The Current State of Senolytic Drug Candidates

Here, find an examination of the current state of senolytic drug candidates, compounds capable of selectively destroying senescent cells. All of those established by the research community appear to work by provoking lingering senescent cells into taking the final steps into apoptosis and self-destruction. Near all senescent cells in fact undergo apoptosis on their own, or are destroyed by the immune system. The few that remain seem primed for apoptosis, but are held back by a small number of inhibitor mechanisms. Drugs that target those mechanisms have been shown to clear up to 50% of senescent cells from aged tissues, the actual amount varying widely by tissue and drug type - in some tissues, the effect is negligible for the drugs tried to date.

The accumulation of senescent cells with age is one of the root causes of degenerative aging and age-related disease. These cells secrete a harmful mix of signals that promote inflammation, disorder extracellular matrix structures required for correct tissue function, and encourage bad behavior in nearby normal cells. In older individuals, this becomes a significant driver of the damage of aging. The most straightforward approach to this problem is to remove these unwanted cells; they are only a fraction of most tissues, and so can be safely cleared out. Studies in mice have demonstrated an extension of healthy life and reversal of aspects of aging through the use of senolytic therapies; it is an exciting field.

Aging at the cellular level is called "cell senescence", and it contributes profoundly to whole-body aging. The most promising near-term prospects for a leap in human life expectancy come from drugs that eliminate senescent cells. Programs in universities and pharmaceutical labs around the world are racing to develop "senolytic" drugs, defined as agents that can kill senescent cells with minimal harm to normal cells.

By analogy with chemotherapy for cancer, the value of a senolytic treatment is measured by its ability to kill senescent cells without doing harm to normal cells. The index called SI50 (SI for "selectivity index - 50%") is defined by analogy to LD50, the "lethal dose" of a toxin, the dose at which half of all cells die. SI50 is defined as the ratio of LD50 for normal cells and LD50 for senescent cells. It is the concentration of the agent at which half the normal cells die, divided by the concentration at which half the senescent cells die. A recent study in which researchers killed senescent cells by interfering in the crosstalk between FOXO4 and P53 reported an SI50 about 12. My guess is that 12 is an encouraging beginning, but it is not high enough to support a useful therapy.

The encouraging fact is that, at the optimal dose, more than 80% of the senescent cells have succumbed to apoptosis, while the number of eliminated normal cells is still below detection. Unfortunately, senolytic agents studied previously, including dasatinib, quercetin and ATTAC, did not include measurements of SI50 that we might use for comparison. The authors of the FOXO4 study were in a rush to publish. They used a fast-aging strain of mice, and even for these, they did not wait to see survival curves. The indicatators of rejuvenation that they do report look positive: increased activity levels, regrowth of lost fur, and improvement of kidney function lost with age.

I had missed the two papers about senolytic drug candidates ABT-263 and ABT-737. Both ABT-263 and ABT-737 were identifed in screens for agents that block BCL-2. BCL-2 is the founding member of another family of proteins that signal a cell to resist apoptosis. The ABT-263 paper included some in vivo results, indicating enhanced growth of blood stem cells after senescent cells have been removed. In vivo testing of ABT-737 was limited. Neither group reports the selectivity index (SI50), but from graphs that they do present, it is clear that ABT-263 is more selective than ABT-737, and that neither is as selective as the more recent FOXO4 method.

The idea of removing senescent cells has a lot of appeal, and enjoys broad empirical support in mammals. There is now a world-wide effort, making rapid progress toward specificity in senolytic treatments. The FOXO4 approach involves the newest agent, and it shows the best ratio yet for killing senescent cells while avoiding collateral damage to healthy cells. It cannot be taken orally and must be injected, but perhaps this is not such a drawback for a treatment that is needed only intermittently, every few years. How will such promising mouse results translate into human health and life extension? We have as yet no data, not even anecdotes. But perhaps we are near the point where hope and courage will motivate the first self-experimenting volunteers. This is a fast-moving field in which researchers are in a rush to publish and (presumably) pharmaceutical companies are taking pains to keep their results hushed up. Sharing of information and resources could push this research over the top and give us the first full decade of human life extension.

Link: https://joshmitteldorf.scienceblog.com/2017/03/28/senolytics-against-aging-snapshot-of-a-fast-moving-field/

Comments

I wonder at what point of the development pipeline is each company (UNITY, Oisin, CellAge, etc.) and particularly when each of them expects to start human trials.

Posted by: Antonio at March 29th, 2017 9:16 AM

I find it curious how Mitteldorf tries to argue that the success of senolytics supports the programmed theories of aging instead of the damage theories of aging that motivated the development of senolytics in the first place.

Posted by: Antonio at March 29th, 2017 9:32 AM

We will probably need a combination of senolytics if we are to succeed in clearing these senescent cells.

Posted by: Tj Green at March 29th, 2017 11:08 AM

I was not aware selectivity was an issue. Reading the graph in his post, it seems to me the issue of selectivity would be easily addressed if it is a major issue by using less aggressive but more frequent doses. Say a dose that would clear 20-25% of sentient cells at a time, would provided a sentient/healthy cell kill ratio of greater than 20-1. It also makes sense to me the body would be better able to process the killed sentient cells if done in smaller batches.

Posted by: JohnD at March 29th, 2017 12:14 PM

The selectivity index of the Oisin Biotechnologies approach should be much higher than that of these drug candidates, by virtue of the way it works, even in the early stages.

Posted by: Reason at March 29th, 2017 12:39 PM

Hey Reason,

With all these new treatments approaching clinical trials, will you let us know when and if you start using some of them. I know that for now you only really recommend healthy lifestyle + CR but when that changes it would be nice to have a sticky article!

Cheers

Posted by: Mathieu Cloutier at March 29th, 2017 1:39 PM

So there are different types of senescent cells that require different drugs that need to be delivered to different organs and tissues. Can they really develop a universal therapy or a cocktail of drugs in the near future that addresses all senescent cells throughout the body, regardless of the blood-brain barrier or whatever? Correct me if I'm wrong, but I thought Unity and other companies are for now only concentrated on developing a therapy for one single body part, just aiming for the proof of concept, such as clearing senescent cells in the knee, helping arthritis patients. If that's the case, clearing the whole body should be orders of magnitudes more complex, requiring many additional years of research.

Posted by: DarwiN at March 29th, 2017 3:23 PM

Post a comment; thoughtful, considered opinions are valued. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.