On the Topic of Senescent Cells: Should We All be Trying to Take Navitoclax?

Senescent cells accumulate with age, and secrete an unfortunate combination of signals that harms organs and tissues in numerous ways, such as via the production of increased chronic inflammation. This is one of the root causes of aging and age-related disease. Safe and effective clearance of senescent cells has been on the SENS rejuvenation biotechnology agenda for fifteen years, but only recently has progress in scientific funding and demonstrations of improved health and life spans in mice snowballed to the point at which startup companies could make a real go of it. Things are moving fairly rapidly in this field now. With the recent $116 million venture investment in UNITY Biotechnology's work on senescent cell clearance, and other companies angling for their own launch, it is fair to say that this line of research and development is underway for real. Clinical trials of senescent cell clearance will be underway soon, funded by UNITY Biotechnology, and using drug candidates such as navitoclax developed in the cancer research community, noted for their ability to induce apoptosis, a form of programmed cell death. Senescent cells are primed for apoptosis, and it takes little to tip them over the edge in comparison to a normal somatic cell, which means that there may well be quite a large stable of existing drugs that will have some useful effect.

The question here is one that is only now starting to be useful to ask: should we all be running out today to obtain and take a drug (such as navitoclax) or drug combination (such as dasatinib and quercetin) that were shown to clear some fraction of senescent cells in rodents? Certainly there have been no shortage of people chasing after whatever the current hype of the day was in past years; I'm sure you all recall resveratrol and other alleged calorie restriction mimetics or telomere length enhancers. All a waste of time and effort. The difference between the science behind those and the science behind senescent cell clearance is considerable, however. The items of the past have all been associated with altering metabolism so as to modestly slow aging, at best, and we have the very good examples of calorie restriction and exercise to show us the immediate bounds of the plausible on that front in our species. Senescent cell clearance on the other hand is legitimately and actually a form of rejuvenation, turning back one facet of the aging of your tissues to an earlier time. You probably don't have to keep taking the treatment, unlike those that slightly slow aging. An efficient senescent cell clearance treatment is something that you would undergo once every few years, perhaps. These first attempts won't be efficient, of course, but they should certainly have a sizable effect in comparison to most of the nonsense that gets peddled to the credulous.

It is helpful to look at the question of whether you and I should jump on this bandwagon through the lens of navitoclax, or ABT-263, which is a likely candidate for UNITY Biotechnology to choose for their trials. The people involved with UNITY Biotechnology have worked with it, and it has been used in a range of clinical trials for cancer, which makes it harder for the FDA to mount their usual expensive objections and requests for more data. Navitoclax can be purchased, and dosages can be established from the human cancer studies and the senescent cell clearance rodent studies (there is a fairly standard method of going from mouse or rat dosage to human dosage). There is comprehensive human safety and side-effect data to look at, but only rodent data for its effects on senescent cells - no-one was looking at that in the cancer studies, which is entirely understandable, but a pity. The current methods of senescent cell clearance with published rodent data show a degree of clearance for fairly short treatments varying from negligible to more or less 50% by tissue type, with different drugs having different profiles. So from a technical point of view, the open question is whether or not it works in people to a useful degree. It is entirely reasonable to expect some drugs to do well in mice and terribly in people when it comes to killing senescent cells, and vice versa. The only real way to find out is to try it. Since clinical trials are coming up soon, from my perspective you would have to be something of an enthusiast to jump in ahead of that right now; a year or two seems a fine amount of time to wait for more certainty.

If taking the leap now, you would have to establish the degree of effect yourself. To do that rigorously you'd need a friendly lab capable of a biomarker assay in a skin sample before and after, say, which isn't impossible to find, just quite specialized. The necessary equipment for those who know how to use it is certain readily available for sale. But without that, you might want to try before and after comprehensive bloodwork to look at markers of inflammation, or even simpler assessments such as blood pressure, given the recent suggestions that senescent cell clearance might help with tissue elasticity, and loss of elasticity in blood vessel walls drives age-related increase in blood pressure. There are other possible options to consider. The point being, don't just run the experiment and feel good about it. Prove to yourself that something happened.

The real issue that puts navitoclax on the wait and see list is that it is expensive, a fairly common problem for newer drug candidates. There is no widespread usage yet, so no-one has invested in the facilities needed for mass production at a reasonable cost, and until such time as someone invents some sort of nanotechnological universal chemical synthesis device, it will remain an expensive, people-intensive business to run up custom lots of specific drug compounds to order. In this case, replicating the doses used in cancer trials would cost something like $700-$1500 per day, which makes it less a matter of thinking carefully about costs and benefits and more a matter of being beyond affordable to anyone inclined to self-experiment. This, more than any of the other factors tells us that we're all going to be waiting on the matter of navitoclax. What if the price was $1 per day, however? Would it be worth it? I'd say probably yes as an experiment, if you were comfortable with what you read of the side effects in the results from the cancer trials, and were willing to put in the work to gather some data about its effects on your own tissues.

As a comparison, we can consider the combination of dasatinib and quercetin - which actually doesn't turn out to be much of a comparison at all. It is very similar, starting with being in much the same place as navitoclax from the point of view of data: dasatinib is used in human cancer trials, but senescent cell clearance results have been published for mice only. Based on the mouse data, you would have to use both rather than just the one: it is a synergistic effect, and just the one or the other isn't anywhere near as useful. Quercetin is a readily available supplement and pretty cheap, so there is that at least. Dasatinib is not, however. It isn't as costly as navitoclax, but still hundreds of dollars for the sort of daily dose used in human trials. Further, the side-effects for dasatinib at these dosages appear somewhat worse that those for navitoclax.

This is the sort of thing that should be going through your mind when looking into making the plunge: cost and reliability of the source; finding good data on dosage, safety, and side-effects; ability to determine whether or not it is actually doing something if you are taking it. In addition, think about what is coming down the line. Is new human data to be expected soon that would reduce the risk of trying something that works in rodents but not so well in people? Are better approaches in the works, such as the gene therapy from Oisin Biotechnologies that should have few to no side-effects? Would it hurt to wait two years, or five years, for an actual product to arrive and for the costs to fall as production increases? These are all questions that we can only answer for ourselves, for our own case.


"These are all questions that we can only answer for ourselves, for our own case."

Couldn't agree more.

Posted by: Claus at November 1st, 2016 3:58 PM

1) I have been searching for good articles about: Effect of Fasting on Senescent Cells. Google is not at all helpful.
2) In all the articles about Fasting, I never see some specificity of what that fasting is like in term of eating. Is just water and zero calories for 3-days or what ?
Any feedback would be appreciated.

Posted by: joseph sarkis at November 4th, 2016 4:39 PM

@joseph sarkis: I see nothing out there in the recent literature on fasting and cellular senescence after a quick search. Even the effects of calorie restriction on cellular senescence are pretty sparsely covered.

Posted by: Reason at November 4th, 2016 5:35 PM

I just confirmed with Valter Longo today that he is working to see if there is a connection between fasting and clearance of senescent cells. He wouldn't give any more details, but promised to let me know when data is available.

Posted by: Josh Mitteldorf at April 6th, 2017 7:32 PM

This article asks some interesting questions, which have actually (surprisingly) been answered in the past few months.

If you want to get rid of your senescent cells and replace them with young, undamaged stem cells, there's an easy way to do it: fasting for five days a month, then (at the end of the five days) doing a re-feed.

You can either do a water fast, or a fasting-mimicking diet (FMD) which imitates the effects of a water fast but is considered safer.. Valter Longo recommends that the FMD have these characteristics:

Day 1: 1,090 calories. Protein: 27 grams. Fat: 68 grams. Carbs: 93 grams.
Days 2 through : 725 calories. Protein: 16 grams. Fat: 35 grams. Carbs: 85 grams.

The diet HAS to be low protein or it won't work. When it's deprived in this way of protein, your body will scavenge your cells for amino acids to make proteins, then will start killing off senescent cells for raw materials. Then during the re-feed, when you eat ample protein, fats and carbs, it will create all new stem cells which do not have autoimmune problems. (Or so the theory goes. There is ample evidence to suggest that something like this does indeed happen.)

What I have personally found interesting is to combine the 5 day "fast" with other anti-aging modalities. I've been doing this by adding things like resveratrol, quercetin, trehalose and PQQ, all of which promote and deepen autophagy and apoptosis. I also eat corn and mushrooms sauteed in butter (both are very low protein and are sources of spermadine, also shown in laboratory studies to prolong life in laboratory animals). I also drink black coffee and green tea, both of which also promote autophagy. Remember that it's not necessarily a water fast. You can eat some food, as long as it's low enough in calories and protein. It can actually be surprisingly high in carbs (see values above).

The fast (whether it's water or just a very low protein eating regimen) should ideally last for the full five days. To work properly, it MUST be followed by a stretch of eating ample nutrients, particularly protein, in order to replace the cells that were sacrificed during the five day "fast." Longo recommends doing it under the supervision of a doctor if you have a medical condition.

Posted by: Nils at April 20th, 2017 2:54 PM

Nils, apologies if I'm missed some important work, but can you point to a study showing that fasting (or eating a FMD) will remove senescent cells? There's evidence that certain types of autophagy are increased with FMD diets, and energy-restricted diets, done correctly, will certainly reduce the formation of /new/ senescent cells, but I've not see evidence that senescent cells can be removed via diet. Sorry if I've missed an obvious paper! There is of course reason to believe that enhanced immune surveillance via energy-restriction might remove a small number of senescent cells, but, again, I've not seen any evidence that this actually happens.

Posted by: Brian M. Delaney at May 1st, 2018 5:40 PM

Isn't the idea to take a senolytic once or a few times only? What amount of Navitoclax would make sense for killing senescent cells? If it's a one-shot deal, maybe it's affordable for some of us. I am actually considering it for one of my elderly dogs, who could stand to lose some senescent cells, and I also read it might help with mitral valve problems (which she has) by stabilizing proteostasis (http://www.nature.com/articles/nrcardio.2017.89?WT.feed_name=subjects_molecular-biology). They don't replace mitral valves in dogs, except in Japan, so options are limited. Might be able to afford enough to treat my 20 lb dog... Anyone have some thoughts on this for me?

Posted by: Rob at July 6th, 2018 2:09 AM
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