Henry? Are you sure this is the way to the breakfast buffet? You know I can’t poop without my morning yogurt!

 

Today I want to write about a couple of interesting studies linking probiotics to increased longevity in animals. As always, what’s true for another species may not hold true for us, but I found these papers intriguing nonetheless and thought I would share.

The suggested connection between probiotics and longevity is nothing new. For anyone old enough to remember, there was a famous Dannon yogurt ad that aired in the United States in the 1970s. It purported to show some very, very old folks going about their farm work in Soviet Georgia.

What got me thinking about this topic was a recent paper that studied various probiotic strains fed to Caenorhabditis elegans (C. elegans) for effects on longevity. (1) C. elegans, for those that don’t know, is a worm.

No doubt some of you are wondering what the hell a worm could teach us about humans. You’d be surprised.

In 1963, South African biologist Dr. Sydney Brenner introduced the study of this worm to the field of developmental biology and neurology. There are a number of reasons why it’s proven highly useful in investigating genetics and human health.

These little buggers contain exactly 959 cells and were the first organisms whose genome was completely mapped. It’s transparent so it makes it super easy to track cell development. Many of its genes are shared by humans, and it has many of the same insulin-signaling pathways we do.

Studying the effects of oxidative stress and its relation to aging has been a favorite subject of study for researchers using this animal model as this worm has a short three-week lifespan making any increase in longevity readily apparent. And it is oxidative stress, after all, that underlies so many diseases we associate with aging like cancer, cardiovascular disease and age-related macular degeneration.

So getting back to this study, did any particular probiotic strain inhibit oxidative stress in C. elegans and extend its lifespan? The answer, my faithful readers, is yes.

Worms were fed a large assortment of various probiotic bacteria and subjected to oxidative stress induced by adding hydrogen peroxide to their cozy little Petri dishes. 62 Lactobacillus, nine Streptococcus and six Bifidobacterium species were investigated.

None of the Streptococcus or Bifidobacterium conferred any protection against oxidative stress or resulted in increased lifespan in our nematodes. That was not the case for Lactobacillus.

Lactobacillus caseiLactobacillus jonhsonii and Lactobacillus rhamnosus were found to reduce cellular stress in these animals. After further evaluation, only a particular type of L. rhamnosus, CNCM I-3690, proved significantly effective and became the probiotic these researchers chose to focus on.

Further tests revealed that this bacterium affected the expression of 1,278 genes in the worms who fed on it. That’s some powerful probiotic!

The upshot to all this was that this particular bacterial strain was able to extend lifespan in these worms by 20%. It was also capable of influencing insulin signaling and fat metabolism.

Now I’m sure you’d all agree that while this is all very interesting, it’s a bit of a stretch to jump to conclusions about human longevity based on one probiotic used in a worm. Unless you’re a blinkered researcher at the Cleveland Clinic, validation of the longevity-increasing effects of this or any other probiotic must be conducted in higher animals, especially humans.

That said, this isn’t the only paper to hint at the possible “fountain-of-youth” potential of beneficial gut flora. A second study done in mice, and conducted in Japan, offers some fascinating insights into how gut flora may retard the inevitable ravages of growing old. (2)

What piqued the curiosity of these Japanese scientists were several well-known facts. First, the lifespan of germ-free rodents is longer than for conventional rodents. (3) Now I don’t recommend running around with a sterile gut to extend your life, far from it. Nevertheless, this does suggest that at least in lab animals anyway, intestinal gut flora has something to do with longevity.

Another known fact is that elderly human populations undergo quite dramatic changes in gut flora composition reflected by less gut flora diversity and a shift in bacterial types. (4) Older people are also far more susceptible to endotoxemia than their younger counterparts. Finally, shifts in gut flora composition impact immunity for the worse as I wrote about here.

So these researchers set out to test whether probiotic supplementation would increase lifespan in mice by feeding them bifidobacteria, specifically Bifidobacterium lactis (LKM512).

Middle-aged, ten-month old retired female mice (retired, that is, from their job of pumping out babies) were studied until they died. As an aside, the scientists noted that females had to be used because males, known to have violent tempers and continually fight with each other, would have introduced stress into the equation and affected the results.

So what happened? Well, dudettes given B. lactis lived longer than their sorority mates who just ate regular-old rodent chow and marched ever so glumly into the light at a quicker pace:

 

Courtesy: Longevity in Mice Is Promoted by Probiotic-Induced Suppression of Colonic Senescence Dependent on Upregulation of Gut Bacterial Polyamine Production

Courtesy: Longevity in Mice Is Promoted by Probiotic-Induced Suppression of Colonic Senescence Dependent on Upregulation of Gut Bacterial Polyamine Production

 

The red line represents mice fed the LKM512 strain of B. lactis. Survival rates began diverging significantly between weeks 15 and 20. The scientists noted that these differences could not be accounted for by caloric restriction, a method used in the past to extend lifespan. As the following chart shows, there were no differences in weight between either group:

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So much for weight control being the be all and end all of a healthy and long life!

 

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These are photos of some of our aging ladies at 20 months of age. If you haven’t figured it out already, the probiotic-fed mouse is pictured on the left looking healthy in her shiny coat and ready for a night out on the town with a well-behaved and chivalrous Mickey. Very fetching don’t you think?

The second and third photos are the control animals. The female in the middle has skin ulcers, and her friend on the right has a protruding tumor. They’d need some seriously good Estee Lauder makeup to cover that up!

 

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These two charts illustrate the total occurrence of tumors and skin ulcers in both groups. As seen in graph D, there was no tumor incidence in the LKM512 probiotic group. Skin ulcers were also far fewer in number in this group.

 

ColonYikes! Here are some images of mice colon harvested from a couple of the participants after they left this world for that great rodent wheel in the sky.

The colon on the top is from a probiotic-fed mouse. Looks pretty pink and healthy to me. Not so the bottom one.

Now, how effective do you think the colon from the control animal was at keeping bacterial pathogens and gut contents from crossing over into systemic circulation? My hunch is not very, but why guess when we have proof right here:

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This displays colon permeability at 25 weeks of age after ingestion and urinary excretion of a sugar solution containing lactulose and rhamnose. Colonic permeability was significantly elevated in the control group.

Hmmm, I think there was some serious translocating of lipopolysaccharides across that gut wall, don’t you? As confirmation of this, levels of the inflammatory cytokine tumor necrosis factor alpha were significantly higher in the control group:

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These results were further confirmed by increased gene expression for this particular family of cytokines in the non-probiotic group:

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The yellow bar represents inflammatory cytokine expression in the young. While failing to reach comparable levels as seen in the young-ins, the addition of B. lactis was enough to roll-back the clock, so to speak, in this group.

As many of you have no doubt guessed, the reason for the reduced inflammatory markers in the probiotic group was due to the maintenance of gut wall integrity:

 

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Both Muc2 and Muc3 are genes that express mucin production from goblet cells in the colon. As I’ve mentioned before, the mucus layer of the gastrointestinal tract is an extremely important physical barrier against the luminal contents of your GI tract. Its diminution, for whatever reason, always results in increased intestinal permeability and inflammation.

B. lactis was not only able to increase mucin expression in these mice, it actually raised levels of Muc3 to a level higher than that seen in the young. Also higher was gene expression for two tight-junction proteins, occludin and zona occludens protein 1 (ZO-1), once again attesting to the well-known effects of probiotics to strengthen gut-barrier defenses.

It’s a shame no analysis of mouse small intestine was included in this paper. I imagine that the condition of this part of the digestive tract in the control group was similarly dire.

In about 50% of the control mice who survived until week 45, water content in feces was consistently lower. In contrast, the probiotic mice had 60% to 70% water content in their poop. As low water content is a symptom of constipation (the longer formed feces stays in the colon, the drier it gets), the control mice were experiencing the same symptoms many of the elderly (and not so elderly) suffer from.

Bifidobacteria administration also altered other gut bacteria by increasing counts of Prevotella while decreasing Clostidium, Enterobacteria and Enterococcus. Lower counts of these latter two families of bacteria are typical in the young.

 

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These two charts graph levels of the polyamines spermidine and spermine. Levels were higher in the probiotic group.

Polyamines (PAs) like spermine, putrescine and spermidine are organic compounds containing two or more amino groups. They are required for cell growth, cell differentiation and the synthesis of DNA, RNA and proteins.

Back in the 70s, PAs were implicated in cancer development, and many researchers at the time considered them carcinogens. However, most of these early studies only examined how PAs influenced cells in existing tumors, not how they affected normal cellular function. Since then, research has demonstrated that these compounds do not promote cancer.

On the contrary, they appear to have anti-inflammatory effects by inhibiting cytokine production in immune cells. They also are involved in maintaining intestinal gut wall integrity. (5)

PAs are scavengers of free radicals, increase tolerance to acids and regulate genetic stress responses. They are produced by beneficial gut flora and inhibit gene mutations or mutagenicity. (6) (7)

This ability to counteract gene mutations is important as this process is a necessary precondition for cancer development.

 

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This graphs levels of mutagenicity between groups. The addition of spermine (S9) to rodent chow inhibited this effect in both groups with most improvement seen in the bifidobacteria group.

Now what’s intriguing about this increase in spermine levels, is that according to this research group, B. lactis does not have the necessary pathways to synthesis it. I suspect that what happened here was that supplementing with this probiotic changed environmental conditions in the colons of these mice which facilitated the blooming of other beneficial strains capable of producing these anti-inflammatory compounds.

And speaking of inflammation and oxidative stress, this chart graphs levels of urinary haptoglobin, a measure of intestinal inflammation:

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Again, we see confirmation of what we saw in those earlier photos of harvested colon.

There is one other interesting point about this study I want to mention before I wrap things up. Autophagy, a cellular house-keeping process, was up-regulated in the mice fed B. lactis. Autophagy is a process that disposes or recycles cellular material that is unnecessary or dysfunctional.

This process also degrades and disposes of bacteria or viruses hiding out in cells to escape immune detection and destruction. Autophagy is activated by fasting and is the reason short-term, intermittent fasting can be highly beneficial to health. Suffice it to say that this mechanism is immensely important in keeping cells and us healthy as we age.

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I’ll leave you with this flow chart illustrating the mechanisms these Japanese researchers believe were at work in extending the lifespan of these mice. It’s pretty self-explanatory given what I’ve already covered. The only aspect of this chart that I didn’t talk about was gut flora’s impact on the immune complexes of the small intestine. However, as I covered that topic here there’s no reason to go into it again.

So are the results of these two studies applicable to humans? That’s a good question and one I can’t honestly answer in the affirmative. It’s certainly plausible given the many overlapping biological processes we share with both C. elegans and mice. Nevertheless, any level of certainty will only come as a result of extensive study in humans.

In the meantime, I’ll be continuing my habit of eating fermented food and consuming probiotics and prebiotics. Who knows, maybe if I reach 100 I’ll be chopping wood like that old geezer in the Dannon ad.

 

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