Fight Aging!

The Life Extension Advocacy Foundation volunteers recently published a long and interesting interview with Peter de Keizer, the researcher who led development of the FOXO4-p53 approach to selective destruction of senescent cells. As senescence cells cause aging and age-related disease, there is considerable interest in developing means to remove them, and thus produce rejuvenation. The FOXO4-DRI used in de Keizer's study is probably the best of the current crop of senolytic compounds, as while the degree to which it kills senescent cells is broadly similar to the others, the evidence to date suggests that it produces insignificant side-effects; its method of action is much more localized to senescent cells. A company, Cleara Biotech, has been funded to develop this research into a commercial therapy.

It doesn't seem like as many people in Europe talk about aging as in the U.S. Is being in Europe instead of the U.S. better or worse for your research?

As usual, the U.S. innovates, China imitates, and Europe hesitates. I returned to Europe for personal reasons, but I have been talking to American investors who want to explore Europe a bit more, and there are possibilities. People here do acknowledge aging as a problem, and the Undoing Aging conference in Berlin was a success. The downside with Silicon Valley is that there are big budgets and a great spirit, but we also need a style of research, which is, in every city, a little bit different. In Europe, the focus is very much molecular. I would like to combine the great vision and budget of Silicon Valley with European quality and maybe a bit of skepticism. We never publish anything unless we are really convinced. In that sense, I like Europe because people are interested in aging here; you just have to talk to the right people, and many people are skeptical. When I talk to scientists about what we do, they also get excited.

Are the regulations regarding trials more stringent than in the U.S.?

Yes, that's true, especially for animal work. There's a lot of societal pressure not to do animal work. We have to deal with these hurdles, but there's good money in science here, certainly in Western Europe, and we can make do quite well. This is generalizing, but we tend to talk less and do more.

Would you say that a potential side effect of the drug, if not used at the proper dose, could be excessive lysis?

The honest answer is "We don't know." I've seen in mice that you can go too far; if you look at the cell data, it's tenfold more potent against senescent cells. That sounds like a lot, but if you want to treat relatively healthy people with this, if one in ten cells that will be destroyed is basically a healthy cell, I find it very risky. So, you need to have a perfect dose or a perfect range.

With mice, we could scale it and we could say if it's too much or not, but for humans, it's more difficult. What we're doing now is trying to optimize this to make it tenfold more selective. This is version 4, and the published paper is on version 3; the first two were generated in the US in 2012, and they were not so effective. The first step was very short and had a very poor solubility, the second step lasted much longer, and the third peptide we made in D-amino acid is the one we published now. Now, we're making the fourth one because we know where the critical amino acids and the non-important and important ones are in the interaction domain of the two proteins, FOXO4 and p53. We plan on giving number 4 to a team of drug development experts to get it to a hundredfold selectivity, and then it should be much safer for use.

How long would you say it's going to be for this safe version four to be optimal?

That's the fun part. It took me ten years to come to this third version because in academia, we always have 20 other things that are also interesting. Now, we actually teamed up with a company, Cleara, that we founded just recently. The team has 20 people, with 10 structural experts, and they're going crazy on this. Every week, we have a meeting at which they have made some more progress, and it is super fast. We gave ourselves four months for a library screen on the first version, and then it's another ten rounds of optimizations. Once we have a lead candidate, we will start doing all the things that academia never wants to look at, like a liver update and all the stuff that scientists aren't interested in but is important to have. I want to do ten rounds of that, and it's three weeks per round, then we'll know roughly where the weak spots are in our current version, and we can go back and add heavy metal toxicity, etc. We gave ourselves a year for optimization, but I hope sooner.

How well does this treatment compare to other treatment options, such as fasting?

With fasting, you don't kill, you just delay the secretions from senescent cells. It's like rapamycin and aspirin; it just blocks the secretion profile. Fasting offers a transient benefit for sure, but a week later, you eat again, and they're just there again. It's just making them dormant. We have not seen evidence that senescent cells are removed by fasting, in mice or in cells.

Have you looked at other senolytics?

We tried a lot, and the BCL inhibitors look the most promising. What we saw when comparing them to FOXO4-DRI is that they are toxic at low levels and should not be given to healthy people. That's the downside of these drugs. In vitro, if you do low-level navitoclax on healthy cells, you get 10, 20 percent cell death. That's relatively stable. That's a decrease in viability because you're affecting some cells that are apparently sensitive to BCL inhibition. We did not see that with FOXO4, and that's what's reported in our paper. As for quercetin and dasatinib, I'm absolutely not a fan of those. We've tried a couple of experiments; we've never seen a good result.

How often do you think people would need senolytic treatments, will they be for older or younger people?

In mice, over a year; we did it once a month. It seemed to be enough, and I think we can actually reduce that frequency. But, I still have to do the experiment. If we do it once in a while, once every three months, once every half a year in mice, it might actually be sufficient. I don't think they accumulate that fast. Maybe later in life, you'll do it a bit faster. Early in life, there's really no reason to do it so often. It's like a car. If it's only a couple of years old, you don't go to the mechanic as often.

Link: https://www.leafscience.org/dr-peter-de-keizer/