麻豆传媒

WHY do we age? As youngsters, we seem invincible. We climb trees, frolic in the dirt and blithely share alarming quantities of mucus. At college, we can thrive on a diet of ramen and beer, party all night and still sit an exam the next day. But in our 30s, we start to wind down. It becomes harder to maintain muscle tone and avoid illness. Our joints start to ache and our memory begins to dim. And it is mostly downhill from there.

People have long attempted to stop or reverse this process. But fountains of youth and secrets of immortality remain firmly in the realms of fiction. Our bodies wear out, even if we no longer do the back-breaking physical labour our ancestors did. And the world seems determined to grind us down with a plethora of disease-causing microbes. To help fend off these pathogens, our bodies recruit other microbes, vast numbers of which reside in our intestines, where we feed them in exchange for their services. But, as we age, this gut microbiota becomes less effective at fighting diseases too.

This raises an intriguing possibility. Perhaps the secret of longevity lies not in the body itself, but in our gut microbes. We still have much to learn about this complex assemblage of bacteria, viruses, fungi and archaea, yet it turns out that people who achieve a healthy old age often have a distinctive gut flora. What鈥檚 more, we are finding ways to manipulate this world inside us. As strange as it seems, there is gathering evidence that we can increase our lifespan by changing our gut microbes.

Even before you were born, your gut microbiome 鈥� the collection of genes that comprise the microbiota 鈥� was developing. The uterus was assumed to be a sterile environment, but recent research suggests it , which are ingested by the growing fetus. At birth, a baby is gifted more gut microbes if it passes through the birth canal. Other early colonisers come from the environment and especially the diet. In another surprising discovery, researchers have found that breast milk also contains a microbiome of its own.

鈥淓ven before you were born, your gut microbiome was developing鈥�

A baby鈥檚 gut flora is dominated by bacteria that consume milk sugars, especially Lactobacillus and Bifidobacterium. Other bacteria start to replace these when infants begin to eat solids 鈥� although, if the diet contains milk-based foods, a small contingent of the original microbes will remain. Two groups are especially prevalent: Firmicutes, which like to feast on dietary fibre, and Bacteroidetes, which consume sugar and fat. The gut microbiome isn鈥檛 static, though. Over time, , partly as a result of the global fast-food culture. What鈥檚 more, . Although it recovers with time, it sometimes comes back in a less diverse form that, in studies on mice, have been linked with susceptibility to diabetes, inflammation and early death.

At puberty, there is another big change in gut flora, marked by a divergence between the sexes. This timing suggests the shift is influenced by sex hormones: the stable level of testosterone produced by boys and men seems to favour a relatively consistent mix of microbes in the gut, whereas oscillating oestrogen levels are thought to explain why girls and women have a more diverse and variable gut microbiome. This difference may have profound effects. There is a growing realisation that your gut microbes influence your brain and moods, and it has been suggested that why psychiatric conditions aren鈥檛 gender-neutral: why, for example, women are more likely to suffer from depression, whereas autism is far more common among boys and men.

Gender differences aside, microbial diversity appears to be a key factor in longevity and healthy ageing. Earlier this year, a team led by in Seattle reported a study of 9000 adults which found that people鈥檚 and unique with age. This trend continues in healthy people over 80, but not in less healthy individuals. The analysis revealed that a gut microbiome linked with healthy ageing contains fewer bacteria in the genus Bacteroides, a member of the Bacteroidetes, and more Akkermansia and Christensenella, bacteria associated with lower inflammation, better sugar and fat metabolism and a lean body type.

Hallmarks of longevity

These findings resonate with other recent research showing a link between a diverse gut microbiota and healthy ageing. For example, Korean villages characterised by the longevity of their inhabitants were found to have greater diversity in their gut flora and a higher ratio of Firmicutes to Bacteroidetes. Furthermore, the microbes of centenarians still living independently were more diverse than those living in care homes.

While we can now identify some hallmarks of a gut flora associated with healthy ageing, it isn鈥檛 yet clear how these microbes might extend a person鈥檚 lifespan and healthspan. One possibility is simply that microbial diversity increases the chances of your hosting beneficial microbes. , for instance, found that a healthy centenarian had a gut microbiome rich in Odoribacteraceae that feed on bile. Bile is produced by the liver and works as a kind of detergent, breaking down dietary fats so they can be absorbed. Most of it is then recycled. But Odoribacteraceae microbes convert some into secondary bile acids, which act as antibiotics against pathogens, including antibiotic-resistant ones, reducing the risk of infection.

The right balance of intestinal microbes might also help physically protect the ageing gut. A healthy gut flora is a resilient ecosystem that treats pathogens as invasive species and typically destroys them upon entry. However, pathogens can sometimes throw it out of balance and then damage the gut lining. That spells trouble because if gut microbes get into the bloodstream, the heart will pump them to every organ, resulting in damage and inflammation throughout the body. We run this risk any time we have an infection or food poisoning, so the longer we live, the greater the odds of this happening. .

Another clue comes from a Chinese centenarians which found that their gut flora seemed to enhance their ability to respond to inflammation. Inflammation is the immune system鈥檚 response to damage. It is always on a razor鈥檚 edge because it has to react swiftly to kill and mop up pathogens, but also needs to wind down rapidly to limit collateral damage of tissues, which then become inflamed. As we age, the immune system becomes less effective at achieving this balancing act. It isn鈥檛 yet known exactly how the right gut microbes might help reduce this age-related effect, known as inflammaging, but in recent years it has emerged that gut flora in the functioning and regulation of the immune system.

鈥淢icrobial diversity is a key factor in longevity and healthy ageing鈥�

Inflammation is at the root of many age-related conditions, including type 2 diabetes, heart disease, cancer and dementia. And with an unbalanced gut microbiota. But that doesn鈥檛 necessarily make gut microbes the cause of inflammation. A team at University College Cork in Ireland decided to test this link. , fed middle-aged mice a diet enriched with a prebiotic called inulin, a dietary fibre that increased levels of good bacteria including Akkermansia. They were interested in microglia, immune cells of the brain that become plump and mobile as a result of inflamm aging, potentially damaging nerve cells. , Cryan鈥檚 team revealed that after 14 weeks of the prebiotic, microglia shrunk and hunkered down and inflammation subsided.

the link between the gut flora and healthy ageing. This time, the team used faecal transplants to transfer the gut microbes of young mice into old ones. This had a similar effect on microglia and brain inflammation as in the previous study 鈥� and some other intriguing results. 鈥淚t brings about major changes in the biology of the ageing brain,鈥� says Dinan. These include changes in the hippocampus, a region crucial to memory processing and stress responses. In addition, the old mice were better at learning and remembering than they had been before the transplant. 鈥淔aecal transplantation from a young to an old animal has a rejuvenating impact,鈥� says Dinan.

鈥淭his shows conclusively that the microbiota is important for healthy brain ageing,鈥� says Cryan. Better yet, it suggests that we might be able to manipulate the human gut microbiome to reduce or even reverse the ravages of time. 鈥淭hese studies point toward a future where there will be a focus on microbiota-targeted interventions that will promote optimum gut health and immunity in order to keep the brain young and healthy,鈥� he says. In fact, the whole body could benefit. 鈥淚 believe that gut microbiota changes are a major factor in generating frailty,鈥� says Dinan.

But we mustn鈥檛 get carried away. Not all mouse studies translate directly to humans, says gastroenterologist , Los Angeles. 鈥淢any factors explain this 鈥榣ost in translation鈥� phenomenon, including the dramatic brain differences between mice and humans.鈥� He also points out that transplanted microbes usually can鈥檛 settle permanently inside the gut ecosystem of another individual because of resistance from the resident flora.

Take back control

鈥淲e need to be careful about overselling studies in animals,鈥� agrees Cryan. However, he points to other research showing that faecal transplants cause rejuvenation in worms, flies and fish too. Conversely, faecal matter transferred from old animals to young ones has been shown to . Although we currently lack such cause-and-effect studies in humans, Cryan and his colleagues have shown that rats that receive faeces from humans with depression , demonstrating at least some cross-species commonality of the microbiota.

鈥淲e may be able to manipulate our microbiome to reverse ageing鈥�

Despite the potential benefits, many people would baulk at the prospect of a faecal transplant. Luckily, there is an alternative. 鈥淪everal studies give credence to the ability to change one鈥檚 microbiota by diet,鈥� says Cryan. 鈥淗opefully, this research will provide an impetus to food companies to develop products that will stave off frailty and cognitive decline in the elderly,鈥� says Dinan. Already there are some hints as to what we should be eating to cultivate a youthful microbiome (see 鈥�Rejuvenate your gut microbes鈥�). 鈥淧ersonally, I have become much more aware of the amount of fibre I take, especially plant fibres,鈥� says Cryan. Dinan thinks the key to maintaining microbial diversity as we age is a varied diet including plenty of vegetables and fruit together with fermented foods and fish.

Billions of dollars are spent each year on diseases of ageing, typically with little recognition of the key role played by the gut flora. Of course, multiple factors affect ageing, so cultivating the correct microbiota is unlikely to be the elixir of youth. But it does hold the promise that we can live longer, healthier lives 鈥� not merely adding years to our lives, but perhaps also some life to those years.