Scientists hope that one day a “cocktail” of drugs will be available to allow people to live full lives until the very end by averting the major killer diseases that accompany ageing, such as dementia, cancer, cardiovascular disease. Is this an attainable goal?
Linda Partridge envisions a future where people would just die of old age and not of the diseases that so frequently plague or seriously incapacitate the ageing human population. With that in mind, Partridge, a british geneticist specialized in the biology of ageing and age-related disease, is putting to the test a “public health” approach of ageing, based on the prevention of age-related diseases rather than their treatment. As she explained in a talk provocatively titled “Drugging ageing” that she gave in September at the Champalimaud Centre for the Unknown, during the Champalimaud Research 2017 Symposium, she and her team at the Max Planck Institute for Biology of Ageing in Cologne, Germany, are currently evaluating the health benefits of three different human drugs on ageing mice. Their project is to determine whether, when given at some point in much smaller doses than for the treatment of disease, a combination of these drugs could have a beneficial impact on the people’s health later in life.
The idea is to develop a pill, or a set of pills, that would allow us to have better quality of life in old age?
Yes, I think that’s really what these pills are about. Life expectancy is still going up, and the problem is that the period of ill health before death is stretching out. We want to tackle old age ill health.
Thus, people would just die of old age, not of disease?
Yes! It think it’s what most people would want for themselves. To just die in their sleep at some point. And feel fine up till then.
In the lab, with mice or even monkeys, what we see is that the animals that have had an anti-ageing intervention (for instance dietary restriction) are fine one day and dead the next – whereas with the controls, there is usually something very obvious that killed them: a huge tumor or something gone wrong with the lungs. In the animals that have had the intervention, you often can’t see why they died. They don’t get sick before they die. That’s what we’re after.
Do you think that having drugs that humans could take to make this come about is a feasible project?
Yes, I do, although we may need lifestyle interventions too. Some of the things that we are doing to ourselves are so unhealthy that it’s hard to see how any drug is going to be able to do much if we don’t change that. For instance, trying to prevent a smoker from getting lung cancer would be really tough. But, provided you keep your environmental risk factors down, then these drugs could be very helpful.
In your talk, you mentioned three drugs in particular.
Lithium, rapamycin and trametinib. They are all drugs that have human uses.
What does lithium do?
Therapeutically, it is given against bipolar disorder. But we also know that lithium extends lifespan in worms and flies. At the moment, we don’t know exactly how it does it, and we don’t know which tissue is improved or how it’s improved, or why that makes the fly or the worm live longer. We don’t know whether it’s really important in nerves or muscle or the heart or something else, so we need to do more work to find out. We’re trying it in mice at the moment.
How do you evaluate the effects of the drugs in your experiments with mice?
Lifespan is an easy way to measure the impact of anti-ageing interventions in animals. But there are many others. You can put mice through a battery of tests, to see how they’re doing in different modalities. You can tell a lot from the blood, of course, by looking at all kinds of inflammatory markers, glucose, insulin. You can charge them with glucose and see how good they are at clearing it and how sensitive they are to insulin. You can evaluate neuromuscular function with various agility-balance-strength tests; you can also test their cognitive abilities (there are a number of behavioral tests). You can look at cardiac function, you also want to be sure they aren’t getting obese. You can look at their skin, at the quality of their fur. You can ask a lot of questions about health and function during ageing in mice.
You basically start out with two cohorts, and to one of them you give the drug and just let them lead their lives, simply noting any pathologies that become obvious, and let them die from natural death. And then you have a completely separate cohort where you do all these functional tests that I just mentioned, and you also look at each tissue individually, at the histology.
Provided it is safe, where would you expect lithium to act in these animals as they age?
We’re too early in the experiment, so we don’t know the answer. But my guess it that it is going to be particularly beneficial in the brain, and I would expect these mice to maintain their cognitive and behavioral abilities into old age longer than the controls. That’s my guess, neural function.
The second drug, rapamycin, is an immunosuppressive drug. How can this be beneficial in ageing?
It is true that, in humans, its only licensed use is as an immunosuppressant, and it is used at very high and continuous doses for that. But there’s also other data in humans that indicates that at much lower doses, and for short periods of time, it actually stimulates the stem cells in the bone marrow [which include the precursors of immune cells].
In an old person, where the stem cells are normally just sitting there, quiescent and useless, you don’t get a good response to immunization (with the flu vaccine, for instance). But give them a jolt of rapamycin first and then you see a very nice response.
There was actually a human trial with rapamycin to potentiate the effects of vaccination against the flu. And it seems very clear that this drug induces a huge immune memory effect.
They did a three-week treatment, and then they tracked the participants through the ensuing winter. And right through that winter, those people were resistant to flu infection. It was an incredibly strong effect for such a short duration of the treatment.
We also know that rapamycin extends lifespan in mice, and I suspect it’s going to affect multiple tissues – including the brain. It crosses the blood-brain barrier, as of course does lithium. And again, I would expect there to be cognitive effects in these mice, and I think it’s really important to know whether there are or not.
And the third drug, trametinib?
It’s licensed use is entirely against cancer, but I suspect it’s going to have much wider effects – although this is the one where I’d be more concerned about potential side-effects, particularly in the brain.
I think it’s going to reduce the incidence of cancer. And it might also be quite relevant in metabolic disease, because it clearly has effects on lipid metabolism.
If you were to give, in a futuristic scenario, these three drugs safely to people, what type of age-related problems do you think you could impact?
Anything for which that underlying ageing process is a risk factor could be affected. But with these particular interventions that we’re talking about, we don’t know. They do prevent cataract, for instance, but I don’t know whether they would have any effect on age-related hearing loss, which can also be a big problem in old age.
You’ve mentioned dementia and cancer, but not cardiovascular disease, which is also a big killer.
Mice are not really good models for cardiovascular disease, unfortunately. That’s not what kills mice. It would be more interesting to try it in monkeys.
When do you think people would have to start taking this kind of multi-therapy to avert age-related killer diseases?
The very first time they saw a lifespan extension in mice with rapamycin, they had started treatment in middle-aged animals. So clearly, there can be an effect even if you start late in life. But whether this is as good as starting earlier, we don’t know.
What are you currently testing on mice at your lab?
We’re looking at all three drugs. We won’t need to look separately at rapamycin, since other labs have already done that, but we will look at it in combination with the others. That’s going to be one big line of activity in the lab over the next few years, as proof of principle of whether these drugs will be of any use. And if so, to determine whether it should be exactly these drugs or some modified versions.
Let’s say you come up with an anti-ageing “formula”, how would you go about trying it out on people?
As I’ve already mentioned, rapamycin is already being tried to potentiate immunization against the flu. And the people who did that study are also looking at immunization against other things, like pneumonia. So they’re really starting to look more broadly at the immune responses.
What about combining the three drugs?
Our lab got permission for that for the mice, so we are doing that as well, but for lithium and trametinib, we first need to know whether they work separately and at what dose.
And then you would have to test the combinations in clinical trials, since these drugs are not given together to humans.
Yes. But for all of them, we’d be talking about much lower doses than those that are being used therapeutically. Rapamycin doses that extend mouse lifespan are much lower than those used in patients for immunosuppression.
How long do you think it will take to develop something that could actually make a difference for the elderly in terms of quality of life?
My guess is that potentiating response to immunization will spread pretty quickly – though it might not be based on rapamycin, because there are actually other ways of doing that.
We’ve got this insane situation in the UK [and other countries, including Portugal] where immunization against the flu is targeted to the elderly on the grounds that the elderly are much more likely to be badly affected if they do get get the flu – but completely ignoring the fact that they don’t respond to the vaccine. There’s no point in vaccinating them, unless you do the potentiation. So I think that’s going to change quite quickly. I wouldn’t be surprised if it takes less than 10 years.
And for the other drugs – lithium, trametinib?
That’s going to take much longer. We need much stronger pre-clinical evidence. But at some point, I think there should be sufficient pre-clinical evidence to start looking at what’s happening in humans.
There’s already been a clinical trial and a meta-analysis of the effects of lithium in dementia. And the meta-analysis says that the effects are markedly positive. So I wouldn’t be surprised if we start to see some more clinical trials for that – or some more specific, targeted drugs.
My own view, though, is that they are intervening much too late. If someone’s already undergone a lot of neuronal loss, nothing is going to reverse that short of tissue engineering. So I think they need to identify people whose IQ is going down but who have not got to the point where they’re really starting to suffer measurable cognitive impairment.
Ana Gerschenfeld works as a Science Writer at the Science Communication Office at the Champalimaud Neuroscience Programme
Edited by: Catarina Ramos (Science Communication Office). Photo: Tor Stensola (CCU).