Fight Aging!

This popular science article covers some of the high points of current work on methods of clearing senescent cells from old tissues, with a focus on the better funded groups - Unity Biotechnology and the research groups involved in that company. So it omits mention of the long years of advocacy prior to 2011, in which the Methuselah Foundation, SENS Research Foundation, and allies called for work on destroying senescent cells based on the compelling evidence for their role in aging that has existed for decades, and were rebuffed. It also omits mention of the other research groups and companies working in the field. This tends to be the way things go, of course - those who are first to raise significant funding tend to be those guiding the presentation of history.

Regardless, this is an enormously promising area of development, and the first rejuvenation therapies to arrive in the clinic in the years ahead will involve some form of senescent cell clearance. Indeed, adventurous individuals could self-experiment with any of the candidate senolytic drugs today, though I think it wiser to wait a few years for the first human trials to report their results. The article plays up indications of variation and typing in senescent cells - that there are tissue-specific differences that will require different approaches for destruction - but I think the concerns here are overblown. Significant health benefits are being achieved in mouse studies even with only partial clearance via one given method, and the variance is nowhere near as large as is the case in cancerous cells.

Although many cells do die on their own, all somatic cells (those other than reproductive ones) that divide have the ability to undergo senescence. But, for a long time, these twilight cells were simply a curiosity. "We were not sure if they were doing something important." Despite self-disabling the ability to replicate, senescent cells stay metabolically active, often continuing to perform basic cellular functions. By the mid-2000s, senescence was chiefly understood as a way of arresting the growth of damaged cells to suppress tumours. Today, researchers continue to study how senescence arises in development and disease. They know that when a cell becomes mutated or injured, it often stops dividing - to avoid passing that damage to daughter cells. Senescent cells have also been identified in the placenta and embryo, where they seem to guide the formation of temporary structures before being cleared out by other cells.

But it wasn't long before researchers discovered the dark side of senescence. In 2008, three research groups revealed that senescent cells excrete a glut of molecules - including cytokines, growth factors and proteases - that affect the function of nearby cells and incite local inflammation. They described this activity as the cell's senescence-associated secretory phenotype, or SASP: hundreds of proteins involved in SASPs. In young, healthy tissue these secretions are probably part of a restorative process, by which damaged cells stimulate repair in nearby tissues and emit a distress signal prompting the immune system to eliminate them. Yet at some point, senescent cells begin to accumulate - a process linked to problems such as osteoarthritis, a chronic inflammation of the joints, and atherosclerosis, a hardening of the arteries. No one is quite sure when or why that happens. It has been suggested that, over time, the immune system stops responding to the cells.

Surprisingly, senescent cells turn out to be slightly different in each tissue. They secrete different cytokines, express different extracellular proteins and use different tactics to avoid death. That incredible variety has made it a challenge for labs to detect and visualize senescent cells. "There is nothing definitive about a senescent cell. Nothing. Period." The lack of universal features makes it hard to take inventory of senescent cells. Researchers have to use a large panel of markers to search for them in tissue, making the work laborious and expensive. A universal marker for senescence would make the job much easier - but researchers know of no specific protein to label, or process to identify. "My money would be on us never finding a senescent-specific marker. I would bet a good bottle of wine on that."

But there's a silver lining to these elusive twilight cells: they might be hard to find, but they're easy to kill. Senescent cells depend on protective mechanisms to survive in their 'undead' state, so researcher began seeking out those mechanisms. They identified six signalling pathways that prevent cell death, which senescent cells activate to survive. Then it was just a matter of finding compounds that would disrupt those pathways. In early 2015, researchers identified the first senolytics: an FDA-approved chemotherapy drug, dasatinib, which eliminates human fat-cell progenitors that have turned senescent; and a plant-derived health-food supplement, quercetin, which targets senescent human endothelial cells, among other cell types. The combination of the two - which work better together than apart - alleviates a range of age-related disorders in mice.

By now, 14 senolytics have been described in the literature, including small molecules, antibodies and a peptide that activates a cell-death pathway and can restore lustrous hair and physical fitness to ageing mice. So far, each senolytic kills a particular flavour of senescent cell. Targeting the different diseases of ageing, therefore, will require multiple types of senolytics. "That's what's going to make this difficult: each senescent cell might have a different way to protect itself, so we'll have to find combinations of drugs to wipe them all out." For all the challenges, senolytic drugs have several attractive qualities. Senescent cells will probably need to be cleared only periodically - say, once a year - to prevent or delay disease. So the drug is around for only a short time. This type of 'hit and run' delivery could reduce the chance of side effects, and people could take the drugs during periods of good health.

Link: http://www.nature.com/news/to-stay-young-kill-zombie-cells-1.22872