A game-changing result this week from the laboratory of Dario Valenzano (Max Planck Inst). A single treatment of antibiotics in middle-aged fish followed by transplant of gut bacteria from young fish resulted in extension of mean lifespan by 41%, max lifespan by 30%. Treated fish remained active at ages where untreated fish were slowing down. I say “game-changing” because up until now the gut microbiome has been a fascinating but peripheral discipline in the study of health. This single study raises the possibility that understanding the microbiome as a system could be a powerful new avenue toward health and longevity. [Preprint of Journal Article] [News Article in Nature]
There have been intriguing hints that the ecosystem of bacteria in the intestine have major effects on mood, on wellbeing and on disease. But there has been no way to get a handle on the causal variables involved. The mix of gut bacteria varies widely from person to person, depending on diet, genetics, social contacts and environment. Thousands of species of commensal bacteria form a constantly-shifting ecosystem.
Who is working for whom? Do we think of the microbiome as a parasitic colony that manipulates the host’s biochemistry for its own ends? or as as managed by the host (that’s your body)?
I’ve seen articles about the former proposition, but I’m skeptical because I can’t imagine an evolutionary mechanism. It seems that these thousands of bacterial species don’t stay together from one individual to another. They are not readily transmitted (in nature) as a group, except perhaps from mother to infant. And if there is natural selection on the microbiome ecosystem as a whole, it must be for something that maximmizes opportunities for transmission. It’s easier to imagine individual species, specialized to living in the human gut, that learn to gain an advantage over other species by manipulating the human metabolism in ways that favor that particular species over its rivals.
The latter possibility — that our immune systems have a handle on who may live and who may die in our intestines — is both easier to conceptualize and more promising. It raises the possibility that part of the way the body regulates its own metabolism is indirectly, via bacterial secretions. I have advocated the position that aging, like development, unfolds on under central regulation. The medium for instructing the body in age-appropriate behavior is likely to be signal molecules in the blood. Could it be that some of those signal molecules originate not in our brains or our endocrine systems, but in the bacterial reservoirs of our guts?
Eleven years ago, Valenzano introduced African Killifish (Nothobranchius furzeri) as a new lab model for study of aging. Evolved for a life cycle in short-lived African ponds that dry up after a brief rainy season, they have one of the shortest life cycles of any vertebrate. As a grad student, Valenzano demonstrated substantial lifespan increases adding resveratrol to the fish’s water.
Loss of diversity is one of the ways that the gut microbiome is known to change with age, both in humans and in fish.
There has been a great deal of study and writing over the last decade, but so far only one clinical intervention, plus this guidance for the general public: a high fiber diet encourages beneficial bacteria.
Four years ago, Michael Pollan wrote about microbiomes for the NYTimes magazine. Mark Lyte has connected the microbiome to psychology: depression, anxiety, maybe autism (popular article in the NYTimes two years ago). Turns out that gut bacteria produce some powerful hormonal signals that go right into our bloodstreams and are decoded by our brains.
Gut microbiomes vary widely from one individual to the next, but, strikingly, different sets of bacteria are able to perform similar services. The bacterial gene profiles in healthy individuals don’t vary nearly so much as the specific component bacterial do [ref].
In hospitals and in people treated with antibiotics, a new disease has arisen in recent years characterized by intestinal infection with a bacterium called Clostridium difficile. Symptoms include chronic diarrhea, stomach cramps ad nausea. The most effective treatment developed to date (90% cure) is a transplant of fecal matter from a healthy individual. This can be accomplished with enema, but there is some indication that it is more effective if the fecal matter is introduced from the other end, into the stomach, and this has inspired freezing and encapsulation technologies to get around the disgust factor.
Beyond this one clinical application, there is speculation about treating other intestinal disorders with fecal transplants, including ulcerative colitis, inflammatory bowel, and Crohn’s disease, extending to Type 2 diabetes, obesity, and even flatulence. Having the right mix of microbes is important for triglycerides, glucose regulation, and the insulin metabolism [ref]. There have been multiple studies in rodents and one (successful!) study in humans of fecal transplant to treat diabetes.
Many of the diseases of old age, (arthritis in particular), are connected to autoimmunity. Intriguing, if speculative, work has been done connecting gut microbiomes to autoimmunity [review]. Maybe the ubiquity of antibiotics in the developed world has led to a hyper-sensitivity, connected to increases in asthma, lupus, type 1 diabetes, possibly autism. Maybe the mechanism by which this has hit us is through our gut microbiomes.
Nearly two decades ago, scientists put forth a concept called the ‘hygiene hypothesis’. According to this hypothesis, an improvement in personal hygiene as observed in the developed countries has led to an increase in the risk of allergic and autoimmune disease [ref]. Increase in incidences of various inflammatory and autoimmune diseases like inflammatory bowel disease (IBD), asthma, type 1 diabetes (T1D), and rheumatoid arthritis in the developed countries support this concept.
It is suggested that gut microbiomes are connected to immune function more generally. Both in mice and in humans, resistance to sinus and bronchial, including pneumonia, has been demonstrated with the right kind of gut microbiota.
Gut microbiomes in supercentennarians have been analyzed, and differences from average people have been distinguished as specific bacterial familes that seem to be associated with longevity [ref].
Summary of the Killifish Results
Turquoise Killifish normally live 16 weeks (black line). At 9½ weeks, fish were treated with antibiotics to kill their gut microbiota. Those that received no transplant at all lived a little longer (purple line), and those that received gut biota from same-age fish (9 weeks) lived insignificantly longer (red line). But those that received transplants from younger fish lived 22 weeks (green).
Fish that received young transplants were more active and showed more exploratory behavior later in life. The authors performed proteome analysis on the microbiome as a whole, and found gene expression that suggested a stronger resistance to infections in the young-transplanted fish.
Young fish transplanted with the microbiota of old fish quickly recovered their youthful biodiversity and their lifespans were unaffected.
Authors note that
- Microbiomes of killifish are comparable in complexity to mammals, including humans.
- Although short-lived, killifish suffer many of the same declines as humans in old age, including neurodegeneration, muscle loss, and increased risk of cancer, heart disease, and diabetes.
- The four most abundant phyla of gut bacteria in the killifish are the same four that predominate in human intestines.
- Like humans, fish lose diversity of their gut microbiomes with age. The bacteria lost with age in fish and in humans include those that digest complex carbohydrates.
- Fish in the lab have comparable lifetimes and comparable gut microbiomes to fish in the wild.
- Microbiomes transplanted at 9 weeks persisted, and were mostly intact at the end of the fishes’ lives 10-15 weeks later.
The authors were able to characterize explicitly the network of bacteria associated with youth (and also with enhanced longevity), naming the specific species that seemed most important. Some of the most important species were able to digest carbohydrates and ferment them into short-chained fatty acids, which are known to be anti-inflammatory.
In their “discussion” section, the authors suggest that the gut microbiome may be managed by the host (fish)’s immune system, and that management becomes lax in old age, allowing some commensal bacteria to disappear and more pathogenic types to predominate. They go on to speculate that perhaps there is a feedback loop between the immune system and the gut microbiome that is activated with age: poorer management of the gut ecosystem by the host immune system results in takeover by bacteria that further weaken the host immune system, leading to a vicious circle.
Remember that life extension percentages in short-lived species are always diluted when applied to long-lived species. Sometimes they disappear altogether. Resveratrol extends life of killifish by 60%, but failed to extend lifespan in most mice.
The microbiome transfer in killifish was done at 9 weeks of age, and it lasted the rest of their lives, which was another 8-15 weeks. People live much longer, and the microbiome transplants would probably have to be repeated and maintained to have an effect.
Just in the last decade, the importance of the microbiome for many aspects of health has been uncovered. But the microbial ecosystem has been considered too diverse, too irregular, too complex for study with the reductionist paradigms that Western science is so good at. Transplanting entire microbiomes has proved to be quite feasible, however, if not to everyone’s taste.
If these results hold up (it looks to me like a very careful experiment, and Valenzano has an impeccable reputation), there is now strong motivation for studying microbiome transplants en masse, and this will certainly be accompanied by proteomic analysis. It’s hard for me to imagine that life extension in humans will prove to be so simple as in killifish, but I wouldn’t be surprised if a host of benefits appear from youthifying our intestinal flora.
The intriguing possibility is that in addition to metabolic self-regulation by the rich network of hormones, RNAs and signal molecules, the body is also managing its metabolism by managing the bacterial mix in the intestine (and the chemicals they produce, many of which are bio-active). A more disturbing possibility is that the gut’s microbial ecosystem manipulates the body for its own benefit; but I’d bet against this because it seems implausible from an evolutionary perspective.