathologic features
of estrogen receptor-negative, progesterone
receptor-positive, HER-2 negative breast carcinomas
271 Factors associated with the perceived benefits and
barriers to physical activity in liver cirrhosis
277 Exercise training program in children with lower-
limb amputation
282 Effect of pulsed electromagnetic field therapy in
patients with supraspinatus tendon tear
287 Salivary glands of fetuses are adversely affected by
artificial food colorings in rats
292 Abdominal drain amylase on the first day after
pancreatectomy: a predictive factor for pancreatic fistula
297 Is there a relation between computed tomography
findings and electrocardiography findings in COVID-19?
REVIEW ARTICLES
302 Effectiveness of early therapeutic intervention
in phases one and two after COVID-19 infection:
systematic review
313 Predictors associated with sickle cell nephropathy: a
systematic review
318 Guillain-Barré syndrome associated with SARS-CoV-2
infection: a scoping review
335 Nuances between sedentary behavior and physical
inactivity: cardiometabolic effects and cardiovascular risk
ISSN 0104-4320
ISSN 1806-9282 (On-line)
173
Rev Assoc Med Bras 2021;67(2):173-177
SUMMARY
The aging process occurs due to the decline of vital physiological functions and adaptability of the body, being inuenced by genetics
and lifestyle. With advances in genetics, biological aging can be calculated by telomere length. Telomeres are regions at the ends of
chromosomes that play a role in the maintenance and integrity of DNA. With biological aging, telomere shortening occurs, causing
cellular senescence. Several studies show that shorter telomeres are associated with acute and chronic diseases, stress, addictions, and
intoxications. Even in the current COVID-19 pandemic, telomere shortening is proposed as a marker of severity in individuals infected by
the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the other hand, healthy lifestyle habits increase telomere length
and balance of various cellular functions, preventing diseases.
KEYWORDS: Telomere. Telomere shortening. Telomere homeostasis. Telomerase. Biomarkers. Aging. Cellular senescence. Chronic disease.
Telomere length: biological marker of cellular
vitality, aging, and health-disease process
Marcus Zulian Teixeira1*
SHORT COMMUNICATION
https://doi.org/10.1590/1806-9282.67.02.20200655
INTRODUCTION
e irreversible aging process is marked by a decline in vital
physiological functions and the adaptability of the body, being
strongly inuenced by genetics, environmental factors, and
lifestyle. Currently, the aging process is divided into two main
components, namely, chronological age and biological age,
which may dier for the same individual. Biological aging can
be calculated by telomere length (TL)1,2 and DNA methylation
levels (epigenetics)3,4.
Telomeres are noncoding regions of the genome, located at
the ends of chromosomes (functioning as protective covers of
chromosomes), which consist of long series of short and repeated
sequences formed by nitrogen bases 5-TTAGGG-3 and associ-
ated proteins, which play an important role in the maintenance
and integrity of DNA. Telomere shortening may compromise
the replicative potential of cells, contributing to the natural pro-
cess of cellular senescence. To counteract this process, the telo-
merase enzyme promotes the maintenance of telomere length
by synthesizing the repetitive sequences of lost telomeric DNA.
In 2009, Elizabeth H. Blackburn, Carol W. Greider, and
Jack W. Szostak received the Nobel Prize in Physiology or
Medicine for discovering the protective role of telomere and
telomerase enzyme in chromosomes5-7. ese extremely signif-
icant ndings paved the way for researchers to further explore
the role of telomere homeostasis in cell aging and chronic dis-
eases in general.
Mechanism of action of Telomeres
During cell division or duplication, cells are unable to repli-
cate approximately 50 pairs of nitrogen bases from the ends of
chromosomes, as conventional DNA polymerase cannot repro-
duce the 3 end of a linear molecule (end replication problem).
isleads to progressive chromosome shortening along the divi-
sions of a cell lineage, resulting in loss of replicative capacity and
induction of cellular senescence. is mechanism of action is
the main cause of cell aging and age-related chronic diseases8-10.
To avoid this progressive telomere shortening that occurs at
each cell division and the loss of respective genetic information,
1Instituto de Psiquiatria, Hospital das Clinicas, Faculdade de Medicina – Universidade de São Paulo (SP), Brazil.
*Corresponding author: marcus@homeozulian.med.br
Conflicts of interest: the authors declare there are no conflicts of interest. Funding: none.
Received on August 18, 2020. Accepted on August 19, 2020.
Telomere length: biological marker of cellular vitality, aging, and health-disease process
174
Rev Assoc Med Bras 2021;67(2):173-177
periodically, the lost DNA segments are recovered by the action
of a ribonucleoprotein enzyme complex called telomerase.
iscomplex has a small RNA component that is a template
for the synthesis of the repetitive sequences, which make up the
telomere. In the recovery of lost telomeric DNA, nucleotide
bases are added individually and in the correct sequence, and
telomerase progresses discontinuously, i.e., the RNA mold is
positioned on the initiator DNA, several nucleotides are added to
it, and nally the enzyme translocates to restart the process10-12.
In neonatal period, telomerase activity is reduced or null, as
evident from the absence in most somatic tissues of the body.
Telomerase is active in early stages of human development (plu-
ripotent embryonic cells), and throughout life, in blood stem
cells, germ cells and cells of adult tissues undergoing continu-
ous renewal, such as endometrial tissue13. Due to gradual loss
of telomerase activity, in each cell division, the telomere termi-
nals of these cells are shortened, reaching a minimum length
that precludes cell division14.
On the other hand, 90% of cancerous somatic cells, which
reach “immortality,” have high expressiveness of telomerase
(increasing the telomere length). In these tumor cells, the reac-
tivation of the telomerase silencer gene has been one of the
mechanisms used to circumvent the natural system of cellular
senescence and apoptosis, allowing cancer cells to promote con-
tinuous telomere elongation and replicate in an uncontrolled
and uninterrupted manner15,16.
Role of Telomeres in health disorders
Several studies show that shorter telomeres are associated with
a number of chronic diseases: congenital dyskeratosis, aplastic
anemia, idiopathic pulmonary brosis, and liver cirrhosis17;
cardiovascular diseases in general18,19, such as atherosclerosis20,
arterial hypertension21, and stroke22; diabetes mellitus type
223-25; autoimmune diseases, such as systemic lupus erythema-
tosus26 and rheumatoid arthritis27; psychiatric diseases28; and
dementia29,30, among other age-related diseases31.
In cancer, telomere sizes play a dual role as follows: telomere
shortening can lead to the induction of chromosomal instabil-
ity and the onset of tumor formation (precancerous lesion); on
the other hand, initiated tumors need to reactivate telomerase to
stabilize chromosomes and gain “immortal” growth capacity32,33.
e same telomere shortening is observed in other health
disorders, addictions, and intoxications, namely: obesity34;
inammatory and oxidative processes35; smoking36, alcohol-
ism37 and drug dependence38; and exposure to pollutants and
mineral particles39-41, among the others.
Even in acute diseases, such as the current coronavirus dis-
ease 2019 (COVID-19), telomere shortening is proposed as
a marker of disease severity42,43 identifying patients at risk of
higher morbidity and mortality from severe acute respiratory
syndrome coronavirus 2 (SARS-CoV-2) infection. Studiessug-
gest that T-cell lymphopoiesis may be discontinued in the
infected individuals with short telomeres44.
In cancer-surviving children, a study shows the decrease
in telomere size associated with chronic health disorders as
a result of the treatment received (radiotherapy and chemo-
therapy)45. Similarly, other treatments have demonstrated the
same shortening eect on telomere (e.g., immunosuppressive
drugs46, proton pump inhibitors47, and insulin48).
On the other hand, some therapies are being assessed to
counteract telomere shortening and act on telomere diseases:
sex hormones (aplastic anemia and idiopathic pulmonary bro-
sis)17,49, antidiabetic agents without acarbose (type 2 diabetes)50
and lithium (bipolar disorder)51, among the others. Similarly,
natural compounds and their extracts have demonstrated to
increase telomerase activation (Astragalus membranaceus or TA-65,
Centella asiatica, Euterpe oleracea, oleanolic acid, maslinic acid,
and multi-nutrient formulas)17,52,53, which may be indicated in
the treatment of diseases related to telomere shortening.
Given that in most cancer cells telomerase activity is higher,
dierent anti-cancer approaches have been designed in the
search for telomerase inhibitors: small-molecule inhibitors,
antisense oligonucleotides (imetelstat), G-quadruplex stabiliz-
ers, immunotherapy, gene therapy using telomerase promot-
er-driven expression of a suicide gene, and chemicals that block
telomerase biogenesis17,54,55. Among the natural compounds,
anthraquinone56 and wogonin (extract from Scutellaria baical-
ensis)57 appear as promising anti-tumor agents.
Analogous to physical disorders, traumatic social exposures
or lifelong psychoemotional disorders, such as chronic stress and
childhood traumas (abuse, violence, racism, bulling, low socio-
economic status, maternal depression, family disorder, and insti-
tutionalization, etc.), also cause a decrease in telomere length58-65.
Finally, in addition to natural and chronological aging, telo-
mere shortening can be inuenced by physical activity, body
mass index, chronic inammation, oxidative stress, hormone
therapy, drugs, dietary antioxidants, and vitamins, among oth-
ers. Studies show that individuals who follow a healthy lifestyle
have longer telomeres66.
CONCLUSION
Functioning as an important biomarker of cellular vitality or
activity, longevity or aging, and the health–disease process,
measuring the telomere length of leukocytes DNA extracted
from peripheral blood67 provides clinical and dynamic param-
eters of health and well-being and can be used as a diagnostic
and prognostic method of the illness process31,68-70, as well as
Teixeira, M. Z.
175
Rev Assoc Med Bras 2021;67(2):173-177
measuring the ecacy and eectiveness of various therapies
employed, conventional71 or nonconventional (e.g., homeop-
athy72, acupuncture73, and meditation74).
According to vitalist medical rationalities75, such as home-
opathy and acupuncture, cellular activity, physiological homeo-
stasis, and the health–disease process would be related to vital
force or chi (tsri), respectively; cellular senescence, physiological
imbalance, and the disease manifestation would occur due to
the disturbance of the body vitality. In order to approximate
dierent rationalities, recent studies correlate the characteristics
and properties of the homeopathic vital principle with those
of the genome (exome plus epigenome), suggesting that the
genome would be the biological representation or substrate of
the organic vital force, according to biomedical episteme76,77.
Inthis context, the telomere length could be used as an import-
ant biomarker of the eectiveness of homeopathic treatment in
maintaining vitality, physiological balance, and health.
Current knowledge about telomeres and telomerase reiter-
ates the importance that should be devoted to healthy lifestyle
and health-promoting measures, such as regular physical activity,
balanced diet, body weight control, spiritual and contemplative
activities, and integrative and complementary practices in health,
that increase telomere length and balance of various cellular func-
tions, preventing diseases, and other somatic and psychic disorders.
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... This is due to the fact that aging is the leading cause of most pathological conditions that compromise healthspan and promote age-related diseases (ARDs), which constitute a constant and growing burden on healthcare systems around the world (2). The aging process is modulated by many genetic and non-genetic determinants, and it can be defined by chronological and biological age (3). Individuals of the same age show differences in many aspects of health status, implying that chronological age, i.e., the number of years that have passed since birth, does not reflect the functional individual status in the best way, which was the main reason for the development of the concept of biomarkers of aging (BoAs) (4). ...
... Composite BoAs have the potential to exceed age and should be investigated more in the future. Considering the entanglement of telomere dysfunction in disease onset, cellular vitality or activity, aging or longevity, measuring the LTL provides a clinical parameter that can be useful for diagnosis and prognosis (8,(164)(165)(166), together with the evaluation of various therapies' efficiency, both conventional (167) and nonconventional (3). Because the level of telomere erosion is so important for the assessment of human health and course of the aging process, TL is by far the most researched biomarker of ARDs. ...
Article
As research related to healthspan and lifespan has become a hot topic, the necessity for a reliable and practical biomarker of aging (BoA), which can provide information about mortality and morbidity risk, along with remaining life expectancy, has increased. The chromosome terminus non-coding protective structure that prevents genomic instability is called a telomere. The continual shortening of telomeres, which affects their structure as well as function, is a hallmark of agedness. The aforementioned process is a potential cause of age-related diseases (ARDs), leading to a bad prognosis and a low survival rate, which compromise health and longevity. Hence, studies scrutinizing the BoAs often include telomere length (TL) as a prospective candidate. The results of these studies suggest that TL measurement can only provide an approximate appraisal of the aging rate, and its implementation into clinical practice and routine use as a BoA has many limitations and challenges. Nevertheless, measuring TL while determining other biomarkers can be used to assess biological age. This review focuses on the importance of telomeres in health, senescence, and diseases, as well as on summarizing the results and conclusions of previous studies evaluating TL as a potential BoA.
... Telomeres have been postulated as a universal biological clock that shorten in parallel with the division and aging of cells. The length of telomeres, particularly the abundance of short telomeres, has been proposed as a biomarker of senescence, aging, and general health status [1]. Telomeres are unique structures at the ends of eukaryotic chromosomes that protect them from degradation. ...
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Telomere length, a hallmark of cellular senescence, decreases with age and is associated with age-related diseases. Environmental factors, including dietary and lifestyle factors, can affect the rate at which telomeres shorten, and telomere protection prevents this from happening. The protection of telomeres by natural molecules has been proposed as an antiaging strategy that may play a role in treating age-related diseases. This study investigated the effect of a cycloartane-type triterpene glycoside (astragaloside IV). Astragaloside IV is one of the primary compounds from the aqueous extract of Astragalus membranaceus, and it provides telomere protection both in vitro and in vivo. In a study cohort with 13 participants, telomere length in human skin samples was analyzed after daily treatment for 4 weeks. A comparison of the average median telomere length between the treatment and control groups (5342 bp vs. 4616 bp p = 0.0168) showed significant results. In the second clinical cohort with 20 participants, skin parameters at baseline and after 4 and 8 weeks were measured in vivo. The results show that the product improved hydration by 95%, the skin appeared brighter by 90%, and wrinkle visibility was reduced by 70%. The combination of biologically active compounds in the cream possesses telomere-protecting properties and notable antioxidant activity in vitro and in vivo.
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Aim.- Anti-tuberculosis drug-induced hepatitis (AT-DIH) is a common and serious adverse drug reaction of tuberculosis treatment. Evidence demonstrated that many factors could affect the occurrence of AT-DIH, such as ageing, smoking, alcohol, oxidative stress, etc, while these factors could also promote telomere shortening. Therefore, relative telomere length (RTL) is indirectly related to the occurrence of AT-DIH. The present study aimed to explore and validate this relationship in Chinese tuberculosis patients. Methods.- A 1:4 matched case–control study was undertaken using 202 AT-DIH cases and 808 controls. Logistic regression models were used to estimate the association between RTL and AT-DIH with odds ratios (ORs) and 95% confidence intervals (CIs). The area under receiver operating characteristic curve (AUC) was calculated to estimate the discriminative performance for distinguishing AT-DIH cases from controls. Results.- The average RTL in AT-DIH cases was significantly shorter than that in controls (1.24 vs. 1.46, P = 0.002). Patients with longer RTL were at a reduced risk of AT-DIH (OR = 0.79, 95% CI: 0.66-0.94, P = 0.009), and a dose-response relationship also existed between RTL and lower AT-DIH risk (P for trend = 0.012). Under the optimal RTL cut-off value of 1.22, the corresponding AUCs were 0.57 (95% CI: 0.53-0.62, P = 0.001) in the univariate model and 0.62 (95% CI: 0.57-0.66, P<0.001) in the multivariate model. Conclusion.- This study showed that the shorter the RTL, the higher the risk of AT-DIH during an anti-tuberculosis treatment. The short RTL could potentially serve as a risk factor or a predictive test of the hepatotoxic risk associated with anti-tuberculosis treatments.
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Lung cancer is a severe and the leading cause of cancer related deaths worldwide. The recurrent h-TERT promoter mutations have been implicated in various cancer types. Thus, the present study is extended to analyze h-TERT promoter mutations from the North Indian lung carcinoma patients. Total 20 histopathologically and clinically confirmed cases of lung cancer were enrolled in this study. The genomic DNA was extracted from venous blood and subjected to amplification using appropriate h-TERT promoter primers. Amplified PCR products were subjected for DNA Sanger sequencing for the identification of novel h-TERT mutations. Further, these identified h-TERT promoter mutations were analysed for the prediction of pathophysiological consequences using bioinformatics tools such as Tfsitescan and CIIDER. The average age of patients was 45 ± 8 years which was categorized in early onset of lung cancer with predominance of male patients by 5.6 fold. Interestingly, h-TERT promoter mutations were observed highly frequent in lung cancer. Identified mutations include c. G272A, c. T122A, c. C150A, c. 123 del C, c. C123T, c. G105A, c. 107 Ins A, c. 276 del C corresponding to −168 G>A, −18 T>A, −46 C>A, −19 del C, −19 C>T, −1 G>A, −3 Ins A, −172 del C respectively from the translation start site in the promoter of the telomerase reverse transcriptase gene which are the first time reported in germline genome from lung cancer. Strikingly, c. −18 T>A [C.T122A] was found the most prevalent variant with 75% frequency. Notwithstanding, other mutations viz c. -G168A [c. G272A] and c. −1 G>A [c. G105A] were found to be at 35% and 15% frequency respectively whilst the rest of the mutations were present at 10% and 5% frequency. Additionally, bioinformatics analysis revealed that these mutations can lead to either loss or gain of various transcription factor binding sites in the h-TERT promoter region. Henceforth, these mutations may play a pivotal role in h-TERT gene expression. Taken together, these identified novel promoter mutations may alter the epigenetics and subsequently various transcription factor binding sites which are of great functional significance. Thereby, it is plausible that these germline mutations may involve either as predisposing factor or direct participation in the pathophysiology of lung cancer through entangled molecular mechanisms.
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Background: Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of COPD and idiopathic pulmonary fibrosis (IPF). Methods: Total RNA from the human lung tissues of non-smokers, smokers, and patients with COPD and IPF were processed and analyzed using a Nanostring platform based on their ages (younger: <55 years and older: >55 years). Results: Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 & 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 & 2, GADD45A), and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases including the SARS-CoV-2 infection. Lung immunoblot analysis of smokers, COPD and IPF subjects revealed increased abundance of proteases and receptor/spike protein like TMPRSS2, furin, and DPP4 in association with a slight increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor ACE2 levels. Conclusions: Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in COPD and IPF is associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis as pharmacological targets for COVID-19.
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Within the past several decades, the emergence of new viral diseases with severe health complications and mortality is evidence of an age-dependent, compromised bodily response to abrupt stress with concomitantly reduced immunity. The new severe acute respiratory syndrome coronavirus 2, SARS-CoV-2, causes coronavirus disease 2019 (COVID-19). It has increased morbidity and mortality in persons with underlying chronic diseases and those with a compromised immune system regardless of age and in older adults who are more likely to have these conditions. While SARS-CoV-2 is highly virulent, there is variability in the severity of the disease and its complications in humans. Severe pneumonia, acute respiratory distress syndrome, lung fibrosis, cardiovascular events, acute kidney injury, stroke, hospitalization, and mortality have been reported that result from pathogen–host interactions. Hallmarks of aging, interacting with one another, have been proposed to influence healthspan in older adults, possibly via mechanisms regulating the immune system. Here, we review the potential roles of the hallmarks of aging, coupled with host–coronavirus interactions. Of these hallmarks, we focused on those that directly or indirectly interact with viral infections, including immunosenescence, inflammation and inflammasomes, adaptive immunosenescence, genomic instability, mitochondrial dysfunction, epigenetic alterations, telomere attrition, and impaired autophagy. These hallmarks likely contribute to the increased pathophysiological responses to SARS-CoV-2 among older adults and may play roles as an additive risk of accelerated biological aging even after recovery. We also briefly discuss the role of anti-aging drug candidates that require paramount attention in COVID-19 research.
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Aging is one of the key contributing factors for chronic obstructive pulmonary diseases (COPD) and other chronic inflammatory lung diseases. Cigarette smoke is a major etiological risk factor that has been shown to alter cellular processes involving mitochondrial function, cellular senescence and telomeric length. Here we determined how aging contribute to the alteration in the gene expression of above mentioned cellular processes that play an important role in the progression of COPD and IPF. We hypothesized that aging may differentially alter the expression of mitochondrial, cellular senescence and telomere genes in smokers and patients with COPD and IPF compared to non-smokers. Total RNA from human lung tissues from non-smokers, smokers, and patients with COPD and IPF were processed and analyzed based on their ages (younger: <55 yrs and older: >55 yrs). NanoString nCounter panel was used to analyze the gene expression profiles using a custom designed codeset containing 112 genes including 6 housekeeping controls (mitochondrial biogenesis and function, cellular senescence, telomere replication and maintenance). mRNA counts were normalized, log2 transformed for differential expression analysis using linear models in the limma package (R/Bioconductor). Data from non-smokers, smokers and patients with COPD and IPF were analyzed based on the age groups (pairwise comparisons between younger vs. older groups). Several genes were differentially expressed in younger and older smokers, and patients with COPD and IPF compared to non-smokers which were part of the mitochondrial biogenesis/function (HSPD1, FEN1, COX18, COX10, UCP2 & 3), cellular senescence (PCNA, PTEN, KLOTHO, CDKN1C, TNKS2, NFATC1 & 2, GADD45A) and telomere replication/maintenance (PARP1, SIRT6, NBN, TERT, RAD17, SLX4, HAT1) target genes. Interestingly, NOX4 and TNKS2 were increased in the young IPF as compared to the young COPD patients. Genes in the mitochondrial dynamics and other quality control mechanisms like FIS1 and RHOT2 were decreased in young IPF compared to their age matched COPD subjects. ERCC1 (Excision Repair Cross-Complementation Group 1) and GADD45B were higher in young COPD as compared to IPF. Aging plays an important role in various infectious diseases. Elderly patients with chronic lung disease and smokers were found to have high incidence and mortality rates in the current pandemic of SARS-CoV-2 infection. Immunoblot analysis in the lung homogenates of smokers, COPD and IPF subjects revealed increased protein abundance of important proteases and spike proteins like TMPRSS2, furin and DPP4 in association with a slight increase in SARS-CoV-2 receptor ACE2 levels. This may further strengthen the observation that smokers, COPD and IPF subjects are more prone to COVID-19 infection. Overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition add to the pathobiology of lung aging in COPD and IPF and other smoking-related chronic lung disease in associated with alterations in SARS-CoV-2 ACE2-TMPRSS2-Furin-DPP4 axis for COVID-19 infection.
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The medical, public health, and scientific communities are grappling with monumental imperatives to contain COVID-19, develop effective vaccines, identify efficacious treatments for the infection and its complications, and find biomarkers that detect patients at risk of severe disease. The focus of this communication is on a potential biomarker, short telomere length (TL), that might serve to identify patients more likely to die from the SARS-CoV-2 infection, regardless of age. The common thread linking these patients is lymphopenia, which largely reflects a decline in the numbers of CD4/CD8 T cells but not B cells. These findings are consistent with data that lymphocyte TL dynamics impose a limit on T-cell proliferation. They suggest that T-cell lymphopoiesis might stall in individuals with short TL who are infected with SARS-CoV-2.
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Bipolar disorder (BD) may be associated with accelerated cellular aging. However, previous studies on telomere length (TL), an important biomarker of cellular aging, have yielded mixed results in BD. We aimed to evaluate the hypothesis that BD is associated with telomere shortening and whether this is counteracted by long-term lithium treatment. We also sought to determine whether long-term lithium treatment is associated with increased expression of telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase. We determined TL and TERT expression in 100 BD I patients and 100 healthy controls. We also genotyped three single nucleotide polymorphisms associated with TL. TERT expression was significantly increased in BD I patients currently on lithium treatment. TERT expression was also significantly positively correlated with duration of lithium treatment in patients treated for 24 months or more. However, we did not find any significant effect of lithium treatment on TL. Neither did we find significant differences in TL between BD patients and controls. We suggest that long-term lithium treatment is associated with an increase in the expression of TERT. We hypothesize that an increase in TERT expression may contribute to lithium's mood stabilizing and neuroprotective properties by improving mitochondrial function and decreasing oxidative stress.
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Exceptionally long-lived individuals (ELLI) who are the focus of many healthy longevity studies around the globe are now being studied in Israel. The Israeli Multi-Ethnic Centenarian Study (IMECS) cohort is utilized here for assessment of various DNA methylation clocks. Thorough phenotypic characterization and whole blood samples were obtained from ELLI, offspring of ELLI, and controls aged 53–87 with no familial exceptional longevity. DNA methylation was assessed using Illumina MethylationEPIC Beadchip and applied to DNAm age online tool for age and telomere length predictions. Relative telomere length was assessed using qPCR T/S (Telomere/Single copy gene) ratios. ELLI demonstrated juvenile performance in DNAm age clocks and overall methylation measurement, with preserved cognition and relative telomere length. Our findings suggest a favorable DNA methylation profile in ELLI enabling a slower rate of aging in those individuals in comparison to controls. It is possible that DNA methylation is a key modulator of the rate of aging and thus the ELLI DNAm profile promotes healthy longevity.
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Telomerase has become one of the new popular targets for the development of anti-tumor drugs. Based on the structural characteristics of the BIBR1532 which has entered the stage of clinical research, six series total of 64 new compounds with diverse structural characteristics were designed and synthesized. The inhibitory activity against SGC-7901, MGC-803, SMMC-7721, A375 and GES cell lines and their telomerase inhibitory activity were tested. Among them, eight compounds showed good activity against cancer cells, among them compounds 56, 57 and 59 also showed low toxicity. Some of them showed excellent telomerase inhibitory activity with IC50 values ranging from 0.62 μM to 8.87 μM. Based on above, in depth structure-activity relationships were summarized, the compounds by replacing methyl group with cyanide and retaining amide moiety had good anti-tumor activity, moderate cytotoxicity, and better telomerase inhibitory activity. The results should be used for reference in BIBR1532-based structural optimization for further development of small molecule telomerase inhibitors.
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Cancer, characterized by uncontrolled malignant neoplasm, is a leading cause of death in both advanced and emerging countries. Although, ample drugs are accessible in the market to intervene with tumor progression, none are totally effective and safe. Natural anthraquinone (AQ) equivalents such as emodin, aloe-emodin, alchemix and many synthetic analogs extend their antitumor activity on different targets including telomerase, topoisomerases, kinases, matrix metalloproteinases, DNA and different phases of cell lines. Nano drug delivery strategies are advanced tools which deliver drugs into tumor cells with minimum drug leakage to normal cells. This review delineates the way AQ derivatives are binding on these targets by abolishing tumor cells to produce anticancer activity and purview of nanoformulations related to AQ analogs.
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Cancer, a global havoc is a group of debilitating diseases that strikes family as well as society. Cancer cases are drastically increasing these days. In spite of many therapies and surgical procedures available cancer is still difficult to control. These are due to limited effective therapies or targeted therapies. Natural products can produce lesser side effects to the normal cells which are the major demerit of chemotherapies and radiation. Wogonin, a natural product extracted from plant, Scutellaria baicalensis has been studied widely and found with a high caliber to tackle most of the cancers via several mechanisms that include intrinsic as well as extrinsic apoptosis signaling pathways, carcinogenesis diminution, telomerase activity inhibition, metastasis inhibition in the inflammatory microenvironment, anti-angiogenesis, cell growth inhibition and arrest of cell cycle, increased generation of H2O2 and accumulation of Ca2+ and also as an adjuvant along with anticancer drugs. This article discusses the role of wogonin in various cancers, its synergism with various drugs and the mechanism by which wogonin controls tumor growth.
Article
Purpose We aimed to analyze and compare leukocyte telomere length (LTL) and age-dependent LTL attrition between childhood cancer survivors and noncancer controls, and to evaluate the associations of LTL with treatment exposures, chronic health conditions (CHC), and health behaviors among survivors. Experimental Design We included 2,427 survivors and 293 noncancer controls of European ancestry, drawn from the participants in St. Jude Lifetime Cohort Study (SJLIFE), a retrospective hospital-based study with prospective follow-up (2007–2016). Common nonneoplastic CHCs (59 types) and subsequent malignant neoplasms (5 types) were clinically assessed. LTL was measured with whole-genome sequencing data. Results After adjusting for age at DNA sampling, gender, genetic risk score based on 9 SNPs known to be associated with telomere length, and eigenvectors, LTL among survivors was significantly shorter both overall [adjusted mean (AM) = 6.20 kb; SE = 0.03 kb] and across diagnoses than controls (AM = 6.69 kb; SE = 0.07 kb). Among survivors, specific treatment exposures associated with shorter LTL included chest or abdominal irradiation, glucocorticoid, and vincristine chemotherapies. Significant negative associations of LTL with 14 different CHCs, and a positive association with subsequent thyroid cancer occurring out of irradiation field were identified. Health behaviors were significantly associated with LTL among survivors aged 18 to 35 years (Ptrend = 0.03). Conclusions LTL is significantly shorter among childhood cancer survivors than noncancer controls, and is associated with CHCs and health behaviors, suggesting LTL as an aging biomarker may be a potential mechanistic target for future intervention studies designed to prevent or delay onset of CHCs in childhood cancer survivors. See related commentary by Walsh, p. 2281