Working Towards Therapies that Block the Contribution of Cellular Senescence to Aging and Cancer

One of the research advocates with the Major Mouse Testing Program recently wrote a popular science article on cellular senescence in aging, and more importantly the growing interest in methods of removing senescent cells. You'll find it linked below. Growing numbers of senescent cells is one of the root causes of degenerative aging, contributing to declining tissue function, progression of age-related disease, and ultimately death. Just this year researchers published results from a study of mice genetically engineered to destroy their own senescent cells, and which lived 25% longer than their unaltered peers. Other drug-based approaches to destroy senescent cells have not yet been used in full life span studies, but have been shown to improve health markedly in rodents, even after a single treatment in old age. Two startup companies are presently in the early stages of working on senescent cell clearance therapies, Oisin Biotechnologies and UNITY Biotechnology, and as more evidence accumulates there will no doubt be other players in this field.

Senescence is a cellular state of arrested replication, and is accompanied by many other altered behaviors, such as secretion of inflammatory and damaging molecules into surrounding tissues, a phenomenon called the senescence-associated secretory phenotype, or SASP. Cells become senescent in response to internal damage or a toxic environment - which can include the SASP of nearby senescent cells. At least initially senescence probably serves to reduce cancer risk, removing the ability to replicate from the cells most likely to suffer cancerous mutational damage. Most senescent cells are destroyed shortly after entering this state, either by their own programmed cell death processes, or by roving immune cells attracted by signals in the SASP. Some linger, however. Growth in the number of these persistent senescent cells occurs throughout life, but speeds up in later years: the level of damage to cells and tissues is higher, so more cells become senescent in response, and at the same time the immune system declines in effectiveness. As the presence of senescent cells increases, their collective SASP becomes a real issue, and actually makes cancer risk and progression worse than would otherwise be the case.

Researchers are still engaged in cataloging all of the ways in which senescent cells interact with important functions in our tissues. This is a slow and expensive process, just like all such work aimed at fleshing out the grand map of human metabolism and how it changes with age. The beauty and simplicity of aiming to destroy senescent cells, however, is that the scientific community doesn't need a full understanding of the detrimental effects, all the way down to the detail level of molecular interactions. All that is needed is to periodically remove these cells and validate the resulting benefits to health and longevity, a much easier prospect, as demonstrated by the numerous approaches presently under development or illustrated in animal studies.

The Two Faces of Aging: Cancer and Cellular Senescence

Aging, inflammation, cancer, and cellular senescence are all intimately interconnected. Deciphering the nature of each thread is a tremendous task, but must be done if preventative and geriatric medicine ever hope to advance. A one-dimensional analysis simply will not suffice. Without a strong understanding of the genetic, epigenetic, intercellular, and intracellular factors at work only an incomplete picture can be formed. However, even with an incomplete picture useful therapeutics can and are being developed. Depending on the context in which they are operating a single gene can have positive or negative effects on an organism's phenotype. Often the gene is exerting both desirable and undesirable influences at the same time. This is called antagonistic pleiotropy. Cellular senescence is a protective measure; it is a response to damage that could potentially turn a healthy cell into a malignant one. By halting its own division a senescent cell removes itself as an immediate tumorigenic threat. Yet the accumulation of senescent, non-dividing cells is implicated in a host of pathologies including, somewhat paradoxically, cancer.

Our bodies are bombarded by insults to their resilient but woefully vincible microscopic machinery. Oxidative stress, DNA damage, telomeric dysfunction, carcinogens, assorted mutations from assorted causes, necessary or unnecessary immunological responses to internal or external factors, all take their toll. In response cells may repair themselves, they may activate an apoptotic pathway to kill themselves, or just stop proliferating. After suffering these slings and arrows, p53 is activated. Not surprisingly, mice carrying a hyperactive form of p53 display high levels of cellular senescence. Abnormalities in p53 are found in most, if not all, cancers. Knocking out p53 altogether produced mice unusually free of tumors, but find themselves prematurely past their prime. There is a clear trade-off here. SASP (senescence-associated secretory phenotype) is associated with chronic inflammation, which itself is implicated in a growing list of common infirmities. Many SASP factors are known to stimulate phenotypes similar to those displayed by aggressive cancer cells.

p53 and mTOR interact with one another in ways that make mTOR inhibitors potentially useful, but since mTOR inhibitors such as metformin and rapamycin have their share of unwanted side effects, more and better drugs capable of destroying senescent cells - known as senolytics - must be explored in greater detail. Starting with a simple premise, namely that senescent cells rely on anti-apoptotic and pro-survival defenses more than their actively replicating counterparts, researchers created a series of experiments to find the Achilles' Heel of senescent cells. After comparing the two different cell states, they designed senolytic siRNAs. Of 39 transcripts selected for knockdown by siRNA transfection, 17 affected the viability of target senescent cells more than healthy cells. Similarly, dasatinib, a cancer drug, and quercitin, a common flavonoid found in common foods, have senolytic properties. The former has a proven proclivity for fat cell progenitors, and the latter is more effective against endothelial cells. Administration together into elderly mice resulted in favorable changes.

There are other senolytic approaches under development. Please embark on your own journey through the gallery of encroaching options for those who would prefer not to become chronically ill, suffer immensely, and, of course, die miserably in a hospital bed soaked with several types of their own excretions - presumably, hopefully, those who claim to be unafraid of death have never seen this image, or naively assume they will never be the star of such a dismal and lamentably normal final act. There is nothing vain about wanting to avoid all the complications that come with time. This research is quickly becoming an economic and humanitarian necessity. The trailblazers who move this research forward will not only find wealth at the end of their path, but the undying gratitude of all life on earth.

Comments

It looks like the author of the linked article accidentally said p53 *knockout* produces rapidly aging and cancer-free mice when they meant p53 *hyperactivation*. p53 is a tumor suppressor that when removed causes rapid tumor onset: http://www.ncbi.nlm.nih.gov/pubmed/9110404.

Anyway, the recent work on senescent cell clearance is really great to see. I think it's making SENS-style anti-aging engineering much more credible to the public. Just last week I presented the recent Baker paper on clearing senescent cells at journal club and my lab was very impressed. My favorite comment was "Usually I look at Nature papers and wonder how they got in, but this one really deserves it."

Posted by: James at April 18th, 2016 12:07 PM

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