Well Aging

Researchers found that approximately one in 40 human bone marrow cells carry massive chromosomal alterations without causing any apparent disease or abnormality. Even so-called normal cells carry all sorts of genetic mutations, meaning there are more genetic differences between individual cells in our bodies than between different human beings. The discovery was enabled by a single-cell sequencing technology called Strand-seq, a unique DNA sequencing technique that can reveal subtle details of genomes in single cells that are too difficult to detect with other methods. In a study led by Jan Korbel at the European Molecular Biology Laboratory (EMBL) and Ashley Sanders at the Berlin Institute for Medical Systems Biology of the Max Delbrück Center (MDC-BIMSB), researchers have found that approximately one in 40 human bone marrow cells carry massive chromosomal alterations -- copy number variations and chromosomal rearrangements, for example -- without causing any apparent disease or abnormality. In addition, cell samples from people over the age of 60 tended to have higher numbers of cells with such genomic alterations, suggesting a previously unidentified mechanism that may contribute to ageing-related diseases. The study was published in the journal Nature Genetics. "The study highlights that we are all mosaics," said Korbel, who is Senior Scientist in the Genome Biology Unit and Head of Data Science at EMBL Heidelberg. "Even so-called normal cells carry all sorts of genetic mutations. Ultimately, this means that there are more genetic differences between individual cells in our bodies than between different human beings." Both Korbel and Sanders, Group Leader at the Max Delbrück Center study how genetic structural variation -- deletions, duplications, inversions, and translocations of large sections of the human genome -- contributes to the development of disease. In the cancer field, it is well known that genetic mutations can cause cells to grow out of control and lead to the formation of a tumour, explained Sanders. "We are applying similar concepts to understand how non-cancerous diseases develop," she added. The discovery was enabled by a single-cell sequencing technology called Strand-seq, a unique DNA sequencing technique that can reveal subtle details of genomes in single cells that are too difficult to detect with other methods. Sanders is a pioneer in the development of this technology. As part of her doctoral research, she helped develop the Strand-seq protocol, which she later honed with colleagues while working as postdoctoral fellow in Korbel's lab. Strand-seq enables researchers to detect structural variants in individual cells with better precision and resolution than any other sequencing technology allows, Sanders said. The technology has ushered in an entirely new understanding of genetic mutations and is now being widely used to characterise genomes and to help translate findings into clinical research. "We are just recognising that contrary to what we learned in textbooks, every cell in our body doesn't have the exact same DNA," she said. Genetic mosaicism is common The study represents the first time anyone has used Strand-seq technology to study mutations in the DNA of healthy people. The researchers included biological samples from a range of age groups -- from newborn to 92-years-old -- and found mutations in blood stem cells, which are located in the bone marrow, in 84% of the study participants, indicating that large genetic mutations are very common. "It's just amazing how much heterogeneity there is in our genomes that has gone undetected so far," said Sanders. "What this means in terms of how we define normal human ageing and how this can impact the types of diseases we get is really an important question for the field." The study also found that in people over the age of 60, bone marrow cells carrying genetic alterations tended to be more abundant, with populations of specific genetic variants, or sub-clones, more common than others. The frequent presence of these sub-clones suggests a possible connection to ageing. But whether the mechanisms that keep sub-clones from proliferating in check break down as we age, or whether the expansion of sub-clones itself contributes to diseases of ageing is not known, said Korbel. "In the future, our single cell studies should give us clearer insights into how these mutations that previously went unnoticed affect our health and potentially contribute to how we age."

Research from India's Tata Memorial Centre suggests that free radicals (ROS) generated upon mixing two nutraceuticals—resveratrol and copper—can help ameliorate various diseases by inactivating cell-free chromatin particles MUMBAI, India, Jan. 17, 2023 /PRNewswire/ -- Chromatin comprises a complex mixture of DNA and proteins and forms the structural basis of chromosomes in the cellular nuclei. When cells die, they release cell-free chromatin particles or "cfChPs" into the circulatory system. Emerging evidence indicates that cfChPs exert toxic effects by damaging the DNA of healthy cells and activating pro-inflammatory processes. Researchers from the Advanced Centre for Treatment, Research & Education in Cancer (ACTREC), Tata Memorial Centre (TMC), India, have recently demonstrated therapeutic benefits of a pro-oxidant mixture of resveratrol and copper, R-Cu, in patients undergoing chemotherapy for advanced gastric cancer. Combining R with Cu (R-Cu) leads to the generation of free oxygen radicals which can inactivate the offending cfChPs. Professor Indraneel Mittra, Dr. Ernest Borges Chair in Translational Research and Professor Emeritus, Department of Surgical Oncology at TMC/ACTREC, tells us how his team "launched a single-arm phase II clinical trial to study the effect of R-Cu in reducing the toxic side effects of chemotherapy by cfChP inactivation in patients with advanced gastric cancer undergoing docetaxel-based multi-agent chemotherapy, and used a grading system for the assessment of unwanted physiological effects." The results were promising—although R-Cu did not reduce haematological toxicities, it markedly reduced the incidence of non-haematological toxicities comprising hand-foot syndrome, diarrhoea, and vomiting. Moreover, R-Cu reduced docetaxel exposure compared to the control arm without affecting efficacy in terms of overall survival. This study was supported by Department of Atomic Energy, Government of India, through its grant CTCTMC to Tata Memorial Centre, awarded to Prof. Mittra. Prior to this, two studies from Prof. Mittra's group used mouse models to demonstrate the benefits of R-Cu administration in prevention of ageing and sepsis. The first of these indicated that the cfChPs that are released from the billions of cells that die in the body every day and damage healthy cells is the underlying cause of ageing, and prolonged oral administration of R-Cu leads to the downregulation of multiple biological parameters of ageing including neurodegeneration, which is associated with Alzheimer's disease. The other study showed how cfChPs trigger sepsis after bacterial infection in mice; administering R-Cu prevented this pathological process, including the prevention of fatality. The research group has also conducted human studies. One of their previous works suggested that cfChPs released from dying cancer cells enter surrounding surviving cancer cells, trigger DNA damage and inflammation, and further contribute to their aggressive behaviour—effects that could be mitigated by R-Cu administration. Another study reports reduced grade 3/4 mucositis and reduced levels of inflammatory proteins (or "cytokines") in the serum and saliva of R-Cu-treated patients receiving bone marrow transplants with high-dose melphalan—a chemotherapeutic used to treat plasma cell cancers. Dr. Mittra, who is the corresponding author of these articles, concludes, "Our evidence suggests that R-Cu can be a novel, cost-effective, and non-toxic agent which can be used for multiple disease conditions including cancer and metastasis prevention." Reference Title of original paper: A pro-oxidant combination of resveratrol and copper reduces chemotherapy-related non-haematological toxicities in advanced gastric cancer: results of a prospective open label phase II single-arm study (RESCU III study) Journal: Medical Oncology DOI: Contact: Indraneel Mitra +91-9769769720 352117@email4pr.com