A Newfound Interest in Mapping the Signs of Cellular Senescence

Now that selectively clearing senescent cells from aged animals has been proven to produce benefits to health, tissue function, and life span, and its role in aging is well appreciated, there is a lot more interest in the research community in mapping out the biochemistry of these cells. Up until about five years ago, it was a real challenge to generate both this interest and the funding to sustain it, but better late than never. Below I'll point out a few recently published items in that theme, representative of much more work that is presently taking place. Researchers not actively working on methods of senescent cell destruction are looking for better definitions of what exactly constitutes cellular senescence, better biomarkers for these cells, and a better understanding of how exactly a comparatively small number of these cells can cause such harm to the rest of the tissue that contains them. This is all largely irrelevant to the first generation of senescent cell clearance therapies under development in companies like Oisin Biotechnologies and UNITY Biotechnology - the existing targets and methodologies are good enough for a first pass. When the second generation of therapies are under construction, however, the burning question will be the degree to which they are improvements over what already exists.

Cells become senescent in response to damage, the consequence of toxic and cancer-prone environments, or once they reach the Hayflick limit imposed on cell divisions for ordinary somatic cells. Senescent cells also transiently arise as a part of the wound healing process, and further are involved in shaping the body during embryonic development. Senescence predisposes a cell to self-destruction, and most destroy themselves via apoptosis. Those that do not self-destruct still remove themselves from the cell cycle of replication and begin to secrete a potent mix of molecules that spur inflammation, restructure the nearby extracellular matrix, and encourage surrounding cells to change their behaviors in a range of ways, few of them good in the long term. The immune system is attracted to these cells and destroys those that do not self-destruct, but nonetheless some senescent cells linger. That number grows with age, to the point at which a few percent of all the cells in a tissue or organ might be senescent. These cells collectively cause significant harm, by destroying functional structures in complex tissue, by secreting signals that alter and degrade function in healthy cells, and by producing enough chronic inflammation to meaningfully speed progression of age-related disease.

Given sufficiently comprehensive clearance of senescent cells, all of these contributions to the process of aging will go away, and we'll be healthier and longer-lived as a result. The first generation therapies are at present clearing as many as half of the identified senescent cells in a single treatment in laboratory mice. It remains to be seen how much that can be improved through longer treatment programs and tweaking the present treatment methods. It is interesting to ask whether the currently identified cells represent the full count of senescent cells, and whether or not they represent multiple different types of senescence, some better or worse for health than others. The answers to that will come in time, but the research and development community will still produce pretty good therapies in advance of those lines of further inquiry reaching their conclusions.

New method to detect ageing cells - and aid rejuvenation therapies - developed by researchers

Scientists have discovered a new way to look for ageing cells across a wide range of biological materials; the new method will boost understanding of cellular development and ageing as well as the causes of diverse diseases. Frustrated by the limitations of commercially available biomarkers the researchers have developed a universally applicable method to assess senescence across biomedicine, from cancer research to gerontology. Cellular senescence is a fundamental biological process involved in every day embryonic and adult life, both good - for normal human development - and, more importantly to researchers, dangerous by triggering disease conditions. Up to now available senescence detecting biomarkers have very limited and burdensome application. Therefore, a more effective, precise and easy-to-use biomarker would have considerable benefits for research and clinical practice. "The method we have developed provides unprecedented advantages over any other available senescence detection products - it is straight-forward, sensitive, specific and widely applicable, even by non-experienced users. In addition to helping researchers make significant new breakthroughs into the causes of diseases - including cancer - through more effective understanding of senescence in cells, the new process will also aid the impact of emerging cellular rejuvenation therapies. By the better identification - and subsequently elimination of - senescent cells, tissues can be rejuvenated and the health span extended."

Genes that control cellular senescence identified - Potential applications for cancer treatment and development of anti-aging products

The research group had previously discovered that cell senescence was effectively induced by using low concentrations of anticancer drugs on cancerous cells. In anticancer treatment, drugs are carried to the cancerous tissue via the bloodstream. The researchers predicted that differences in concentrations of the anticancer drugs would arise based on the distance of the cells from the blood vessels, and so even in the normal cancer treatment process senescent cells would emerge. Therefore, if we simultaneously administer a medicine that inhibits cell senescence during standard cancer treatment, there is the potential for a dramatic increase in treatment effectiveness. Previously the research group found that if cancerous cells are treated with a low concentration (10 μM) of the anticancer drug etoposide this induces cell senescence, and if they are treated with a high concentration of the drug (100 μM) this induces apoptosis. For this research, they treated cancerous cells under three different conditions: A) with no etoposide; B) with a low dose of etoposide (10 μM); and C) with a high dose of etoposide (100 μM). They then used DNA microarrays to identify the genes in which a rise in transcription levels could be observed.

They predicted that genes which showed increased expression in response to treatment B were mainly related to cell senescence, genes expressed in response to C were mainly those involved in apoptosis, and among the genes which specifically showed increased expression in B compared to C would be genes that play an important role in implementing cell senescence. There were 126 genes where three times as much expression was recorded under treatment B compared to A, and 25 genes that showed twice as much expression in B compared to C. These 25 genes are expected to express specifically in senescent cells since the other factors caused by DNA damage are removed, and researchers confirmed that the genes involved in causing cell senescence were among them. If we can develop a drug that targets and regulates the activity of the genes that control senescence identified in this research, by administering it together with conventional anticancer treatment we can limit the emergence of senescent cells and potentially increase the effectiveness of cancer treatment. Additionally, it has been reported that one of the causes of individual aging is the accumulation of senescent cells. This means that drugs which control cell senescence could have potentially large benefits for the development of anti-aging medication products.

CellAge Database of Cell Senescence Genes

Cell senescence can be defined as the irreversible cessation of cell division of normally proliferating cells. Human cells become senescent from progressive shortening of telomeres as cells divide, stress or oncogenes. Primarily an anti-tumour mechanism, senescent cells accumulate with age in tissues and have been associated with degeneration and ageing of whole organisms. Many proteins have been linked to cell senescence as biomarkers and as causal drivers. To facilitate studies focused on cell senescence, we developed CellAge, a database of genes associated with cell senescence. Our manually-curated data is based on gene manipulation experiments in different human cell types. A gene expression signature of cellular senescence will also be made available in due course. CellAge is in the beta phase of development and therefore still being improved and expanded. Collaborations and contributions are welcomed, please contact us if you wish to be involved.

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