By using this service and related content, you agree to the use of cookies for analytics, personalised content and ads.
You are using an older browser version. Please use a supported version for the best MSN experience.

Can we delay ageing?

The Financial Times logo The Financial Times 10/03/2017 Cynthia Kenyon

Quietly, over the past few decades, remarkable discoveries have been made about the biology of ageing. Since we all get older, it might seem that ageing “just happens” and can’t really be changed. In contrast, age-related disease does not seem inevitable, since not everyone gets cancer, heart disease or dementia. Accordingly, much research funding has been directed towards individual diseases, whereas very little has been directed towards ageing itself.

This is regrettable, since ageing is the greatest risk factor for many diseases; far greater than, say, smoking. If we could gain control over the ageing process, we should be able to maintain health and youthfulness for longer, and increase our resistance to age-related disease.

Ageing is a natural progressive decline that affects all organ systems and coincides with an increased risk of death. Many processes in biology, like the formation of muscles in an embryo, are governed by key “regulatory genes”, genes that can co-ordinate an entire programme of events. Evolutionary biologists long argued that regulatory genes for ageing would not exist. Ageing happens after reproduction, they argued, so a gene controlling ageing should have no effect on reproductive fitness, and so would have no way to arise by natural selection.

Thus it was surprising to discover that the rate of ageing of an entire animal could be changed dramatically by altering single genes.

This was first discovered in a microscopic roundworm called C. elegans, where changing a single base-pair in the DNA could more than double the lifespan. The long-lived roundworms aged more slowly than normal, and looked much younger than they were. In human terms, they would be like people who looked 45 years old but were actually 100.


Lighted birthday candles stacked in a DNA genome-like sequence © Provided by Financial Times Lighted birthday candles stacked in a DNA genome-like sequence

In the years since the early worm experiment, mutations in these same genes have been shown to slow ageing and extend lifespan in other species, including mammals. How does this happen? It turns out that animals have an evolutionarily ancient genetic circuit that can protect cells and tissues in response to stressful conditions, such as food limitation or other harsh circumstances. The circuitry contains many sensors, each tuned to specific metabolic signals, and it shuttles between two physiological states. When conditions are favourable, it promotes cell growth and robust metabolism. Under harsh conditions, it shifts to a physiology that favours cell protection. Defective proteins and structures such as mitochondria (the cells’ energy factories) are replaced, and chaperones, proteins that stabilise and fold other proteins, are activated. Genes that detoxify harmful chemicals are turned on.

This shift towards cell protection increases the organism’s resistance to environmental stress, and also — presumably because it protects the tissues from damage — extends lifespan. Thus, each species seems to have a hidden potential to live longer, possibly much longer, than it usually does. So it looks like there are “genes for ageing” after all. Since these genes can help increase the survival of endangered young animals before they reproduce, they could well be subject to natural selection. Thus we have a plausible evolutionary explanation for their existence. In more practical terms, genes that control ageing may provide us with entry points for interventions that could keep us young and healthy for a longer time.

What are the chances that using a drug to shift this network towards cell protection might slow ageing and increase lifespan in humans? We don’t know. However, mutations that have this effect may be responsible, at least in part, for the longevity of some familiar animals. Mutations predicted to activate this cell-protective system not only under harsh conditions but under “good conditions” as well are present in Brant’s bats, which live 40 years (much longer than, say, mice, which live two to three years) and also in small dogs, which tend to live longer than large dogs. (One consequence of shifting the body’s physiology to the cell-protective state is to reduce rates of growth. However, it is possible to tweak the system — in laboratory animals — such that lifespan is increased with no effect on size.) These natural cases are reassuring, as they demonstrate, at the very least, that life-extending mutations need not come with crippling side effects.

So far, we do have life-extending drugs for mice. Rapamycin, which targets a stress sensor called TOR, extends the average lifespan of mice by about 25 per cent, and experiments with pet dogs are under way, co-ordinated by scientists at the University of Washington in Seattle. But rapamycin can have side effects in humans (where it is used to modulate the immune system following organ transplants), so its usefulness may be limited for now.

The lifespan of a mouse can also be increased by feeding it nicotinamide riboside (NR), a nutraceutical that raises energy levels (but buyer beware: clinical trials have not been carried out). On the other, more pessimistic, hand, it is possible that we humans, with our long lifespans, have an already-active cell-protection system. Like small dogs and bats, we live longer than expected for our body size. (Among most species of mammals, a larger body size correlates with longer lifespan.)

Right now, many researchers, even those not thinking about ageing, are trying to make drugs that boost this cell-protective network. Their motivation stems from the fact that this network not only counteracts ageing, it also counteracts age-related disease. For example, elevating the levels of FGF21, a hormone normally made in response to starvation, has beneficial effects on overweight mice fed a “western diet”, and thus might counteract diseases associated with obesity, such as diabetes. Activating this cell-protection system suppresses many types of cancer in laboratory mice, and several of its components are targets for cancer interventions. Activating the system can also improve the weakened response that elderly people have to flu vaccinations. So the wheel is turning and, before too long, we should learn whether humans are broadly susceptible to the pro-longevity, healthful effects of this system.

What if we cannot activate this cell-protection system in humans, or not without side effects? A different life-extending, cell-protective pathway switches on in roundworms and other experimental animals when mitochondria (the microscopic power-packs that provide energy to all living cells) are unable to work at full speed. It is possible that we could learn how to switch on this cell-protective pathway in ourselves, as a way to slow ageing. Here again, it may be that nature has already found a way to switch on this cell-protective pathway during the evolution of longevity. Larger animals, which, as mentioned above, tend to live longer, also have reduced rates of metabolism. Perhaps their longevity results, in part, from switching on this mode of cell protection.

Another possible route for intervention is by tamping down inflammation. Inflammation is an excessive activation of the immune system that promotes many diseases we associate with ageing, such as atherosclerosis, arthritis, dementia and other diseases. The mutants described above, that live long because their natural stress-sensing network is turned on, have lower levels of inflammation and lower levels of “senescent cells”, which are inflammatory cells that accumulate with age. Remarkably, genetically activating or repressing inflammation genes in the brain of a mouse can affect the lifespan of the whole body, decreasing or increasing it, respectively.

One cause of cell senescence is the age-dependent shortening of telomeres (the protective DNA caps at the end of chromosomes), and interventions that extend the telomeres of old mice have been reported to extend lifespan. Likewise, killing senescent cells in ageing mice greatly improves their health and extends their average lifespan. Together these discoveries support the idea that interventions that target inflammation might also have beneficial effects on ageing and age-related disease in humans.


By joining the circulatory systems of young and old mice, scientists have discovered that young animals produce blood-borne substances that can rejuvenate the cells of old animals. Conversely, the blood of older animals contains substances, in some cases inflammatory factors, that promote ageing. Whether these circulating substances can extend lifespan is unknown. However, they can have beneficial effects on mouse cognition, and clinical trials are now evaluating the effect of transfusing the blood of young people into elderly people at risk of Alzheimer’s disease.

Recently, a new type of intervention was reported, one that recalls the biology of germ cells (the embryonic cells that become either eggs or sperm). One of life’s great mysteries is how, through the germ cells, mature adults can have babies that are born with no signs of age. This ability to “erase age” is not confined to germ cells; cells from adult tissues, such as skin, can acquire a new youthfulness and behave like germ cells in response to the activation of four genes named Yamanaka genes (after Shinya Yamanaka, the Nobel Prize-winner who discovered them).

In a wild experiment, scientists introduced extra Yamanaka-factor genes into mice that carry a “progeria” mutation, which accelerates their ageing and shortens lifespan. Long-term exposure to the Yamanaka factors is lethal, because the tissues lose their identities as they become germ-like cells. However, remarkably, short pulses of Yamanaka factors were able to maintain the youthfulness of the mice while keeping their tissue identities intact. As a consequence, the mice lived much longer.

This surprising study raises many questions. First, would the Yamanaka factors rejuvenate and extend the lifespan of a normal mouse, or do they just prevent the progeria mutation from having its effect? Longer-term experiments with normal mice have not been completed but, encouragingly, the Yamanaka factors did help normal mice recover from metabolic disease and muscle injury. Another question: if these factors can really turn back the clock and rejuvenate the tissues, would memories be erased? It’s early days, but stay tuned.

In summary, many interventions have now been found to extend lifespan in animals. Some are not well understood molecularly, and may turn out to define new biological mechanisms.

Still more may lie undiscovered. For example, very long-lived animals, such as the mouse-sized naked mole-rat, which can live 30 years (or, in fact, we long-lived humans), may utilise yet undiscovered strategies for longevity — strategies that scientists can discover and amplify. Considering all that we know about ageing, and all we have left to explore, the dream of adding some youthful, disease-free years to our lives seems increasingly likely to come true.

Cynthia Kenyon discovered some of the first long-lived mutants, which changed how scientists think about ageing. She is a member of the US National Academy of Sciences and vice-president of Ageing Research at Calico, a research and development company working on interventions to increase lifespan


More from the FT

The Financial Times
The Financial Times
image beaconimage beaconimage beacon