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Senolytic Drugs to Kill Off Senescent Cells and Thereby Slow the Progression of Degenerative Aging

As we age, an increasing number of cells fall into a senescent state in which they cease dividing and begin to secrete all sorts of compounds that both harm surrounding tissue structure and raise the odds of nearby cells also becoming senescent. This seems to be a tool of embryonic development that now also acts to suppress cancer risk by removing the ability to divide from those cells most likely to become cancerous. Unfortunately it harms tissue function in doing so, and worse, only actually suppresses cancer risk when there are comparatively few senescent cells. Given a lot of these cells their activities cause chronic inflammation and other issues that in fact raise the risk of cancer, and help cancer cells to prosper where they do arise. By the time we reach old age, a high proportion of cells in many tissues are senescent.

The Strategies for Engineered Negligible Senescence, SENS, is a package of research programs based on repair of the known forms of cellular and molecular damage that cause aging. It is the path to true rejuvenation therapies, rather than merely slowing the progression of aging, and thus is worthy of far more attention and funding than it has at present. Some parts of the SENS research programs have gained more attention in recently years, however. It seems to me that I was on the ball a few years back when I suggested senescent cell clearance would be the first SENS technology to arrive. Since the 2011 demonstration of senescent cell clearance to slow down degenerative aging in a laboratory lineage of aging-accelerated mice, an increasing amount of attention has been given to removing senescent cells. A startup was funded early this year to work on one possible attempt, for example.

A few years ago I thought that meaningful progress here would be something along the lines of repurposing the targeted cell killing technologies under development in the cancer research community: identify a clear molecular signal for cellular senescence, assemble a treatment based on a sensor mechanism attached to a destructive payload, and introduce millions of them into the body. I still think that is the best way forward to obtain high degrees of cell clearance. However, the present research industry is very focused on drugs, and especially focused on the reuse of existing drugs even if the outcome is marginal. So it may very well be that the first senescent cell clearance therapies are (a) not all that great in terms of degree of clearance, and (b) based on drug candidates that already exist or are slight modifications of what already exists.

Still, as this news shows, senescent cell clearance is a part of the mainstream now. The people pursuing it are never going to mention SENS, but fifteen years of persistent advocacy and small-scale funding of early staging research for SENS goals has brought senescent cell clearance as a strategy to its present position. Let that not be forgotten. Let it also be noted that the effects of actually trying to repair some of the damage outlined in the SENS viewpoint are already more impressive than most of the efforts to slow aging over the past decade: drugs aiming to alter metabolism by targeting targeting sirtuins, mTOR, and so forth. This is what we should expect. Repair should always produce better results that simply tinkering with the mechanism to slightly slow the pace of damage. Full healthspan and lifespan studies in mice remain to be carried out for this approach, however, so the degree to which it affects the bottom line as well as other measures has yet to be determined.

Scripps Research, Mayo Clinic Scientists Find New Class of Drugs that Dramatically Increases Healthy Lifespan

The scientists coined the term "senolytics" for the new class of drugs. "We view this study as a big, first step toward developing treatments that can be given safely to patients to extend healthspan or to treat age-related diseases and disorders. When senolytic agents, like the combination we identified, are used clinically, the results could be transformative. The prototypes of these senolytic agents have more than proven their ability to alleviate multiple characteristics associated with aging. It may eventually become feasible to delay, prevent, alleviate or even reverse multiple chronic diseases and disabilities as a group, instead of just one at a time."

Senescent cells - cells that have stopped dividing - accumulate with age and accelerate the aging process. Since the "healthspan" (time free of disease) in mice is enhanced by killing off these cells, the scientists reasoned that finding treatments that accomplish this in humans could have tremendous potential. The scientists were faced with the question, though, of how to identify and target senescent cells without damaging other cells. The team suspected that senescent cells' resistance to death by stress and damage could provide a clue. Indeed, using transcript analysis, the researchers found that, like cancer cells, senescent cells have increased expression of "pro-survival networks" that help them resist apoptosis or programmed cell death. This finding provided key criteria to search for potential drug candidates.

Using these criteria, the team homed in on two available compounds - the cancer drug dasatinib and quercetin, a natural compound sold as a supplement that acts as an antihistamine and anti-inflammatory. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse bone marrow stem cells. A combination of the two was most effective overall.

Next, the team looked at how these drugs affected health and aging in mice. "In animal models, the compounds improved cardiovascular function and exercise endurance, reduced osteoporosis and frailty, and extended healthspan. Remarkably, in some cases, these drugs did so with only a single course of treatment." In old mice, cardiovascular function was improved within five days of a single dose of the drugs. A single dose of a combination of the drugs led to improved exercise capacity in animals weakened by radiation therapy used for cancer. The effect lasted for at least seven months following treatment with the drugs. Periodic drug administration of mice with accelerated aging extended the healthspan in the animals, delaying age-related symptoms, spine degeneration and osteoporosis.

The authors caution that more testing is needed before use in humans. They also note both drugs in the study have possible side effects, at least with long-term treatment. The researchers, however, remain upbeat about their findings' potential. "Senescence is involved in a number of diseases and pathologies so there could be any number of applications for these and similar compounds. Also, we anticipate that treatment with senolytic drugs to clear damaged cells would be infrequent, reducing the chance of side effects."

The Achilles' Heel of Senescent Cells: From Transcriptome to Senolytic Drugs

The healthspan of mice is enhanced by killing senescent cells using a transgenic suicide gene. Achieving the same using small molecules would have a tremendous impact on quality of life and burden of age-related chronic diseases. Here, we describe the rationale for identification and validation of a new class of drugs termed senolytics, which selectively kill senescent cells. By transcript analysis, we discovered increased expression of pro-survival networks in senescent cells, consistent with their established resistance to apoptosis.

Using siRNA to silence expression of key nodes of this network, including ephrins (EFNB1 or 3), PI3Kδ, p21, BCL-xL, or plasminogen activated inhibitor-2, killed senescent cells, but not proliferating or quiescent, differentiated cells. Drugs targeting these factors selectively killed senescent cells. Dasatinib eliminated senescent human fat cell progenitors, while quercetin was more effective against senescent human endothelial cells and mouse BM-MSCs. The combination of dasatinib and quercetin was effective in eliminating senescent MEFs. In vivo, this combination reduced senescent cell burden in chronologically aged mice. In old mice, cardiac function and carotid vascular reactivity were improved 5 days after a single dose.

These results demonstrate the feasibility of selectively ablating senescent cells and the efficacy of senolytics for alleviating symptoms of frailty and extending healthspan.

Comments

Does anything have any thoughts when this would available to the general public if it works out? I am hoping for within 5 years, but maybe it is too optimistic.

Having this available to the public would pave the way for more rejuvenation treatment down the road. Public reaction will probable be huge given the large number of older people.

Posted by: Robert Church at March 9th, 2015 7:05 PM

Robert: The two existing compounds mentioned in the Scripps article are available right now. One is a cancer drug and the other you can buy in a grocery or supplement store. Time to go get some red onions.

Something more broad and more potent? Your guess is as good as mine.

Posted by: Slicer at March 9th, 2015 8:26 PM

I think Reason has been waiting a long time to write this post. I can hear him exhaling all the way down here in Australia :p

@Robert - There are loads of unanswered questions yet to be resolved:
- Are the mouse models used actually representative of normal mouse aging (or human aging) given that they accumulate senescent cells faster than normal mice, and have a reduced life and healthspan compared to normal mice?
- Are the transcript targets in mice conserved in humans?
- What would the clinical endpoints in a human study of these drugs be?

Still, with Judith Campisi's lab at the Buck Institute apparently working on an improved mouse model of senescence, and the Scripps Research Institute/Mayo Clinic now hopefully able to finally access some public funding to research this in 'normal' mice, this line of research may just have become self sustaining.

Posted by: Jim at March 10th, 2015 3:46 AM

Jim, I agree. As this Scripps/Mayo research makes its rounds, I think it is likely that the NIH will open its wallet and put some real funding into this work. They are simply running out of reasons not to. And of course there is Calico and a bunch of biotech startups who want in as well. A combination of early detection of disease and then repairing the human machine to restore full health means that people will live healthy for a long time. You can almost start to see the parts coming together now.

Posted by: Deleo77 at March 11th, 2015 11:55 AM

I'm actually a bit surprised at the muted reaction to this so far? Yes there are still reasons to doubt that something is really going on but... scientists have just announced that they can remove one of the seven categories of damage that are aging or lead to the secondary damage of aging.

I agree that it is surprising that they appear to have managed this with small molecule drugs, given that around 90% of intra-celluar proteins appear to be undruggable with small molecules. Still, I guess that means that there was around a 10% chance that they could just do it with existing small molecule technology, and perhaps they have just got lucky?

Posted by: Jim at March 12th, 2015 9:19 PM

Just read an article on kurzweilai that stated researchers at mayo clinic used apo20187 on wild type mice. This compound removed senescent cells and increased lifespan up to 35% Is this a different study?

Posted by: george at February 14th, 2016 9:35 AM

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