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Senolytic Therapeutics Uses Nanotube-Carried Toxins to Destroy Senescent Cells

Today, I'll point out an analysis from the SENS Research Foundation that covers the approach to selective destruction of senescent cells taken by one of the newly formed biotech startups in the space, Senolytic Therapeutics. This field is hot because it is now well proven that senescent cells are the enemy. They are one of the root causes of aging, accumulating with age to degrade tissue function via the secretion of inflammatory signal molecules. Senescent cells actively maintain an aged, inflamed state of metabolism, resulting in the development of age-related disease and increased mortality.

Senescent cells do serve useful functions when they arise temporarily in response to injury or cell damage, so senescence as a phenomenon cannot be safely suppressed. Since the problems only begin when these cells both fail to self-destruct and evade the immune system's policing of tissues, however, finding ways to periodically destroy all lingering senescent cells is a very viable approach to rejuvenation. When they are removed from old tissues, aged metabolism is quite quickly restored to an incrementally younger state. This point has been quite adequately demonstrated in mice in recent years.

Roughly speaking, there are two approaches to the selective destruction of senescent cells. The first approach is to target a mechanism that is only significant in senescent cells, such as the fact that they are primed for self-destruction via apoptosis, and only held back by the thinnest of threads. A nudge to the apoptotic protein machinery that a normal cell will ignore will tip a senescent cell over the edge. The present crowd of senolytic pharmaceuticals fall into this category. The second approach is to use a therapeutic that will definitely kill any cell, senescent or not, and then limit its application to senescent cells only. Forms of immunotherapy and suicide gene therapy currently under development are examples of the type.

The staff at Senolytic Therapeutics are undertaking an interesting approach to the delivery of a standard chemotherapeutic means of killing cells in which nanotubes are used to ensure that only senescent cells are exposed to the toxin. The hollow nanotubes are filled with chemotherapeutic and capped with a molecule that only senescent cells will remove. Or at least only cells that express large amounts of senescence-associated beta-galactosidase, which might not be exactly the same thing, but the overlap is quite large. This is similar to a wide variety of approaches to targeting of specific cell populations developed in the cancer research community, and most of those are probably also applicable in principle to the task of clearing senescent cells from old tissues.

Smart Bombs Against Senescent Cells

When Dr. de Grey and colleagues proposed ablation of senescent cells (ApoptoSENS) as the "damage-repair" strategy of choice for this kind of aging damage in 2001, you'd've been hard-pressed to find the idea even mentioned (let alone advocated) in the scientific literature - and certainly no one was actively working to develop such therapies. This approach remained largely ignored until a powerful proof-of-concept study in 2011. Soon after that, researchers developed an ingenious drug-discovery strategy that led to the identification of the first two of a new class of "senolytic" drugs - that is, drugs that selectively destroy senescent cells.

In the three short years since the initial breakthrough discovery of the first senolytic drugs, the progress in ApoptoSENS has been astonishing. A torrent of scientific reports have now shown that ablating senescent cells has sweeping rejuvenative effects - wider-ranging, in fact, than we ourselves had predicted. Drugs and gene therapies that destroy senescent cells can restore exercise capacity, lung function, and formation of new blood and immune precursor cells of aging mice to nearly their youthful norms. Senolytic drugs and gene therapies have also ameliorated the side-effects of chemotherapy drugs in mice, and prevented or treated mouse models of diseases of aging such as osteoarthritis; fibrotic lung disease; hair loss; primary cancer and its recurrence after chemotherapy; atherosclerosis; and age-related diseases of the heart itself - as well as preventing Parkinson's disease and (very recently) frontotemporal dementia, a kind of cognitive aging driven by intracellular aggregates of tau protein, which are also an important driver of Alzheimer's dementia.

Scientists use a range of different cell markers to identify senescent cells: no one marker is infallible, and different senescence markers are more dominant in different senescent cell types. But the best-established and perhaps most universal sign of all is the activity of an enzyme called senescence-associated beta-galactosidase, or SA-beta-gal. To create a system that would release of cell-destroying drugs selectively in cells with senescent-cell levels of SA-beta-gal, chemists and nanotechnologists turned to an established platform for the selective delivery of drugs: mesoporous silica nanotubes, or MSNs. What makes MSNs so useful as drug-delivery systems is that their constituent tubes can be packed with any number of different drugs, and their openings on the surface of the nano-balls "capped" with molecular stoppers that keep the drug sealed inside until the MSN encounters chemical or other conditions that can break open the seal. So the trick is to identify a molecular stopper that is sensitive to chemical or physical conditions that are found in the type of cell that you want to target, and not found in innocent cells that you want to leave alone.

SA-beta-gal's actual function in the cell is to breaks down the sugar galactose: senescent cells just produce a whole lot more of it than normal cells. So to target MSNs to senescent cells, the team used galactooligosaccharide (GOS) as the stopper molecule - that is, a series of galactose molecules strung together in a chain. The researchers predicted that with their overabundance of SA-beta-gal, senescent cells would whittle down the chain of galactose molecules until they uncapped the MSNs and released their payload, while the same MSNs would pass through normal cells with their contents still safely sealed up. To test this, the team first drove several lines of cancer cells senescent using palbociclib, a cancer drug that works by shutting down genes that cancer cells require for cell division. They loaded up their GOS-MSN with doxorubicin, a toxic chemotherapy drug that is lethal to normal, cancerous, and senescent cells alike. An additional useful feature of doxorubicin is that it's intrinsically fluorescent, allowing the scientists to easily see where it was released.

GOS-MSN loaded with doxorubicin (DOX-GOS-MSN) passed harmlessly through three non-senescent cancer cell lines, and only released their payload in a small percentage of cells of the same lines that were exposed to palbociclib too briefly to induce widespread senescence. But when cancer cells were exposed to palbociclib for long enough to force them into senescence en masse, they lit up with doxorubicin fluorescence, and programmed cell death raged through the population.

Previous research had already shown that a variety of ApoptoSENS strategies can prevent or reverse idiopathic pulmonary fibrosis (IPF) in mouse models of the disease, as well as reversing the "normal" loss of lung function with age. The team wanted to see if DOX-GOS-MSN could similarly restore lung function in mice with a model of IPF. After first confirming that GOS-MSN distributed evenly across normal and senescent lung tissue they treated mice with either straight doxorubicin or DOX-GOS-MSN for two weeks, starting two weeks after inducing model IPF. Lung dysfunction scores remained stubbornly high in animals treated with plain doxorubicin, but DOX-GOS-MSN restored the lung function of the IPF model mice levels equivalent to young mice not subjected to lung damage. DOX-GOS-MSN also reduced the amount of fibrotic tissue in the animals' lungs, which untargeted doxorubicin was again unable to do.

With those exciting results in hand, the researchers have launched a biotech startup to turn GOS-MSN into a human rejuvenation biotechnology. Senolytic Therapeutics projects that that their therapies will be efficacious in treating multiple disorders which are caused and driven by the accumulation of damaged cells - that is, exactly the conditions that GOS-MSN treated so successfully in their recent proof-of-concept scientific report.

Comments

Does anyone have any thoughts at what age one should start taking the Senolytic Therapeutics assuming it is available?

Posted by: Robert at November 14th, 2018 3:40 PM

@Robert
it highly depends on risk/benefit ration. AFAIK, Quercetin+Fiseting are harmless, so you can take them as soon as you are 20-something. I would advise against taking the more potent stuff before 35, unless you have some other reason like radiation/chemical exposure, genetic disease, chronic inflammation and such. However, if the senolitics are very targeted and safe they could be taken at even younger ages. We don't have a safety profile in humans, and we don't know the efficacy either. So it is a wild guess. After 45, probably the SASP is bad enough to outweigh the risks of toxicity from the senolitics.

Posted by: cuberat at November 14th, 2018 6:47 PM

Wonderful and clever solution. Would be interesting to know though, how difficult is it to produce these nanotubes in large quantities?

Posted by: marten at November 14th, 2018 10:52 PM

Thanks for the info, cuberat. Hmm, I thought the senescent cells start negatively impacting humans around 50 to 60 years old.

I suspect we may have more definitive answer on which ones are more effective and of what frequency to take the treatment over the next couple years. I will be anxiously awaiting (amongst many others) for the answers. Probable one of the main questions is what treatment is the most effective at getting rid of these cells, yet not hazardous for the healthy ones.

Posted by: Robert at November 14th, 2018 11:47 PM

Good to see David Sinclair getting involved in senolytics too, he is also working on epigenetic reprogramming currently too. This approach is elegant.

Posted by: Steve Hill at November 15th, 2018 4:40 AM

@Maarten
Production cost is a factor but I would guess that if it can be done in a laboratory with a modest budget then with mass production the production cost would be acceptable.

Another question is what happens with those nanotubes after they have delivered the payload. Do they have toxic effects on their own?

And since this approach is able to give a second chance to many drugs it's extremely promising not only as v senolitic but as a targeted delivery for some other prominent target. What about beta amyloid?

Posted by: Cuberat at November 15th, 2018 6:02 AM

I'll note that in our (still underway) aged mouse study, we currently see no large difference in "healthspan" or median lifespan increase contrasted with the Mayo transgenic mouse study. But their therapy - which being transgenic presumably kills all p16+ cells - began after weaning and ours began at 2 years of age - while each dose has a reduced benefit compared with a transgene due to our lower transfection efficiency, thus our tentative conclusion is that early start of senolytics is not critically necessary. I'll repeat that this is a tentative conclusion and requires validation as the study progresses and finally terminates. If there is a benefit to early clearance, however, I expect it to be weak.

Posted by: Gary at November 15th, 2018 9:10 AM

@Gary Thanks for that info. I'm looking forward to the updated results of your study. Any chance you can share a new graph which demonstrates the results so far up to week 150 or so? I'm curious how the p16+p53 group compares to the p16 or p53 only group.

Posted by: Sebastian at November 15th, 2018 9:50 AM

We need to wait for the conclusion of the study before publishing anything further; that should happen sometime in the next few months as only a couple of controls are still alive. But the combo group and the p16 group are both doing very well and are now essentially the same in terms of survival. The p53-only group was 10% better than control for a while but nowise comparable to control group survival. (This is to be expected since p53 cells aren't senescent, so the median lifespan benefit to their elimination is fairly weak. And like the Mayo study showed, the benefit to p16+ cell clearance is/will be median - not maximum - L.S. extension...or so we expect.)

Posted by: Gary at November 15th, 2018 10:00 AM

@Gary
Thanks for the feedback. Let's hope that your therapy translates well to humans. Do you think the nano-tube delivery can be used in parallel to the OISIN lipid delivery system to enhance the effects or they are using the more or less the same targets and the synergistic effects is no so big ?

Do you think there are other promising pathways to target ?

A for the expected benefits, even if the max LS is not improved, having even a few percent of the median life expectancy and healthspan would be huge. After all, if we assume 120-125 max LS for the humans, there is a lot of room from the current life expectancy of 70-80.

Posted by: cuberat at November 15th, 2018 1:10 PM

@Gary, do you mean the survival of your mice are the same as in Mayo? If so that is great news !

Posted by: Ariel at November 15th, 2018 7:31 PM

Is there any in human toxicity data for these called nanotubes? Lipid particles work great in mice but are toxic in humans, and Oisins fusogenix proteins are specifically designed to negate this problem, so I'd say Oisin is still streets ahead of this alternative approach.

It is still very good news that more approaches are emerging as drugs that look good can and do fail all the time at the last hurdles.

Posted by: Jim at November 15th, 2018 11:04 PM

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