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.
Sadly I’m finding that gut bacteria have powerful effects. At 64 M I had been eating up to 150 grams a sugar a day in smoothies, dynamite coffee, dried fruit, ect.. I was amazed how my system processed it. I tested my morning glucose every morning and was averaging 90. Last August I tried a product I had tried previously without any bad effects 10 yr ago. It is chlorine dioxide, MMS. It has helped a lot of people and has cured over 10,000 malaria patients in 4 hours. It works like an antibiotic. It seems to to destroy many toxins, bacteria, viruses and heavy metals. I took a suggested dosage for 5 days. To help clean me out and maybe get rid of the virus I might of got from the 1960 polio shots that were had a monkey virus and several of my family were getting rare blood cancers related to this virus. So anyway the very next day after my 1st dose my blood sugar shot up to 110 and since then I can’t eat the amount of sugar I had. I highly suspect I wiped some sort of beneficial bacteria’s that processed sugars for my body. I would love to find that strain again. I’m open to fecal transplants and it sounds exciting to try it from some young healthy living person. Maybe from the likes of the Amish or some remote tribe. Any suggestions would be helpful. I’ve been drinking water kefer made with sugar thinking that strain of bacteria would infect y gut but still no luck.
Maybe proper gut flora keeps one in better health thus adding years of life.
Just a quick clarification.
“But those that received transplants from younger fish lived 22 weeks (green).”
Is it 22 weeks or 28 weeks?
I think this line should read “But those that received transplants from younger fish lived 28 weeks (green).
22 weeks was the median lifespan, 28 was the maximum.
yeah I wouldnt get too excited unless they repeat it with C57 mice
It’s interesting that antibiotic treatment alone, without subsequent FMT, also prolonged lifespan by 14%:
“To test whether resetting a young-like GM in middle age could impact aging and affect life span, we treated middle-age fish (9.5 week-old) overnight with an antibiotic cocktail (VMNA, i.e. vancomycin, metronidazole, neomycin, ampicillin) (Figure 4A, Figure S4A and Materials and Methods).
The antibiotic treatment significantly reduced gut microbial content compared to pre-treatment levels (Figure S4B). Antibiotic-treated fish were then exposed for 12 hours to the following conditions: six-week-old donor fish gut content (Ymt), 9.5-week-old fish gut content (Omt) and sham (Abx) (Figure 4A and Figure S4A).
After antibiotic treatment and 12-hour acute gut recolonization, fish were reintroduced in the water recirculation system in individual tanks and were subjected to regular feeding (Materials and Methods). Their survival under the different experimental conditions was then scored (Table S3A). Ymt fish underwent dramatic life span prolongation compared to three control groups, which received:
(i) antibiotic-only (Abx) (21% life span increase in median life span, Logrank test p value = 5.89E-05),
(ii) antibiotics and same-age (i.e. 9.5 weeks) gut content (Omt) (41% increase in median life span, Logrank test p value = 5.08E-06), or
(iii) no-treatment (wt) (37% increase in median life span, Logrank test p value = 4.04E-09) (Figure 4B and Figure S4C-F).
Noteworthy, acute antibiotic treatment alone was sufficient to increase fish life span compared to the wt group (14% median life span increase, Logrank test p value = 0.0129) (Figure 4B). However, Omt fish did not live longer than the control, wt group (Figure 4B). Since Abx outlived Omt and wild-type fish, while Ymt fish outlived Abx fish, it is plausible that middle-age GM composition might be primed to induce damage in the host and that its removal is therefore beneficial.
However, as the recolonization of middle-age individuals with young fish gut content after antibiotic treatment prolongs life span even more, this implies that young GM, per se, has beneficial effects on host physiology that are additive to the effects of the antibiotic treatment.”
This must be a typo or I am misunderstanding somethng here. The ‘placebo’ group of fish with no treatment are reported as having a 37% increase in median life span.
“(iii) no-treatment (wt) (37% increase in median life span”
Could you clarify this please ?
Bill – I don’t know where you’re getting this. The 37% (or 41% depending how you figure) is for the group that got transplanted microbiomes from young fish. There was also a smaller increase in lifespan from antibiotic alone.
From Yuri Delgin’s comment above, Josh :
“(i) antibiotic-only (Abx) (21% life span increase in median life span, Logrank test p value = 5.89E-05),
(ii) antibiotics and same-age (i.e. 9.5 weeks) gut content (Omt) (41% increase in median life span, Logrank test p value = 5.08E-06), or
(iii) no-treatment (wt) (37% increase in median life span, Logrank test p value = 4.04E-09) (Figure 4B and Figure S4C-F). ”
Or was this comment not accurate ?
Yuri’s comment was quoted directly from the preprint and it was accurate, but the wording is confusing. Look at the beginning, before (i), (ii) and (iii). The meaning is that the Ymt fish lived 21% longer than Abx and 41% longer than Omt.
I’m wondering if there is a way we can put this to practical use while the medical community takes the years it will take to turn it into an approved treatment.
Do we have any indications that things like OTC probiotics are useful? I just don’t think I have the fortitude for DIY fecal transplant.
you could try colostrum
When I change my grandchilds dipers I come in contact with her young microbiome. Maybe we are genetically programmed in such a way that taking care of young people makes us useful for the group and makes us live longer. ??
That’s my kind of thinking.
Which raises the question, where do the micro-flora in the microbiome of a newly born infant come from ?
Mother’s milk, or from the general external environment ?
I don’t know of any parents who set out to encourage the development of their infant’s microbiome.
You’re forgetting that most infants are exposed to a couple of other specific environments — the mother’s brith canal, for vaginal births, or the skin, for ceasarean sections. There have been plenty of studies showing this, and experiments with swabbing c-section newborns with their mothers’ vaginal bacteria.
Yes the environment, the first inoculation occurs as the baby passes through the birth canal and is colonised by the mothers vaginal flora. This is why it is practise to colonise the baby born via c section with the mothers vaginal discharge via helpful health care workers fingers. As it was found there were differences in micro biomes of c section v natural born babies.
Thanks for that Nicholas. Fills in a gap in my thinking
Maybe Rob Knight could add a question about this when people send in fecal samples?
Actually, as I recall, eating small fish, guts and all was associated with longevity in some Scandinavian population. Does antibiotic usage increase lifespan in mammals as it does in killifish? That might give us a clue. In the worm, C. elegans, it is assumed that bacteria in its gut (hard to avoid, as it eats bacteria) are a principle cause of its death as infiltration by food bacteria are the proximate cause of death. That is assumed to be caused by the death of intestinal cells (there are 20) that allow the bacteria to enter. That death is promoted by pathogenic bacteria, and significantly delayed with killed bacteria are fed to the worms. Yet I don’t know of any ill effects, or extension of lifespan with mammals raised in germ-free (gnotobiotic) environments – so if our (mammals) gut bacteria determined lifespan….
In a paper, “You are what you Host: Microbiome modulation of the Aging Process” Heintz, 2014, they gave many very interesting examples: Metformin robustly increased lifespan C.elegans (worms) but only if they had bacteria in gut. Metformin increased AMPK, this inhibits folate, this decreased bacteria making Methionine and as everybody knows, methionine is main amino acids stimulating TOR.
In another study, involving C.elegans (poor little worms can’t make Nitric oxide as lack NO synthase.) Give bacteria that make a lot of Nitric oxide and increase lifespan. Of course, angiotensin II blockers also increase nitric oxide synthase and increase lifespan.
Two studies showing gut bacteria increasing lifespan and came down to the “usual suspects”: TOR suppression, metformin increasing AMPK or NO oxide increase (all roads lead to Rome)
I’ve been wondering about this article Josh. Wondering how to discover if this life extending process is already taking place..
And I have just thought of one : nurses ( and maybe other medical staff ) in pediatric departments of hospitals are constantly handing young children and ( incidentally ) also handling feces of their patients. They are also handling anti-biotics when these patients need such treatments.
I wonder what a longevity study of staff at such a pediatric dpt. would throw up.
I have a personal interest in this : my wife was for 13 years a nurse in such a hospital pediatrics dept. She does not look anything like her chronological age of 41.
Have you seen this article on Ars:
Not just young blood, but umbilical cord plasma it seems helps in mice. Hopefully we can try this in humans.
Also, could you please check your spam filter – I think one of my comments may have ended up in there.
I believe that microbiome transplant is the next era of medicine, an era that will replace the pasteurian medicine, so focused only on pathogenic bacteria.
Poop transplant means to replace the whole microbe ecosystem from a presumably healthy donor to a person with huge disfunctionalities in his/her intestinal ecology.
I think that the magnitutined of the poop transplant is like taking the operating system software from the “hardware” of someone and put it on the other person’s “hardware”. You may take many good things (i.e. software apps), but also lot of disese or predisiposition to many disease, depending of the donor’s profile.
For me, when I reffer to anti-aging strategy, I mean “prolonging of health”, to be healthy and full of vitality at an old age. Anti-aging concept should not be similar with life prolonging or life extension, should be just about preserving the healthy and the characteristics of the younger persons.
So, I like very much the article, but I don’t want to be obsessed by the extension of life, I would rather preffer to discover the biology of the healthy people, to be free of disease. And that is one of the most powerful feature of microbiome manipulation, who can be the most important epigenetic control system of the human body. We have such great results, why bother our mind only with life extension when we have such promising results for human health?
P.S. a very nice video abouth korean “poo wine”, suggesting that hundreds of years ago, lay people knew how to get a huge help from poop, in case of serious accidents like falling from the trees.
Could our actual knowledge explain such possible benefits of that wine for bone fractures and rapid healing at a better rate than in a modern hospital from our times?
Hi Josh, there i an interesting news report here
about faecal transplants causing side affects.
Back in the days of Metchnikov folks thought intestinal bacteria were the cause of aging and death. Metchnikov himself ate yogurt in an attempt to replace his intestinal bacteria (didn’t work). Since then animals have been raised in germ-free environments – but don’t seem to live abnormal ages. It would seem from these results, or so we concluded long ago, that the effects of intestinal bacterial are minor players in aging. Now that may or may not be the same in fish.