Reporting on the 2018 International Cellular Senescence Association Meeting

Research into cellular senescence is at present one of the most exciting areas of the science of aging, as it is in this part of the scientific community that the first real, actual, legitimate rejuvenation therapies were discovered. These senolytic treatments, capable of selectively destroying senescent cells, are now in the process of verification in human trials. They offer the possibility of significant reversal of all inflammatory age-related disease, to a far greater degree than can be offered by any past therapy: osteoporosis; the fibrosis that drives dysfunction of the lung, heart, and kidney; neurodegenerative conditions such as Alzheimer's; atherosclerosis; and more. All of these conditions are either largely or partly caused by the accumulation of senescent cells that takes place in later life.

In the community of self-experimenters, many have chosen not to wait for the results of formal human trials. The evidence in mice from the past five years is robust and compelling; researchers have found it easy to reproduce benefits resulting from the removal of senescent cells, and have used a variety of small molecule drug families and other classes of therapy to achieve this goal. To the extent that an approach can destroy senescent cells, it works. The first generation of senolytic pharmaceuticals are both cheap and readily available, and tens of millions of older people in the US alone could benefit, given only the understanding and the proof of the first formal human data. A sweeping change is coming in what it means to be old, a great improvement in health across the board, at a very low cost per patient.

Meanwhile, the scientific community is forging ahead, building the foundations for the next generation of improved senolytic therapies, capable of removing a greater fraction of senescent cells with fewer accompanying side-effects. The near future of this field is bright, as is the future of our health in later life. We are now truly entering the era of human rejuvenation, a milestone in our technological progress as a species that will not soon be forgotten.

Cellular senescence, geroscience, cancer and beyond

More than two hundred scientists gathered in Montreal in July 2018 for the International Cellular Senescence Association (ICSA) Meeting to discuss the biological and medical impact of cellular senescence. In his welcoming speech, Dr. Ferbeyre summarized the key aspects that have attracted so much interest in cellular senescence including its ability to act as a tumor suppressor mechanism but also to promote aging and age-linked diseases.

One of the most exiting trends in senescence research is the concept of senolysis or the specific elimination of senescent cells. Jan Van Deursen (Mayo Clinic, USA) presented recent evidence that the elimination of senescent cells can induce regression of advanced atherosclerosis without any detectable side effects. Jennifer Hartt Elisseeff (Johns Hopkins, USA) showed that clearance of senescent cells using senolytics attenuates osteoarthritis development.

The connection between senescent cells and immune responses to injury and repair was presented. Darren Baker (Mayo Clinic, USA) presented experimental evidence that senescent cells promote neurodegeneration in mutant tau mice and their elimination attenuates disease. James Kirkland (Mayo Clinic, USA), showed that transplanting senescent cells to young mice caused frailty, diabetes, and osteoporosis, accelerating death from all causes. A cocktail of quercetin and dasatinib, a SRC-family kinase inhibitor, can kill senescent cells and revert their pathological effects both in senescent-cells transplanted young mice or in naturally aged mice, extending median life span up to 36%.

Salvador Macip (University of Leicester, UK) found another kinase, BTK, which activates the tumor suppressor p53 inducing senescence. Ibrutinib, a clinically approved inhibitor for this kinase increased life span in flies and in a mouse model of progeria. Irina Conboy (UC Berkeley, USA) used parabiosis to demonstrate the presence of factors in the serum of old mice that can induce senescence in young mice suggesting that some senescent cells in vivo may originate from extrinsic factors. She also presented interesting data on enhanced myogenesis and reduced liver adiposity, but no improvement in hippocampal neurogenesis in the old 3MR mice, when p16-high cells were experimentally ablated.

Myriam Gorospe, (NIH, USA) identified proteins expressed at the surface of senescent cells. SCAMP4 was found to favor the senescence-associated secretory phenotype (SASP) and DPP4 was found to allow the selective elimination of senescent cells using anti-DPP4 antibodies. Maria Almeida (University of Arkansas for Medical Sciences, USA) discussed the role of senescent osteocytes in age-related bone loss via production of increased levels of RANKL and the therapeutic potential of senolytic agents in preventing and treating osteoporosis by targeting senescent cells in the bones.

The promise that clearance of senescent cells with a therapeutic agent may prolong the health span and treat age-related diseases stimulates the research in finding new senolytic agents, therapeutic strategies, and delivery methods. Daohong Zhou (University of Florida, USA) presented some new development of Bcl-xl-targeted senolytic agents using proteolysis targeting chimera (PROTAC) technology. These Bcl-xl PROTACs that target Bcl-xl to an E3 ligase for ubiquitination and degradation exhibit an improved potency against senescent cells but reduced toxicity to normal cells and platelets compared to navitoclax and thus have the potential to be developed as a safer senolytic agent.

John Lewis (Oisin Biotechnologies, USA) described a clinically viable gene therapy consisting of a suicide gene under a senescent cell promoter delivered in vivo with fusogenic lipid nanoparticles (LNPs) to deplete senescent cells. This approach represents a first-in-class therapeutic that targets cells based on transcriptional activity, rather than surface markers or metabolism. Guangrong Zheng (University of Florida, USA) identified a dietary natural product, piperlongumine, as a novel senolytic agent. It can selectively kill senescent cells by targeting oxidation resistance 1 (OXR1), an important oxidative stress sensor that regulates the expression of a variety of antioxidant enzymes. His finding may lead to the development of better senolytic agents.

Daniel Munoz-Espin (University of Cambridge, UK) described the design of a new targeted-drug delivery system to senescent cells using the technology of the encapsulation of drugs with galacto-oligosaccharides because of the high lysosomal β-galactosidase activity of senescent cells. He showed that gal-encapsulated cytotoxic drugs can selectively target senescent cells in a tumor xenograft mouse model to improve tumor regression and toxicity. At the end of the meeting Ned David (Unity Biotechnology, USA) delivered a talk summarizing how his company is translating basic research on senescence into clinical trials using several senolytics. Senescence is undoubtedly at the forefront of biomedical research.

Comments

Those are all exciting and promising developments. I look forward for more studies and human results.

>...evidence that the elimination of senescent cells can induce regression of advanced atherosclerosis without any detectable side effects...
I would expect side effects like improved skin, hair and such. I would even welcome those :)

Posted by: cuberat at September 12th, 2018 5:36 PM

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