Yogita Dhas, PhD
Content writer – Clinical
Central nervous system health status as an important predictor of longevity.
Published on: February 21, 2024
The presentation emphasized the pivotal role of the central nervous system (CNS) health in determining longevity. Here's a concise summary of the key points covered: 1. Cognitive Function: Preservation of cognitive abilities correlates strongly with longevity. Declines in cognition, observed in neurodegenerative diseases, are associated with increased mortality risk. 2. Neuroplasticity: The brain's adaptability, or neuroplasticity, influences cognitive outcomes. Enhanced neuroplasticity correlates with better cognitive function. 3. Neuroinflammation: Chronic neuroinflammation is implicated in neurodegenerative diseases and cognitive decline. Maintaining low levels of neuroinflammation promotes better CNS health. 4. Neuronal Connectivity: Efficient information processing relies on robust neuronal networks. Maintaining synaptic connections is crucial for cognitive function. 5. Brain Structure: Structural changes in the brain, common in aging and neurodegenerative diseases, impact cognitive function. Preserving brain structure indicates better CNS health. 6. Neurotransmitter Balance: Balance in neurotransmitters is crucial for mood regulation and cognition. Dysregulation is associated with neuropsychiatric disorders and cognitive decline. Determinants of CNS Health: 1. Stress Resilience: Effective stress management is essential for CNS health. 2. Sleep Quality: Adequate sleep supports CNS health and cognitive function. 3. Vascular Health: A healthy vascular system is vital for CNS function. 4. Lifestyle Factors: Adopting a brain-healthy lifestyle promotes neuroprotection and cognitive resilience. Discussion: The presentation also discussed research findings, including the impact of APOE e4 status on cognitive decline, predictive models for cognitive impairment in cerebral small vessel disease (CSVD), brain network reorganization in healthy aging, the role of cognitive reserve in sustaining cognitive health, and neuroimaging-based biomarkers for predicting longevity. Furthermore, by exploring research findings on genetic predisposition, predictive models for cognitive decline, and neuroimaging-based biomarkers, it provided valuable insights into predicting and mitigating age-related cognitive decline. In essence, the presentation conveyed the profound impact of CNS health on overall longevity, advocating for proactive measures to safeguard the brain function and enhance the quality of life in aging population. Conclusion: In conclusion, the CNS plays a critical role in regulating bodily functions and maintaining overall health. Prioritizing CNS health through lifestyle adjustments and targeted interventions may enhance longevity.
Aging - What is it? How to prevent it?
Published on: January 17, 2024
Aging is the time-related deterioration of physiological functions crucial for survival and fertility, marked by the gradual accumulation of cellular and molecular damage. It is a major risk factor for chronic diseases, including neurodegenerative disorders. The major hallmarks of aging include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Promising interventions in preventing or slowing down aging processes include: 1. Calorie restriction 2. Senolytics to remove senescent cells 3. Telomerase activators to lengthen telomeres 4. Mitochondrial rejuvenation therapies to improve energy production and reduce oxidative stress. 5. Gene editing technologies like CRISPR-Cas9 potentially repair DNA damage and address genetic risks. Discussion: Here we will be discussing calorie restriction, which is the most effective non-genetic intervention for delaying aging and it involves a 20-50% reduction in calorie intake while maintaining nutrient adequacy. It shows benefits in human longevity and age-related disease and also alters gene expression and pathways related to muscle quality, aging, and health. Additionally, it has an impact on biological pathways, including proteostasis, circadian rhythm regulation, DNA repair, apoptosis, mitochondrial biogenesis, and inflammation. Further, the Calorie Restriction Study (CALERIE), a 12% CR that impacted muscle and health in healthy individuals, indicated altered gene expression in pathways related to muscle, aging, and health. Despite minor muscle mass losses, muscle strength remained unchanged. Additionally, another study on the effects of long-term caloric restriction on DNA methylation indicates CR slowed the rate of biological aging, as measured by DunedinPACE, but it has limited influence on common DNA methylation clocks like PhenoAge and GrimAge. Research on Aging-Related Parkinsonism and Potential Interventions demonstrated that CR may increase dopamine signaling markers, potentially alleviating Parkinsonian signs. Conclusion: CR may influence aging through autophagy and epigenetic modifications, but it is not a one-size-fits-all solution and may not be suitable for everyone. Thus, identifying specific signaling pathways in CR's anti-aging effects is crucial. Ongoing research may refine our understanding of CR's mechanisms and applications in the future.
Physical and mental stress: Impact on lifespan.
Published on: December 13, 2023
Stress, whether physical or mental, plays a pivotal role in determining the quality and length of human life. Physical stress triggers predictable responses in tissues, organs, and systems, with chronic exposure leading to the release of stress hormones such as cortisol. This hormonal surge can elevate blood pressure, heart rate, and blood sugar levels, contributing to conditions like cardiovascular diseases (CVD) and diabetes, ultimately impacting lifespan. Additionally, stress induces cellular damage through the production of free radicals, accelerating aging processes. Chronic physical stress also weakens the immune system, rendering the body more susceptible to infections and diseases. Moreover, it often results in reduced physical activity due to diminished motivation and energy, essential elements for maintaining overall health and longevity. Mental stress, stemming from various sources, encompasses emotional and cognitive responses to external pressures. Chronic mental stress poses risks of depression, anxiety, and other mental health disorders, disrupting sleep patterns crucial for physical and mental recovery. Unhealthy coping mechanisms, such as smoking, excessive alcohol consumption, and poor eating habits, may emerge as a consequence. The workplace is a significant source of stress, contributing to increased smoking and drinking habits, reduced health-promoting behaviors, and chronic inflammation, which is linked to age-related diseases. Work-related stress also increases the risk of mental health issues, indirectly impacting longevity through reduced motivation for self-care and increased vulnerability to health risks. Discussion Psychological factors, such as unhappiness and loneliness, can accelerate one's biological age, emphasizing the need to acknowledge the psychological component in aging studies. Research indicates that adverse childhood experiences (ACEs), including physical abuse, emotional abuse, sexual abuse, and mental trauma, contribute to accelerated biological aging. Further studies explore the associations between cumulative stress and accelerated biological aging, revealing that individuals with stronger emotion regulation exhibit less GrimAge acceleration at high-stress levels. Additionally, research on the longevity factor Klotho suggests low levels in young women experiencing chronic, high stress. The effects of stress on longevity are multifaceted, varying based on individual factors like genetics, lifestyle habits, overall health, coping mechanisms, resilience, and social support systems. A comprehensive, multidimensional approach that incorporates diverse stress management strategies proves most effective for promoting longevity. Conclusion In conclusion, regular medical checkups and seeking professional help are crucial for individuals experiencing chronic stress or related health problems. Understanding and addressing both physical and mental stressors are pivotal steps toward enhancing overall well-being and potentially extending one's lifespan.
Long-term impact of metformin and sulphonylurea therapies on type 2 diabetes: A two-decade analysis of survival patterns.
Published on: December 06, 2023
Original author: Joshua Stevenson-Hoare, et al. (2023) (DOI: 10.1186/s12889-023-15764-y)
Metformin is a first-line drug used for type 2 diabetes (T2D) treatment. Metformin has been associated with other non-diabetic health benefits, such as extending a healthy lifespan, in addition to its main use in the treatment of diabetes. The benefits of metformin have only been studied in the past for shorter than ten-year intervals, which may not be sufficient to fully capture the true effects of the drug on longevity. The primary aim of this study was to examine longevity in diabetes patients treated with metformin over the two decades. Additionally, they examined survival times for individuals treated with metformin and sulphonylurea therapy who were elderly (over 70 years) at the time of first diabetes treatment. Methodology In this study, researchers used the Secure Anonymized Information Linkage (SAIL) database, an archive of medical and demographic records of the Welsh population in the UK. They collected information for all T2D patients treated with metformin and sulphonylurea therapy. To extract T2D patients, they used NHS Read codes (CV2, CV3) to identify all individuals with an active diagnosis of T2D for twenty years (between January 1st, 1999 and December 31st, 2018). Potential controls were all individuals who were not diagnosed with any form of diabetes. They also extracted information from the Welsh Longitudinal General Practitioner (WLGP) for all individuals on smoking status, cancer, cardiovascular disease (CVD, including heart failure, hypertensive disease), and deprivation index (Welsh Index of Multiple Deprivation). A matched control design survival time was analyzed following the first treatment. Results The study investigated the outcomes of T2D patients treated with metformin, sulphonylurea, and thiazolidinedione. Thiazolidinedione-treated patients were excluded due to insufficient data. The analysis included 129,140 metformin-treated and 68,108 sulphonylurea-treated patients. Notably, 55.8% of sulphonylurea patients had prior metformin treatment, while only 11.1% of metformin patients had received sulphonylurea. Patients on sulphonylurea were older at the onset of treatment and more likely to have a history of cancer, CVD, and hypertension compared to metformin-treated patients. Even after excluding individuals with pre-existing cancer or CVD, sulphonylurea-treated patients still showed higher likelihoods of cancer and CVD. Both metformin and sulphonylurea therapy patients had shorter survival times than non-diabetic controls [survival time ratio (STR) = 0·819 (p < 1 × 10− 50) and STR = 0·778 (p < 1 × 10− 50), respectively]. Survival times for sulphonylurea patients were even shorter when excluding those also treated with metformin [STR = 0·693 (p < 1 × 10− 50)], which was significantly lower than the whole sulphonylurea group (p < 0.05). Cox regression analysis indicated higher hazard ratios for both treatments compared to non-diabetic controls. Among elderly patients (over 70 years) at the time of diabetes treatment, both metformin and sulphonylurea groups had lower survival times than non-diabetic controls. Over 20 years, metformin-treated patients initially had greater survival times than controls, but this was reversed after four years. Sulphonylurea patients had shorter survival times at all study periods, significant for periods of two years or longer. The findings showed that in the first year, T2D patients on metformin had significantly greater survival times than non-diabetic controls (STR = 1·237, p = 1·06 × 10− 10). After three years, this became non-significant, and after four years, it reversed (STR = 0·972, p = 0·049), with the survival time ratio declining even more as study periods increased. Throughout the research, patients on sulphonylurea had shorter survival times than non-diabetic controls; however, this difference was only statistically significant for durations of two years or more (STR = 0·927, p = 0·008). Conclusion Although metformin shows short-term advantages for longevity, these early benefits become outweighed by the impact of T2D when observed over up to twenty years. Consequently, it is advisable to employ more extended study durations when investigating longevity and healthy lifespan. Impact of research The impact of this research lies in its contribution to the understanding of the long-term consequences of different treatments for T2D. The findings provide valuable insights for medical professionals treating T2D patients. Comprehending the enduring consequences of metformin and sulphonylurea treatments can influence treatment decisions and help optimize patient care. This information may be useful in shaping strategies for improving diabetes care and reducing associated complications. The findings could lead to more investigation to confirm and develop the conclusion. Further analysis and replication studies may offer a more comprehensive understanding of the variables affecting T2D outcomes and treatment effects over time.
Easy-to-find irAEs can be used as indicators to predict neoadjuvant chemo-immunotherapy response.
Published on: August 16, 2023
Original author: Ye Tao, et al. (2023) (DOI: 10.3389/fonc.2023.1135140)
Lung cancer is the prominent cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) patients are diagnosed with early-stage disease in only 25% of cases, making them amenable to surgery with a curative goal. The development of neoadjuvant therapy made it possible for locally advanced patients to accept surgical resection, and the addition of immunotherapy further improve the pathological outcomes of these patients. Locally advanced patients might now accept surgical resection due to the development of neoadjuvant therapy, and the addition of immunotherapy significantly improves the pathological results in these patients. Patients with PD-L1-expressing locally progressed or metastatic NSCLC, as well as those with locally advanced disease following radical resection or concomitant chemoradiotherapy, have benefited greatly from the immunotherapy. It has been hypothesized that immune-related adverse events (irAEs) are linked to therapy effectiveness. In this prospective trial, the author explained how the early onset of irAEs was linked to better clinical outcomes. Methodology: This study was a prospective study performed on patients with NSCLC those received neoadjuvant Toripalimab (240mg, every 3 weeks) plus double platinum-based chemotherapy. This study was conducted between December 2020 to March 2022 at Peking University Cancer Hospital. This study (the Renaissance study, NCT04606303) received approval from the Peking University Ethic board (2020YJZ58). Patients who had resectable IIB-IIIB NSCLC without an EGFR/ALK mutation were included in the study. The authors have investigated the association between clinical outcomes and irAEs following neoadjuvant therapy. According to the clinical manifestation, an interdisciplinary team of doctors, surgeons, and radiologists confirmed the irAEs. Analysis was done on the relationship between irAEs and pathological outcomes. Results: A total of 55 patients were enrolled in this study, with a male-to-female ratio of 10:1 and a median age of 62 years old. Out of 55 patients, 44 were diagnosed with squamous cell carcinoma. With a median preoperative waiting period of 67 days (IQR 39-113 days), 48 of 55 patients eventually had thoracic surgery. According to the pathological findings, 24 patients (50%) and 31 patients (64.6%), respectively, had complete pathological responses and major pathological responses. Among the 48 patients who underwent R0 resection, immunotherapy-related thyroid dysfunction, rash/pruritus, and enteritis occurred in 11 patients (22.9%), 7 patients (14.6%), and 1 patient (2.1%), respectively. The median time to commencement of thyroid dysfunction was 45 days (IQR 21-91 days), and six patients (54.5%) with thyroid dysfunction obtained a major pathological response and five (45.5%) achieved a pathological complete response. The median time of onset was 8 days (IQR 6-29 days), six patients (85.7%) with rash or pruritus attained major pathological response and five patients (71.4%) achieved a pathological complete response. In addition, irAEs did not significantly affect preoperative waiting time (93 days vs 97 days, P=0.630), intraoperative blood loss (67.4 mL vs 64.3 mL, p=0.831), or operation duration (170.6 min vs 165.7 min, p=0.775). Impact of research: This clinical trial showed that the immunotherapy-related rash may be associated with pathological outcomes, demonstrating that basic irAEs like rash can be used as indicators to predict response to neoadjuvant chemo-immunotherapy. For patients with resectable NSCLC, this might result in a favorable therapeutic outcome as suggested by some irAEs. Given the potentially favorable signal on treatment-associated effects, this study underlined the significance of appropriately identifying irAEs that may benefit from neoadjuvant immunotherapy.
Phase 2 study of pembrolizumab in patients with recurrent and residual high-grade meningiomas.
Published on: April 12, 2023
Original author: Brastianos, P.K., Kim, A.E., et al. (2022) (DOI: 10.1038/s41467-022-29052-7)
Meningiomas are the most prevalent primary central nervous system tumor, with a prevalence of 170,000 cases in the United States. Maximal safe resection is the cornerstone of meningioma treatment, and adjuvant radiation may be necessary in some cases. Due to lack of effective systemic therapies, there are limited options for additional therapies, especially for recurrent or higher-grade meningiomas. Recent studies suggest, targeting the immunological microenvironment may be a promising meningioma treatment. The authors consequently proposed that pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, would have antitumor activity for high-grade meningiomas. The authors have designed a prospective phase-2 study investigating pembrolizumab in patients with progressive high-grade meningiomas using a dosage schedule that has proven effective in systemic cancers. Methodology A total of 26 patients were enrolled, who had grade 2 or 3 meningiomas that were histologically determined to be progressive, residual, or intracranial. This study was conducted from November 2017 to January 2021. A 200 mg dose of pembrolizumab was injected intravenously every 3 weeks, until the time of disease progression, death, or intolerable toxicity. While dose interruptions for adverse events (AEs) for up to 12 weeks were authorized, dose reductions were not. Every 6 weeks, a brain MRI was taken for restaging. Intracranial and extra cranial responses were assessed. Results Out of a total of 26 patients, 1 patient withdrew consent before receiving pembrolizumab. Hence, 25 individuals served as the sample size for efficacy and safety evaluations of pembrolizumab, a PD-1 inhibitor. The primary endpoint of the study was the proportion of patients alive and progression-free at 6 months (PFS-6). Secondary endpoints comprise progression-free and overall survival, best intracranial response, and toxicity. With a PFS-6 rate of 0.48 and a median PFS of 7.6 months, this study has successfully achieved its primary goal. One (or more) grade-3 or higher treatment-related adverse events have been seen in 20%. Conclusion According to these findings, pembrolizumab shows promising efficacy against a subset of malignant cancers. To determine the biological characteristics of the meningioma tumor microenvironment that may influence the effectiveness of immune-based treatments, additional research is required.
Grading of IDH‑mutant astrocytoma using diffusion, susceptibility, and perfusion‑weighted imaging.
Published on: January 17, 2023
Original author: Yang X, Xing Z, She D, et al. (2022) (DOI: 10.1186/s12880-022-00832-3)
The accurate grading of IDH-mutant astrocytoma is essential to develop therapeutic strategies and evaluating the prognosis of patients. A preoperative classification of these entities could be beneficial for the treatments of patients, particularly in those who have a contraindication to surgery or in cases where the lesions are unresectable. With the aid of apparent diffusion coefficient (ADC) measurements, diffusion-weighted imaging (DWI) can noninvasively evaluate the Brownian motion of water molecules in vivo. The grading of gliomas may benefit from using dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI), which can offer hemodynamic parameters with tumor angiogenesis. Susceptibility-weighted imaging (SWI), a more improved approach, may semi-quantitatively evaluate tumor micro-hemorrhages and vasculature via intratumoral susceptibility signal intensity (ITSS). These techniques have all been used to distinguish between different glioma grades. IDH-mutant astrocytic glioma grading is a topic that is rarely covered in studies. The combination of DWI, DSC-PWI, and SWI may help to increase the accuracy of diagnosis in IDH-mutant astrocytic gliomas. Therefore, the researchers in the present study investigated the usefulness of DWI, SWI, and DSC-PWI in grading IDH-mutant astrocytoma. Methodology In the present study, 107 patients with IDH-mutant astrocytoma who underwent DWI, SWI, and DSC-PWI were retrospectively evaluated. Values for the minimum apparent diffusion coefficient (ADCmin), maximum relative cerebral blood volume (rCBVmax), and intratumoral susceptibility signal intensity (ITSS) were evaluated. ADCmin, ITSS, and rCBVmax values were studied between grade 2 vs. grade 3, grade 3 vs. grade 4, and grade 2 + 3 vs. grade 4 tumors. To rate their diagnostic abilities, receiver operating characteristic (ROC) curve analysis, tenfold cross-validation, and logistic regression were performed. Results The results of the present investigation showed that, in comparison to grade 3 tumors, Grade 4 IDH-mutant astrocytoma’s displayed considerably lower ADCmin and greater rCBVmax (adjusted p <0.001). When compared to grade 4 tumors, grade 3 IDH-mutant astrocytomas had considerably reduced ITSS levels (adjusted p <0.001). Grade 2 and grade 3 IDH-mutant astrocytomas had significantly different ITSS levels (adjusted p = 0.002). The highest AUC for differentiating grade 2 and grade 3 cancers from grade 4 tumors was obtained when the ADCmin, ITSS, and rCBVmax were combined. Impact of research This study demonstrated that DWI, SWI, and DSC-PWI are useful for assessing the tumor grade in IDH-mutant astrocytomas. The diagnostic precision of grading IDH mutant astrocytomas may be enhanced by the combination of ADCmin, ITSS, and rCBVmax. This study proposed that the combination of these advanced techniques could improve the diagnostic efficacy in grading IDH-mutant astrocytic gliomas.
A six-metabolite panel as potential blood-based biomarkers for Parkinson’s disease.
Published on: October 18, 2022
Original author: Stephan Klatt, et al. (2021) (DOI: 10.1038/s41531-021-00239-x)
Parkinson’s disease (PD) is the second most common neurodegenerative disease after Alzheimer’s disease (AD) and affects around five million people worldwide. People with PD typically exhibit symptoms when 50% or more dopaminergic neurons of the substantia nigra are demolished. Therefore, the early introduction of disease-modifying treatments would result in maximum effectiveness. Ideally, this would be before major neuronal death and, hence, long before clinical symptoms become apparent. Currently, there aren't any disease-modifying treatments for PD, thus early and precise diagnosis of PD might help researchers find such treatments. Research into the understanding of the early pathophysiological event in PD would be supported by pre-symptomatic detection. Presently, there is no trustworthy biomarker for pre-symptomatic idiopathic PD (iPD) detection. This emphasizes the significance of the development of a new diagnostic marker to enable early diagnosis and evaluation of new potential treatments. Methodology In this study, 38 iPD-relevant metabolites were extracted from the blood serum of 231 individuals, and the concentration of these metabolites was quantified by using a targeted triple quadrupole liquid chromatography-mass spectrometry (QQQ LC/MS) method, to uncover changes solely based on the disease. This cohort is presently one of the largest metabolomic studies including iPD patients, drug-naive iPD, healthy controls, and patients with Alzheimer’s disease as a disease-specific control group. All the experiments were conducted under The University of Melbourne human ethics committee approval ID1136882. All participants provided written informed consent before their inclusion in the study. They examined the impact of L-DOPA on the tested metabolites along with the impact of age and sex before and after confounder adjustment. Additionally, they examined changes in the ratios and interactions of all targeted metabolites and used this to recognize potential biomarkers. Results The study found six metabolites (3-hydroxykynurenine, aspartate, beta-alanine, homoserine, ornithine, and tyrosine) that were significantly different between iPD patients and control participants. There were no substantial interactions between either age and control/iPD or between gender and control/iPD associated with metabolites. They also investigated all possible ratios and interactions. Comparing the mean ratio/interaction levels between the control and iPD groups, they identified 11 ratios and 23 significantly different interactions (p < 0.00009) between the two groups. In addition, they performed a multivariate analysis including both individual analytes and ratios/ interactions to examine if a panel of markers collectively could provide better discrimination between control and disease groups. Using a combination of feature selection (LASSO) and model selection via Akaike information criterion (AIC) reduction, seven markers including Cys, 2-aminobutyric acid, Tyr, L-KYN, a ratio of Arg/3-AA, a ratio of Asp/L-KYN, and product of β-ala*Orn were selected in a linear model to separate control from iPD participants. These seven metabolites resulted in an AUC value of 0.905 with an accuracy of 86.2%. Using the same method, a set of six markers were selected in a linear model to separate control from AD participants (Asp, Cys, Tryp, Homoserine/N-Acetyl-phenylalanine, Pro/3-HK, and Gln*Typtamine). A multivariate model to predict AD from controls had an area under the curve (AUC) of 0.884, with an accuracy of 79.3%. Impact of research The study measured the concentration of relevant metabolites extracted from the blood serum of 231 individuals to uncover changes solely based on the disease. This study also identified potential biomarkers to distinguish between control and disease (PD and AD). Presently, various tissue- and fluid-based biomarkers are being explored to enhance PD diagnosis, monitor disease progression, assess treatment responses, or categorize PD subtypes. Therefore, a panel of biomarkers could aid to increase the accuracy of iPD diagnosis and treatment outcomes and they have a great potential for utilization in clinical practice. Conclusion iPD and its progression appear to cause global metabolic alterations in peripheral body fluids as well as the brain. This study adds to the evidence that amino acids and metabolites of the kynurenine pathway are changed in patients with iPD. The present study suggested that the panel of metabolites might be used as a potential prognostic or diagnostic assay for clinical trial prescreening, or for assisting in diagnosing pathological diseases in clinics.
