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Three Recent Papers on the Use of Senolytic Therapies to Address Age-Related Disease

Today, a few papers on cellular senescence and the application of therapies to remove senescent cells. Senescent cells are one of the root causes of aging. Over the past five years, once the research community finally started to make progress on ways to selectively destroy senescent cells, the presence of these cells has been directly implicated in a wide range of age related diseases. They cause fibrosis. They produce calcification in blood vessels. They help to upset the balance of bone maintenance to generate osteoporosis. They are at the root of localized inflammatory conditions such as osteoarthritis. They harm lung function. And so on and so forth through a long list of issues. All of this progress in knowledge and methods of therapy could have happened ten or twenty years earlier, in a different world, in which the leadership of the aging research community didn't engage in decades of hostility towards anyone who wanted to treat aging as a medical condition. The evidence was there.

Countless cells become senescent in the body day in and day out. It is the end state of somatic cells that reach the Hayflick limit on replication, quickly followed by programmed cell death or destruction by the immune system. Cells also become senescent in response to injury, a toxic cellular environment, or DNA damage likely to lead to cancer. Again, a quick destruction is their fate. A very tiny fraction of senescent cells evade this fate to linger indefinitely, however. These lingering cells secrete a potent mix of molecules that triggers chronic inflammation, damages the surrounding tissue structures, and changes the behavior of nearby cells for the worse. The harm grows as the number of senescent cells grows.

Fortunately, work on senolytic therapies capable of selectively destroying senescent cells has moved out of the laboratory and into a number of startup companies. Numerous different pharmaceuticals trigger senescent cells to self-destruct by interfering in mechanisms that are only of great importance in the senescent state, and Unity Biotechnology is moving ahead with several of those. Oisin Biotechnologies is pioneering a programmable gene therapy that can destroy cells based on their internal biochemistry. SIWA Therapeutics is working on an immunotherapy approach to the problem of senescent cells. There will be others in the years ahead - there is plenty of room in a market in which every adult over the age of 40 is a potential customer. Effective senolytic therapies would likely be undertaken once every few years at most, to keep the number of senescent cells too low to cause serious issues, thus taming this contribution to degenerative aging. That advance in clinical medicine is just a few years away now.

Strategies targeting cellular senescence

Cellular senescence is a physiological phenomenon that has both beneficial and detrimental consequences. Senescence limits tumorigenesis and tissue damage throughout the lifetime. However, at the late stages of life, senescent cells increasingly accumulate in tissues and might also contribute to the development of various age-related pathologies. Recent studies have revealed the molecular pathways that preserve the viability of senescent cells and the ones regulating their immune surveillance. These studies provide essential initial insights for the development of novel therapeutic strategies for targeting senescent cells. At the same time they stress the need to understand the limitations of the existing strategies, their efficacy and safety, and the possible deleterious consequences of senescent cell elimination. Here we discuss the existing strategies for targeting senescent cells and upcoming challenges in translating these strategies into safe and efficient therapies. Successful translation of these strategies could have implications for treating a variety of diseases at old age and could potentially reshape our view of health management during aging.

Senescent cells: a therapeutic target for cardiovascular disease

Cellular senescence, a major tumor-suppressive cell fate, has emerged from humble beginnings as an in vitro phenomenon into recognition as a fundamental mechanism of aging. In the process, senescent cells have attracted attention as a therapeutic target for age-related diseases, including cardiovascular disease (CVD), the leading cause of morbidity and mortality in the elderly. Given the aging global population and the inadequacy of current medical management, attenuating the health care burden of CVD would be transformative to clinical practice. Here, we review the evidence that cellular senescence drives CVD in a bimodal fashion by both priming the aged cardiovascular system for disease and driving established disease forward. Hence, the growing field of senotherapy (neutralizing senescent cells for therapeutic benefit) is poised to contribute to both prevention and treatment of CVD.

Senescent cells and osteoarthritis: a painful connection

Senescent cells (SnCs) are associated with age-related pathologies. Osteoarthritis is a chronic disease characterized by pain, loss of cartilage, and joint inflammation, and its incidence increases with age. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells' relevance to disease was unclear. In this review, we summarize current knowledge of SnCs in the multiple tissues that constitute the articular joint. New evidence for the causative role of SnCs in the development of posttraumatic and age-related arthritis is reviewed along with the therapeutic benefit of SnC clearance. As part of their senescence-associated secretory phenotype, SnCs secrete cytokines that impact the immune system and its response to joint tissue trauma. We present concepts of the immune response to tissue trauma as well as the interactions with SnCs and the local tissue environment. Finally, we discuss therapeutic implications of targeting SnCs in treating osteoarthritis.

Comments

This a very exciting development. Now I wonder how many years extra years of healthy live could those therapies deliver. And how much improvement could we see on the maximum lifespan

Posted by: Cuberat at April 12th, 2018 12:23 PM

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