Forever Young: Can Science Reverse Ageing?

Ageing happens to each and every one of us, but what is really going on and why does it happen?  Georgia Mills spoke to Judy Campisi, a professor at the Buck Institute for Research on Aging.

Judy - Of course, we don’t have a clear definition of ageing except to say that it’s a process by which multiple systems within the body are declining in function, and it can be driven by any number of external and internal forces that cause this decline.

Georgia - How does aging affect the different parts of the body?

Judy - It’s interesting that ageing affects different tissues in different ways, but also different people and different animals of different genetic background don’t all age in exactly the same way. So there are some declines in tissue function that we recognise as aging: wrinkles in the skin, eventually loss of muscle mass, and loss of cognitive ability, but not all people and not all genetic backgrounds have the same trajectory for each tissue.

Georgia - What is going on then inside us on a cellular basis to cause this gradual decline?

Judy - The short answer is: we don’t know. The longer answer is: we believe that there probably are a few fundamental processes that we define as a so-called ‘basic ageing process’ that can drive the decline in multiple tissues. One of them is a cellular process - this is what we study - it’s called ‘cellular senescence,’ and what it is a stress response to which cells respond by doing three basic things.

The first thing is they stop dividing. This turns out to be a very important mechanism for preventing cancer. You don’t want stressed or damaged cells to proliferate.

The second thing that the cells do is they begin to secrete molecules that can have rather profound effects on neighbouring cells; that is important for alerting the tissue to the possibility that there is a problem - possible damage or possible injury.

The other thing is they initiate a process called ‘inflammation.’ This is a process in which small molecules attract the immune system, and it turns out that initial attraction is also very important for wound healing and tissue repair, so that’s good - right?

The problem is the third part of what happens to senescent cells. They don’t die very readily, they don’t go away and so now the system becomes chronic. So with age, we slowly accumulate senescent cells and we experience a condition that is been termed ‘inflammaging,’ and what it is is low level chronic inflammation. And virtually every age related disease has as either it’s cause or as a major contributor this process of chronic inflammation.

So we believe now that the process of senescence, which evolved for the good purpose of preventing cancer, and promoting tissue repair can be become what we term ‘maladaptive,’ that is it not longer serves us for good purposes as we age and then begin to drive those aging pathologies.

Georgia - There are a number of other ideas about what could be aging in the body and we’ll look at some of them later in the programme. But what drives the fact that one of us might age faster than another? Some 70 year olds run marathons, others can barely make it up the stairs.

Judith - In our environment everyone knows what they need to do to postpone aging, so don’t smoke, eat a balanced diet, eat your veggies, exercise. Exercise is actually one of the best things you can do to preserve tissue health, and the other thing is choose your grandparents wisely because there is a genetic component. As you know, living to be 100 tends to run in families

Some naked mole rats alive today were born in the late 1980s. Most similar animals their size live for about one or two years, so how are they doing it? Georgia Mills spoke to Cambridge University's Ewan St John Smith...

Ewan - Here we’ve got two colonies of naked mole rats. The naked mole rats are mammals; they’re rodents, but there’ rather unusual because they’re naked. They have some hairs down the sides of their body they use for orientating themselves but, unlike our stereotypical mammal, they’re hairless. The polite thing to say is they look like a cocktail sausage with legs and teeth.

Georgia - Why are naked mole rats of interest to scientists?

Ewan - The first thing that made them of interest to scientists was when it was observed they live in these big colonies headed up by a breeding female. We call this eusocial - they have one breeding animal in a colony, it’s a bit like bees and termites. Then they’re cold blooded, that’s makes them interesting to scientists.

But from a biomedical perspective, what’s really interesting is that these animals live for over 30 years. Based on their size - usually bigger animals live for longer - we’d predict them to live somewhere between three and four years so trying to understand how they live healthily for a long time is what a lot of scientists are interested in.

We have a few ideas about why that is: they’re highly resistant to cancer. It used to be the case if people said mole rats don’t get cancer, but now there’s been one or two incidences. But mice, if you look after them in captivity, usually two thirds or more die of cancer between 18 months and 28 months of age.

So they’re highly resistant to cancer and it also appears that they’re highly resistant to cognitive or neurological impairments. As they get older we don’t notice the animals struggling to negotiate their colonies. There’s not many incidents of them developing neurodegenerative conditions but, that said, there hasn’t been a huge amount of study looking at older animals. The animals that were born in my colonies last week, they’ll naturally die when I retire so looking at ageing in a rodent like this is quite complicated.

Georgia - Do we know how they’re resistant to cancer?

Ewan - There’s some information about how they’re resistant to cancer. It appears their cells have more control on the cell growths so they’re better able to detect how a cell is proliferating and put brakes on how that occurs. But, at the moment, I think we’re a long way off trying to understand how exactly the mole rat manages that.

We have better understanding about some of their other adaptations. We know they’re very resistant to hypoxia, so low levels of oxygen. When a human has a stroke, there’s no oxygen being delivered to the brain and parts of the brain start dying, and that’s what underlies the disabilities that people have as a result of the stroke.

Similarly hypoxia is associated with lots of neurodegenerative conditions such as Alzheimer’s and the mole rat is really resistant to this. So without oxygen they don’t become incapacitated for almost 20 minutes and when they are given oxygen again, it’s as though nothing ever happened, they come back to life perfectly normally. We’ve got quite a good understanding on how their brains keep surviving in this low oxygen environment.

Similarly when it comes to looking at their pain behaviour, naked mole rats respond perfectly normally to thermal stimuli, so hot and cold. They respond normally to mechanical stimuli, but certain chemicals such as acid, they don’t show any response at all. And, again, this probably relates to the fact that they live in this underground environment of high carbon dioxide, low oxygen levels.

Carbon dioxide when it mixed with water produces acid, so these animals live in a very safe environment with few predators but it’s acidic so, presumably, over time they’ve adapted to this environment to prevent acid causing pain. From a clinical perspective it’s quite interesting for us to identify the molecules involved in that acid insensitivity because acidosis is associated with lots of inflammatory pain and also certain forms of cancer.

Georgia - Wow! These guys are like the superheroes of the animal kingdom, they’re just resistant to everything. Why haven’t all animals done this, it seems like a quite useful idea?

Ewan - One answer would be that maybe in order to have those things happen to you you end up looking like a mole rat and other animals are too vain.

Some animals appear to be able to reject the processes of ageing completely. Could this ever be the case in humans? Georgia Mills spoke to Aubrey de Grey from the SENS Research Foundation, who believes indefinite lifespan is within the reach of science.

Aubrey - Absolutely. There’s absolutely no reason why. If you look at 100 year old cars today, the people who built those cars 100 years ago would be pretty astonished that any of the cars that they built 100 years were still working in 2017. But the fact is now, if you look at those cars, nobody would say that it would be impossible for those cars to last another 100 years.

The body is fundamentally a machine. It’s a really complicated machine obviously, and it’s taking time to figure out how it works well enough to be able to do preventative maintenance with the same level of effect that we can have with a car or an aeroplane, but the fact is it’s just sort of incoherent, non-scientific, magical thinking to suggest that there would be something there that we inherently couldn’t fix.

Georgia - Aubrey De Grey is chief science officer of SENS research Foundation, a biomedical research charity based in California, which aims to reduce the damage of ageing and allow people to live younger.

Aubrey - The body does a lot of different types of damage to itself throughout life as kind of side effects of the way the body normally works and, in that sense, ageing in a living organism like you or me is exactly the same as ageing of a car or any other simple man-made machine. And so we are adopting very much the same approach that one adopts if one wants to keep a car going longer and, of course, that is simply preventative maintenance.

We identify the various types of damage that are accumulating, and we identify ways to eliminate that damage. So in the case of the human body there are seven major categories of damage. Things that have many examples within each category, but the classification is useful because for each category there is a generic approach to repairing or eliminating that damage.

For example, stem cell therapy is a generic approach to repairing one particular type of damage, namely the loss of cells, where cells die and are not automatically replaced by cell division. Stem cell therapy involves pre-programming cells into a state where you can inject them into the body and they know what to do. They divide and transform themselves into replacements for the cells that the body is not replacing on its own - that kind of thing.

Georgia - How are you looking into these? How are you testing it?

Aubrey - Of course, the details of all of this vary a lot from one project to another but, in general, this is just like any other medical research. We start out by identifying a particular approach that we think is promising for repairing a particular type of damage. And then we work to develop it initially in the laboratory, typically in cells and culture, not even in a living organism. Once we’ve got it reasonably well functioning and working in that context we will start working with mice and eventually, when it’s working well enough in mice, we can start moving to the clinic.

Georgia - Which therapy would you say is the most promising in terms of how soon it might be viable?

Aubrey - Well, stem cell therapies are, of course, in many cases already in the clinic or in clinical trials and that applies certainly for some aspects of ageing, as well as for early life diseases. For example, Parkinson’s disease, that’s a disease which is very much caused by the loss of cells - a particular kind of neuron in a particular part of the brain which happens to have a much higher rate of cell death than most neurons, so we end up losing a lot of them and that’s why we get Parkinson’s disease.

Stem cell therapies to replace those neurons are already very much underway, some clinical trials are happening. The very first attempts to make this work were actually made 20 odd years ago and back then we knew very little about how to manipulate stem cells so the results were extremely patchy. Only a few people benefited, but the people who got lucky and did benefit they were completely cured, so people are very hopeful about that kind of thing.

Diet heavily affects our health, we all know this, so could it affect our lifespan? Well, you can investigate this using the fruit fly. And that’s what Alex Gould and his team at the Francis Crick institute have been using to investigate the impact of diet during development, as Georgia Mills found out.

Alex - I should really say that the inspiration for doing this work came from quite a lot of human epidemiological data, and also studies done in rodents, which show that the nutrition in early life has a very long term influence in the ageing process and, ultimately, in the regulation of lifespan.

Georgia - In general, research is pretty clear: not enough food when you’re developing can be really bad news for your health and your lifespan. But a reduction in just some types of food has an interesting result…

Alex - Work in rodents suggests that a degree of protein restriction, so a moderate to low protein diet during the lactation period can actually produce a slightly longer lifespan than a control diet. It may not all be bad news and it’s a question about finding the right kinds of dietary regime, and the time during development when the growing animal is exposed to this.

Georgia - Alex and his team put flies in their early stages of development - their larval phase - on a low protein diet and then when they were adults, they took the off. And this, it turns out, dramatically affected their lifespan…

Alex - Depending upon the exact conditions that we use, you could get up to a twofold increase in lifespan and this is at least as large, if not larger, than the more usual kinds of dietary manipulation that have been done in drosophila (fruit flies) and in other animals, which is to manipulate the diet of the adult not the larva.

If you manipulate the diet of the adult, and this is called dietary restriction or DR, then you can substantially increase the lifespan as well. But the new angle here was that we found that by manipulating the very early diet during development we could have at least as profound an effect on lifespan.

We don’t fully understand how this long term mechanism works but we did find, quite surprisingly actually, that one of the influences was on the types of lipids, the types of fatty acid derivatives that are produced by the equivalent of the fly skin. So it turns out that on a low yeast diet these animals produce less of these lipids, and that these lipids at high concentrations can actually prove to be toxic and they can decrease the lifespan of flies. These toxic lipids not only shorten the lifespan of the fly that produced the lipids, but because they shed them into the environment they can shorten the lifespan of neighbouring flies, so one fly can influence the longevity of another fly.

Of course, this is all research using this model fruit fly, and the relevance of this to other organisms such as mammals are not yet clear, but there are some intriguing aspects of similarity. One of these is the fact that our own skin, of course, produces these similar kinds of lipids to the ones produced by the fruit flies. These have a beneficial function to prevent us from drying out but also, as in fruit flies, some of these lipids can be toxic.

Georgia - So we’ll have to wait and find out if there’s any relevance to us humans. Seeing as I’m not a fruit fly, and equally not in my larval stage, do we know anything about adult diets and ageing. One diet that has attracted a lot of attention recently is the idea of caloric restriction...

Alex - Caloric restriction can be defined in various ways by various different people but, roughly speaking, it’s something like a reduction of between 20 and 40% in the number of calories. This has been shown to produce various kinds of health benefits in a number of model organisms, but I think it’s fair to say that it’s not really clear what the effects of this would be upon longevity in humans. And one of the rather obvious reasons why this is the case is it’s actually very difficult to persuade people to eat a substantially reduced number of calories for long enough to assess effects on something like lifespan.

However, there have been quite a few shorter term studies where people have found substantial benefits in the short term upon things like obesity, cardiovascular health, and reduced risk of Type 2 diabetes. So as far as the available evidence is around, it does suggest that caloric restriction can produce some health benefits. I think it still remains an open question about whether that will extend human lifespan.

Georgia - You’ve been very careful to let me know that your findings are in fruit flies only at the moment, but if I put you on the spot and said: I want to live a long life, what do I  do? What would you say to me?

Alex - I would say don’t do anything too extreme. It’s important to have a very healthy balanced diet - plenty of fresh fruit and vegetables. And perhaps I might also say that you can try and decrease the amount of foods that have a high glycemic index - sugars which are very quickly metabolised and can produce a spike in our circulating glucose levels, it seems like that can be quite damageing. If you avoid refined sugars, the kind of things present in desserts, and instead focus more on complex carbohydrates. Just really eat a varied and balanced diet - I think that’s really the secret to not only a long life, but a happy one.

Georgia - So fewer Wine Gums for me then?

Alex - I would probably cut down on the Wine Gums and increase the pieces of fruit you eat in a day

Georgia - So a long and almost happy life then!