The Prospects for Rejuvenation through Targeted Destruction of Senescent Cells

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

Comments

An interesting, if now academic question is, what would have happened if the research community had gone for broke when Aubrey de Grey and the Methuselah Foundation had pointed out that senescent cells are bad and should be removed back in 2004/2005?

Would we be much further along than we are today?

Posted by: Jim at October 26th, 2017 1:01 PM

Just how much of this cell senescence has a genetic basis? Some people may have genes, SNP's, alleles that are much more resistant to falling into senescence than others. In those cases it may be a matter of DNA repair or transplantation of resistant genetic variants.

Posted by: Biotechy at October 26th, 2017 1:36 PM

As a genetic example of what I stated above, the CDKN2A gene rs10757278 AA allele slows the cellular accumulation of the senescent marker p16ink4a, and thus, is protective of CAD and abdominal aneurisms (LAPak & Burd, 2013 in Molecular Cancer Research. In that publication they deal with senescence and the balancing act between accumulation of p16ink4a and cancer and aging.

Posted by: Biotechy at October 26th, 2017 2:41 PM

Jim: He said so in 2000. SENS was conceived and exposed in a conference in June 25, 2000. The only part missing then was WILT, that is from March 2002 (but cancer was included as a damage category with no complete solution from the beggining in 2000).

Posted by: Antonio at October 26th, 2017 3:16 PM

Giving credit to SENS for pointing out senescent cells are bad in the early 2000's is total BS. Stating the removal of "Death-resistant cells" is what was suggested. Its a wide general term that could easily be attributed to many aspects of ageing and just because senescence research has caught on, SENS are claiming they were right all along? Seriously?

Posted by: John Dee at October 26th, 2017 3:28 PM

@John Dee: Senescent cells are called out quite clearly in the 2002 paper "Time to Talk SENS: Critiquing the Immutability of Human Aging":

https://doi.org/10.1111/j.1749-6632.2002.tb02115.x
http://www.sens.org/files/pdf/manu12.pdf

"Cell senescence, the finite replicative potential and associated gene-expression changes seen in cell culture, has been suggested to underlie many aspects of aging and to be treatable by telomerase activation. However, senescent cells are very rare in vivo and may often arise by telomere-independent pathways. We therefore feel that any pro-aging role of cell senescence arises from intercellular toxicity and would be best combated by selective ablation of senescent cells. Pro-apoptotic signals can realistically be designed to target cells expressing surface markers diagnostic of the senescent state."

Posted by: Reason at October 26th, 2017 3:47 PM

@John Dee

From "Ending Aging", chapter 1, page 1:

The Eureka Moment

Marriott Hotel, Manhattan Beach, California.
June 25, 2000.
Four o'clock.
In the morning.

It was 4 A.M. in California, but my body insisted on reminding me that it was noon in Cambridge. I was exhausted from the intercontinental flight and by a day spent in debate with some of the most influential personalities in biogerontology, at an invitation-only brainstorming workshop on ideas to combat aging. Evolutionary biologist Michael Rose was there. So were calorie restriction researchers Richard Weindruch and George Roth, nanotechnologist Robert Freitas, and several others. But I couldn't sleep: On top of the mismatch between biological and geographical clocks, I was frustrated at what I saw as the day's failure to make any real progress toward a concrete, realistic anti-aging plan. As I dozed and pondered, a question on the nature of metabolism and aging wormed its way into my brain and wouldn't let go.

In my bleary irritation, I sat up, ran my hands over my beard, and began pacing the room, turning over the quandary in my mind. "Normal" metabolism was just so messy, and the raging debates in the biogerontology literature showed how difficult it was to determine what paced what: which metabolic disruptions were causes of aging, and which were effects (or secondary causes) that would simply disappear if the underlying primary causes were addressed. How could we make a positive difference in such a complex, poorly understood system? How could any meaningful change made in metabolism not be like a butterfly flapping its wings-apt to cause large, unwanted storms further down the line?

Then a second line of thought began to form in my mind-idly at first, just as a notion. The real issue, surely, was not which metabolic processes cause aging damage in the body, but the damage itself. Forty-year-olds have fewer healthy years to look forward to than twenty-year-olds because of differences in their molecular and cellular composition, not because of the mechanisms that gave rise to those differences. How far could I narrow down the field of candidate causes of aging by focusing on the molecular damage itself?

Well, I thought, it can't hurt to make a list...

There are mutations in our chromosomes, of course, which cause cancer. There is glycation, the warping of proteins by glucose. There are the various kinds of junk that accumulate outside the cell ("extracellular aggregates"): beta-amyloid, the lesser-known transthyretin, and possibly other substances of the same general sort. There is also the unwholesome goo that builds up within the cell ("intracellular aggregates"), such as lipofuscin. There's cellular senescence, the "aging" of individual cells, which puts them into a state of arrested growth and causes them to produce chemical signals dangerous to their neighbors. And there's the depletion of the stem cell pools essential to healing and maintenance of tissue.

And of course, there are mitochondrial mutations, which seem to disrupt cellular biochemistry by increasing oxidative stress. I had for a few years felt optimistic that scientists could solve this problem by copying mitochondrial DNA from its vulnerable spot at "ground zero," within the free-radical generating mitochondria, into the bomb shelter of the cell nucleus, where damage to DNA is vastly rarer.

[Then, the story follows explaining how to repair each type of damage, except cancer.]

Posted by: Antonio at October 26th, 2017 4:10 PM

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