Anti-ageing protein reverses senescence

28 March 2017

Interview with

Peter de Keizer, Erasmus Medical Centre, Rotterdam

A drug that reverses the ageing process has been unveiled by scientists in the Netherlands. Administered to mice that were the rodent equivalent of human 80 year-olds, the agent triggered the animals to recover lost hair, move with renewed vigour and reversed age-related decline in their kidney function. The drug causes worn out “senescent” cells to kill themselves, preventing them from exerting harmful effects on surrounding healthy tissue. It works by prising a cell signal, called p53, away from the clutches of a protein called FOXO4, and this triggers the cell’s death programme. Chris Smith spoke with creator Peter de Keizer from Erasmus Medical Centre in Rotterdam...

Peter - Senescence is a state of hibernation. It can occur in cells that are irreparably damaged and cannot cope with the damage, and they basically stop dividing. That, in principle, is a good thing because you don’t want damaged cells going rogue. However, these cells secrete a whole range of factors that are unwanted. As we age we get more and more of these senescent cells and, therefore, we also get more and more of these unwanted factors in our environment of the body, and it’s actually shown that taking out these senescent cells from mice makes them live longer.

Chris - Why would the body elect to hang onto these cells which are, for want of a better word, sitting there poisoning the well? Why doesn’t it get rid of them?

Peter - It is thought that early in life these so-called senescent cells have the benefit over cell death. So, if a cell is irreparably damaged and chooses to die, if we have this too often in our bodies, then we would remain very tiny, and we would be outcompeted by nature back when we were still running around in bear skins. So early in life, it is beneficial to have these senescent cells over dying cells. However, we were never meant to become 80 years of age and, as we age, we get more and more of these senescent cells and that’s when they start becoming problematic.

Chris - What sorts of factors do they squirt out into the body, these senescent cells, which have a deleterious effect?

Peter - Over a hundred different kinds of proteins have been identified to be secreted. Some prominent ones are interleukins, which are proinflammatory factors. Also, proteases which break down the matrix of our tissues, for instance, and that’s undesirable. Also, there are plenty of growth factors which can actually promote tumour growth, for instance.

Chris - You think you may have a way to skew whether or not they choose to become senescent or to die off?

Peter - From a fundamental research point of view, we tried to figure out why is it some cell types die and others do not and they go into senescence? I tried to figure out what could be the molecular switch and we identified a protein and that’s the pivot between death and rest. And by making something to resemble this protein, I could fool the system and therefore we could eliminate these senescent cells.

Chris - Does that mean then, that if you were to administer that signal into an old animal that you could rid the animal’s tissues of these senescent cells which are contributing to the ageing process and therefore you could, at the very worst, potentially arrest ageing and maybe even wind the clock back a bit?

Peter - Yeah, you are spot on actually - that’s exactly the case. We started off in Petri-dishes with cells, and if we make those cells senescent, we could eliminate them by adding this compound. If we did this then in mice that were about two and a half years of age, which is roughly 80 years in terms of human years. They had, for instance, worse fitness; hair loss is a feature; they have worsened organ function, and we could normalise those levels with using this compound.

Chris - Right. So you can actually reverse some of those signs of ageing in these mice?

Peter - I think that’s the big novelty of this study. So far, much of the anti-ageing research has focused on delaying ageing, for instance, eating less and exercising more, but society actually shows the reverse. We exercise less and we eat more so this is a message that doesn’t really appeal to the general audience. We now show that it’s possible that when you are already aged, that we can actually reverse some of these effects and that’s a big novelty of this study.

Chris - What is this stuff and where can I get some, more importantly?

Peter -  This chemical is actually part of a protein called FOXO4, and it’s physically associated with another protein which is called p53. What I designed is a small piece of protein that releases p53 and that leads to cell death.

Chris - So essentially what we’ve got is this FOXO4 sitting there and in a senescent cell, which is just stewing and being miserable, it grabs the p53 molecule and in that situation the cell just sits and stews? Your drug molecule gets between those two, stops the FOXO4 from grabbing the p53, and the p53 then triggers the cell instead to die?

Peter- That’s absolutely correct.

Chris - Now the critical question of course though is whether this stuff does harm because it sounds too good to be true? What happened to the mice that you administered this to, and what happens to a healthy mouse you give it to, do they have side effects?

Peter - This is a very important question we were having; that’s also why the study took us so long, and we showed that there was no toxicity. We’ve been treating healthy mice for over a year now. We started at one year of age, which is around 30/40 years in mouse years and we treated them for over a year, so another 30 or 40 years and they still do not show any negative symptoms. So there’s no accelerated cancer development, there’s no effects on the blood system so, as far as we can tell, this is perfectly safe to healthy mice.

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