Do we want to live as long as possible, or maximise the number of our offspring? This is an evolutionary dilemma faced by all living things. | Photo: Ed Kashi for 1in6by2030

1 — Let down by evolution

One question has been occupying humankind for eons: Why do we grow old and die? After all, evolution has already found excellent solutions for almost everything else. We actually have a perfectly convincing answer: As soon as we are no longer of an age to reproduce, evolution doesn’t care less whether we live or die.

For a long time, we used to believe that death was programmed into our genetic material, just like our development from a fertilised egg to a fully grown living being. But this theory has meanwhile been invalidated. Death isn’t part of the programme, but a result of neglect.

From the perspective of evolutionary theory, what’s most important is that our genes should be passed on to the next generation by way of our germ cells. What happens to the cells of our body after that has barely a role to play. This is why natural selection eliminates those gene variants that can harm us when we’re young. “After we have passed reproductive age, however, the impact of natural selection decreases continuously”, says Thomas Flatt, an evolutionary biologist at the University of Fribourg. He is studying these processes in the fruit fly.

Without the pressure of selection, a population will accumulate more and more genetic liabilities in the form of mutations that are not disadvantageous during our youth, but only develop a harmful impact later on. One example of this is the genetic defect that is responsible for Huntington’s, a neurodegenerative disease. The initial symptoms usually appear between the ages of thirty and fifty. “So back in the Stone Age, when people didn’t get that old anyway, it didn’t have any impact at all”, says Flatt.

There are other things to consider too. There are also gene mutations that are harmful in old age, but beneficial when we’re young. “These could be mutations that help with our development and reproduction”, says Flatt. For example, there are certain variants of the BRCA1/2 gene that have a positive impact on fertility. In old age, however, they increase the risk of breast cancer. There is thus a biological trade-off between reproduction and longevity.

Experiments on fruit flies have meanwhile confirmed this kind of trade-off. Researchers had the longest-living flies reproduce for several generations, and found that flies with a longer lifespan produced fewer offspring.

A further indication of such a trade-off is that eating very little – also known as calorie restriction – prolongs the life of fruit flies, mice and other creatures. “It probably has to do with their energy balance”, says Flatt. It’s possible that organisms produce fewer offspring when they don’t have sufficient energy available – which in turn is why they are healthier in old age. But this doesn’t mean that anyone should refrain from having children in hopes of living longer: “These trade-offs are probably multidimensional and far more complex than we can imagine”, says Flatt.

2 — Things fall apart

The reasons for decay therefore lie in evolution. But it’s less clear just how this decay comes about. In order to bring some order to this complex topic, researchers have defined certain typical hallmarks of ageing – in other words, phenomena that occur more frequently in our cells and bodies over the course of our lives and that accelerate the ageing process, but that when suppressed can actually slow down that process or even reverse it.

The number of these indicators has meanwhile risen to twelve. They include the exhaustion of stem cells, instability of the genetic material, malfunctioning mitochondria, insufficient sensing of nutrients, and chronic inflammation.

Regula Furrer is researching into muscles at the Biozentrum of the University of Basel. She explains how muscles become ever weaker as a result of these hallmarks interacting: “There’s a lack of stem cells for rebuilding muscular tissue, the mitochondria produce less energy, and metabolic changes lead to the fatty degeneration of the muscles”. Our brain degenerates in a similar fashion, our bones become brittle, and our skin increasingly thin. Our sugar metabolism becomes unbalanced, our heart ceases to pump properly, and our immune system goes haywire. All these defects accumulate until our system finally collapses – and we die.

There were early indications that the integrity of our genetic material influences the ageing process. This is because the condition of our DNA constantly deteriorates over the course of our lives. Its repair mechanisms grow weaker, meaning that damage is no longer repaired – such as that caused by UV radiation – and defective cells are no longer eliminated.

What’s more, the ends of our chromosomes – called ‘telomeres’ – become slightly shorter each time a cell divides. This means that a point arrives at which these cells can no longer divide. This is something that affects stem cells, for example – the cells that otherwise ensure that tissue is renewed. Environmental influences also cause our DNA to receive or lose increasing numbers of chemical tags. Such epigenetic modifications also mean that specific genes can be read either more or less well.

In addition to the damage we suffer due to our DNA, the regulation of our metabolism also plays a decisive role. We’ve known about this since the 1930s, when scientists discovered that rigorously restricting the calorie intake of mice could extend their lifespan by up to 50 percent. A minor sensation ensued. This was the first-ever indication that nutrient metabolism is closely linked to lifespan, and that a lower energy metabolism can decelerate many ageing processes. However, to this day we still don’t completely understand just how this works.

One piece of the puzzle was discovered over 30 years ago at the Biozentrum of the University of Basel by a team led by the cancer researcher Michael Hall: the previously unknown enzyme TOR. This enzyme is inhibited by rapamycin, an immunosuppressant. Hall and his team found that switching off TOR ensures that yeast, threadworms, fruit flies and mice live considerably longer. “After this discovery, the field of ageing research literally exploded”, says Hall.

It has meanwhile become clear that TOR plays a central role in controlling our metabolism. It is where all the threads run together, determining whether cells can recognise the presence of nutrients, oxygen, insulin, growth factors and much more besides. Inhibiting TOR also simulates a lack of nutrients, meaning that our metabolism is powered down. “Up to now, TOR is the best explanation for why restricting calorie intake has a life-prolonging effect”, says Hall.

Cell stress also plays a role. It is triggered by the presence of too many highly reactive substances. These so-called free radicals break through the chemical bonds of other substances and can cause considerable damage.

Free radicals are constantly being generated while the mitochondria are producing energy. “But the body has very good defence mechanisms against them, such as enzymes that convert free radicals into harmless substances”, says Michael Ristow. He used to work as a researcher at ETH Zurich and today heads the Institute of Experimental Endocrinology and Diabetology at the Charité Hospital in Berlin, which specialises in ageing research.

More and more of these free radicals are produced in aged mitochondria, and also when our energy metabolism is heightened. The result is that our natural defence mechanisms are ultimately overwhelmed. As a result, damage accumulates in the cells and they die. This, at least, is the theory. 

Cell death is the better option here. Senescence is worse – this is when the cells stop dividing and fall into a kind of dormant state. In recent years, it has increasingly become a focus of research into ageing. Senescence is triggered by the aforementioned malfunctioning of mitochondria, or by damage to the DNA. But such cells are not completely inactive, and secrete a toxic mix of signalling substances that can trigger a permanent state of alarm in the immune system and can cause chronic inflammation such as arthritis.

Despite the boom in ageing research, science is still a long way from achieving a complete understanding of the ageing process. What is certain is that no single mechanism is responsible for it, nor is any single gene. Instead, countless metabolic pathways are involved that are interwoven with each other in many different ways. “Every researcher naturally tends to prioritise their own field”, says Ristow. “But I do believe that all these processes are relevant in their own way, and complement each other”.

3 — Unsubstantiated promises of healing

As we increase our knowledge of the mechanisms of ageing, hope is growing that we might soon be able to delay death or even cheat it altogether. There is a number of active ingredients that already seem promising in this regard. But there’s a catch: almost all their results are based on studies in yeast fungi, threadworms, fruit flies and rodents. In fact, there doesn’t yet exist a single substance that has been proven to prolong human life. This is because there are almost no serious studies on it.

“A controlled study would cost up to a hundred million francs and take at least ten years to carry out”, says Ristow. And if you’re working with new or largely untested substances, administering them to healthy people for such a study would raise extremely tricky ethical questions.

Despite this, there is a host of products that are erroneously considered to prolong life. There are antioxidants, for example, which include the vitamins A and E. They intercept free radicals in our cells and are accordingly supposed to slow down the ageing process. This is why many people take antioxidant supplements in addition to their normal diet.

But Ristow advises against this. “Some people remain completely unaware that antioxidants also have undesirable effects”. For example, it’s been proven that free radicals perform important functions – such as strengthening our natural defences against an excess of free radicals. Too many antioxidants are actually harmful. For example, one study found that taking a vitamin A precursor can promote the occurrence of lung cancer in smokers.

Restricting our calorie intake is another supposed miracle cure. But Furrer has looked into this topic in the course of her muscle research, and she warns that you have to look closely at the studies that have been conducted on animals. “The more complex the organism, the smaller the impact”. It’s also unclear what effect calorie restriction can have under natural living conditions when compared to the controlled, near pathogen-free conditions of a laboratory. It’s better to have a balanced diet in which you control your calories.

We should also be sceptical about active substances that mimic calorie restriction. These include sirtuins and resveratrol, which is found in red wine. All evidence for their impact – which we again only have from animal studies – is today considered highly controversial. Many lifestyle gurus instead take microdoses of the immunosuppressant rapamycin that inhibits the key metabolic factor of TOR. But there’s still no conclusive proof that this could prolong life in humans. Hall won’t rule out the possibility that it has a positive effect. “Rapamycin is an authorised drug, so it at least it won’t cause any great harm”, he says. But he himself doesn’t take it, as he’d first want to see proof that it actually works in humans.

The latest hype is about senolytics. These are substances that specifically destroy senescent cells that no longer divide, but secrete toxins. Tests on mice have shown numerous possible active substances for this, such as quercetin, which is found in plants. But here, too, we are advised to be cautious, because senescent cells are also needed for healing wounds, for example.

So there’s no miracle pill yet in sight. But simply prolonging life is in any case not a priority for those engaged in serious research into ageing. “We are aiming to extend healthy life expectancy, in other words good physical and cognitive functioning with a high quality of life”, says Heike Bischoff-Ferrari. She’s the head of the European DO-HEALTH study and the director of the newly founded Swiss Campus for Healthy Longevity at the University of Basel and the chair of the Department of Acute Aging Medicine FELIX PLATTER, also in Basel.

We already know how this works from large cohort studies. These have shown great consistency in linking a healthy lifestyle to a decreased likelihood of many chronic diseases. Such a lifestyle would include factors such as getting sufficient exercise, a healthy diet, enough sleep, social interaction and an adequate supply of vitamin D. “It is motivating that the DO-HEALTH study has been able to show for the first-ever time that the biological age can be rejuvenated not only in mice, but also in humans, and by means of simple lifestyle measures”, she says.