Biological aging (senescence) is the deterioration of biological function over time that is seen in most lifeforms. It ultimately claims all of us – nobody can elude entropy (the universe’s perpetual tendency towards disorder) forever. But is aging truly inevitable?

More and more research is being dedicated to understanding the aging process, and whether it can be delayed or even reversed. (Check out my podcast with Aubrey de Grey on this subject here!) One growing area of interest is the gut microbiome, the vast and diverse community of microorganisms that occupy our guts. We now recognize that gut microbes play a critical role in many aspects of their host’s physiology, including the immune system, metabolism, and even the brain. Molecular analyses have shown that the gut microbiota undergo characteristic changes over time. Aging subjects generally more pro-inflammatory microbes, a reduction in beneficial metabolites of gut microbes, and compromised integrity of the epithelial lining, all of which may be associated with greater risk of chronic disease. So, could maintaining a youthful microbiome help you to live longer and better?

There is some tantalizing evidence suggesting that this may be the case. A study of more than 1,000 extremely healthy individuals, ranging in age from 3 to over 100 years, found that the composition of the gut microbiota in healthy elderly folks was almost the same as that of healthy 30-year-olds.

An array of factors seem to influence how many and what kind of microbes you have: your genes, environment, exercise, sleep, and so on. But the biggest determinant of the composition of the gut microbiome might be what you eat, which is why dietary interventions seem like perhaps the most promising approach to improving gut health. 

One way to modify the microbial community is to consume live microbial cultures, probiotics. But just installing good bacteria usually isn’t enough – you need to also fuel the growth of this flora with prebiotics, which include some dietary fibers, resistant starches, and polyphenols. Importantly, the fermentation of these compounds generates health-promoting metabolites like short-chain fatty acids and other bioactive compounds, which play roles in energy regulation, inflammation, immune responses, and other chemical reactions that are relevant to the aging process.

With all of this said, could consuming a probiotics and prebiotics together (as a “synbiotic“) help make sure that you have an abundance of the right bugs, shielding your body and mind from the aging process? That brings me to our guest today.

 

GUEST

In this episode of humanOS Radio, I speak with Susan Westfall. Susan has a long-standing interest in natural products derived from traditional Indian (Ayurvedic) medicine and has been using her expertise in biochemistry to investigate potential biomedical applications for these plant extracts.

She is presently a post-doctoral fellow at the Icahn School of Medicine at Mount Sinai, where she is investigating the combined impact of Ayurvedic herbs and probiotics on the gut-brain axis in the context of neurodegenerative disease and metabolic syndrome.

Previously, she was a Ph.D. student at McGill University, where she and colleagues had discovered that a novel synbiotic formulation beneficially affected the gut microbiota and resulted in a variety of health effects in fruit flies. 

What exactly was in this concoction?

The synbiotic formulation that they tested combined three metabolically active probiotics that naturally occur in fermented foods, including:

• • Lactobacillus plantarum NCIMB 8826 (Lp8826)
  • Lactobacillus fermentum NCIMB 5221 (Lf5221)
  • Bifidobacteria longum spp. infantis NCIMB 702255 (Bi702255)

The prebiotic incorporated in this combo was Triphala, a poly-herbal formulation that has been used in Ayruveda as a cornerstone treatment for gastrointestinal disorders. Triphala is composed of equal quantities of Emblica officinalis (amalaki), Terminalia chebula (haritaki), and Terminalia belerica (bibhitaki).

You might be skeptical of the value of an ancient folk remedy like Triphala, and rightfully so. But phytochemical analyses have revealed that Triphala is rich in bioactive compounds, and in vitro studies suggest that Triphala can modify the composition of the microbiota, increasing the relative abundance of beneficial strains.

More recently, Westfall and colleagues at the Prakash lab conducted a study to explore how this combination of probiotics and Triphala affects the lifespans and healthspans of fruit flies. Let’s quickly look at what they did.

 

STUDY

Male fruit flies were divided into groups and assigned the following diets:

1. Control (normal diet)
2. Supplemental Lactobacillus plantarum
3. Supplemental Lactobacillus fermentum
4. Supplemental Bifidobacteria longum spp. infantis
5. Supplemental probiotic formulation (all three probiotic strains)
6. Supplemental prebiotic (0.5% Triphala)
7. Supplemental synbiotic formulation (probiotics plus Triphala)

The probiotics and Triphala had a wide range of effects on the physiology of the insects. But perhaps most impressive, at least at face value, was the effect on longevity.

The control group only lived 40 days. Both the probiotics and the Triphala extended the lifespan of the fruit flies. But the synbiotic had the largest effect: Insects fed the combination of probiotics plus Triphala lived on average 66 days, a remarkable 60% increase in longevity. Wow!

A combination of probiotics and the Ayurvedic supplement Triphala extended lifespan of fruit flies by 60%! Click To Tweet

When the researchers compared the various metabolic, inflammatory, and oxidative stress markers in the flies, it becomes clear why the synbiotic group enjoyed better vitality and longevity.

As they got older, the synbiotic group weighed less than controls and had lower glucose and triglyceride levels. The combination of probiotics and Triphala had synergistic actions on many of the major mechanisms of aging, most obviously in markers of insulin resistance, inflammation, and oxidative stress, some of which remained stable or even improved over the course of the study. Almost as though these flies were drinking from the fountain of youth.

Exciting results, but these are, of course, flies. Do they really apply to us?

Admittedly, one can imagine that the effects would likely not be as pronounced in humans. Intestinal function appears to be an unusually important determinant of degeneration and lifespan in flies, arguably more so than in mammals. However, some recent trials have started investigating the effects of synbiotic supplementation in humans, with results that parallel what was found in this study of flies. For instance, prediabetic adults who were given synbiotics had significant decreases in HbA1c, fasting blood glucose, and insulin resistance compared to placebo.

This study adds to a growing body of evidence suggesting that feeding the gut microbiota – and cultivating the right microorganisms – could have wide-ranging effects on lifespan and, more importantly, healthspan. To learn more about this research and its possible implications, check out the interview!

 

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YOUTUBE

 

SUPPORT

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TRANSCRIPT

Dan Pardi:	00:07	Susan Westfall, welcome to Human OS Radio.
Susan Westfall:	00:10	Thank you for having me, Dan.
Dan Pardi:	00:11	You are the lead author of a study just published in the May edition of the Nature journal, Scientific Reports and titled Longevity Extension in Drosophila or Fruit Flies Through Gut Brain Communication, and I am so pleased to have you on the show to discuss this. Before we get into the details of your current study though, I would love to discuss your previous work that led to the hypotheses that this current paper explored. So to begin, tell us about how your interest in the microbiome and aging began.
Susan Westfall:	00:39	Well, this whole idea came from a lot of different people putting their heads together, actually. It started with the corresponding author on the paper, Dr. Jayprakash he has a background in the gut microbiota, so I met with him and we put together my interest in studying herbals. Especially herbals from India or [inaudible 00:00:58] and his idea of putting together fat with the gut microbiome is reasonably been coming out. This whole gut brain access communication that variations in your gut microflora can change the architecture of your brain and this can influence a lot of different diseases from neurodegeneration and also to a variety of neuropsychiatric disorders. So we really came up with this hypothesis. It’s like, okay, well how can we change the gut microbiota in a sustainable way such that we could prevent the onset of neurodegeneration? So that’s where it all started, but then when we started developing this formulation, combining the [inaudible 00:01:32] curb and the probiotics as outlined in that paper, we saw this really interesting effect that longevity was greatly enhanced. So we went with that and we’re like, okay, what’s happening? What are the mechanisms? How can this be happening and that’s where this paper was born.
Dan Pardi:	01:47	What a wonderful side effect.
Susan Westfall:	01:49	Yes.
Dan Pardi:	01:50	So why don’t we talk about some of the constituents of the formulation. To begin I think people are most familiar with probiotics and prebiotics, but still let’s do an introduction to those. What fundamentally is a probiotic?
Susan Westfall:	02:03	The dictionary definition of a probiotic is any bacteria that when take in adequate quantities elicits a positive health effect on that host. So what that means, it’s basically any bacteria that when you take it, it’s going to change the architecture of your gut microbiota such that you have a positive health effect. Now, one of the misconceptions in this world of probiotics is that, okay, I take say one probiotic and that’s going to make me better because that one probiotic is going to produce something that’s good for me, but that’s not actually what’s happening. When you supplement with probiotics, what you’re actually doing is, as I mentioned, is changing the fundamental architecture of your gut microbiota population. This is a very synergistic system containing thousands of different bacteria working together to create an environment that’s supporting digestion health and as we saw in this paper and also things like longevity and brain health. So that’s what a probiotic is to us and it’s also the motivation for using a competent tutorial formula containing three different probiotics to hopefully create an environment that’s more beneficial than just one probiotic.
Dan Pardi:	03:08	When we change the composition of the bacteria in our microbiota, what are some of the physiological effects that these bacteria have on our physiology that are either good or bad?
Susan Westfall:	03:19	Good point. There are both good and bad things. It’s not all good, but let’s start with the good. One of the best effects that they have is mostly an anti-inflammatory response, so the gut microbiota actually interacts with our gut epithelial lining, and it creates both a physical barrier against the infiltration of toxins and things that cause inflammation, but it can also influence how our different immune cells are interacting with the body. The gut microbiota has this first line of defense against everything that comes into the body. One of the outputs of that is modulating how our body deals with inflammatory stimuli. There’s a lot of other mechanisms, for example, they influence our metabolism. They also directly impact the brain neurological signaling, and they can impact our oxidative status. They can also impact our digestion, so really just the hard dynamics of the gastrointestinal tract.
Dan Pardi:	04:10	How about prebiotics? What are those?
Susan Westfall:	04:12	So prebiotics are literally the food of probiotics. So more traditionally, prebiotics were considered to be fibrous foods like you would find in artichokes or garlic and onions or starches that we’re more familiar with, and these particular fibrous foods would act as specific food sources for the beneficial bacteria that are already living in your gut. These are almost better than probiotics in a way because you don’t need to supplement with bacteria. Rather you just feed the good bacteria that are already there, and this in itself changes the whole architecture of the gut microbiota. One important thing about prebiotics is recently their definition has been expanded to these polyphenol-rich compounds. So this includes things like grapeseed extracts, green tea, blueberries, all these different dietary polyphenols that have a very high concentration of different kinds of polyphenols. This is where our prebiotic came from, our prebiotic being [inaudible 00:05:09] in this context, which is a polyphenol-rich prebiotic rather than the traditional fibrous prebiotic.
Dan Pardi:	05:14	I guess combinatorial probiotic prebiotic had some actual bacteria that you felt were beneficial to human physiology.
Susan Westfall:	05:21	Yes.
Dan Pardi:	05:22	In addition to a polyphenol-rich prebiotic that also helps to feed the healthfulness of the existing bacteria in our guts.
Susan Westfall:	05:30	Yes, it both feeds them and it also provide a novel substrate to produce more bioactive agents that can have beneficial effects on the body. So basically the bacteria are going to digest or ferment the Triphala. It’s going to produce a bunch of bioactives that are going to have additional effects on the body. Why we see a combinatorial effect.
Dan Pardi:	05:51	The microbiome changes over the lifespan. In what ways does it change as we age?
Susan Westfall:	05:56	There’s been a lot of great studies done recently in human participants showing that there is a drastic shifts in the composition of the gut microbiota due to various reasons, but it really depends on diet and whether someone is institutionalized or not. However, some of the basic changes is this shift towards a morepro-inflammatoryy profile of gut bacteria. In different people, you see different increases or decreases in bacteria, but in genera,l you’re going to get a higher level of pathogenic bacteria. Some of the reasons why people think this happens is basically changes in the Ph in the gut environment. Obvious changes in diet, but also because the gut brain axis is a bi-directional communication system, so things that happened during life, including stress, different neurophysiological changes can actually impact the composition of the gut microbiota and these changes can accumulate with age.
Dan Pardi:	06:50	Let’s also talk about your model organism Drosophila or fruit flies. Why is this a relevant model for us to study if we want to understand human health better?
Susan Westfall:	07:00	I get a lot of questions about Drosophila and why we use it. The reason why is fruit flies are actually a very robust model for the mammalian system and about 70% of human disorders that have a genetic basis can actually be modeled in the fruit flies because they have homologous factors. Basically the same of what’s in mammals. The reason why we chose Drosophila was because we really want to study deeply the mechanisms and how the gut microbiota is interacting with the host and what are the particular signaling factors that can be responsible for the effects of the gut microbiota.
Susan Westfall:	07:36	When you’re studying in mammals, although this is a more representative system, you run into the problem where you get a lot of redundancy in the signaling pathways. Meaning that if you’re changing one factor and there’s going to be all these other factors that jump in and compensate for it, hence the mammalian system is more complex. Whereas in Drosophila like for example, in the inflammatory pathway, there’s very limited number of players that are being affected, so it’s easier to pull apart exactly how your treatment is impacting the flies. It gives us a very good way to find markers of how this gut microbiota can be communicating with the host, but clearly, we do need to move up into the mammalian models to reinforce and to make sure that these are actually happening in a more complex system.
Dan Pardi:	08:19	We talked about some probiotics and the polyphenolic prebiotic. What exactly did you do with these flies?
Susan Westfall:	08:27	So that’s actually really, really simple. You basically take these flies. They are just normal wild type flies, no special treatment, no special genetic composition. Basically, you incorporate into a minimal food source these probiotics and prebiotics agents. Now that is key because our particular media that we grew the flies on, as I said, is minimal, so it had a lower level of sugar and also had a lower level of protein and active east components which are normally given to flies. I see criticism online saying, “Okay, well your flies have such a short wild type lifespan.” Well, the reason why that lifespan was short was because we gave them this minimal media so we could really see the effect of supplementing it with our components rather than having them masked by already having a highly nutritious media.
Susan Westfall:	09:10	Then that’s all we did, so we were replacing media every couple of days and score them and see, okay, how long are these guys living? How long are those guys living?  [inaudible 00:09:17] live a lot longer. Then we basically chose different time points days 10, 20 and 30, and then we could analyze it. What are the protein changes, genetic changes, MRNA changes and looking for different mechanistic markers that we thought might be relevant.
Dan Pardi:	09:34	What were the different groups that you actually looked at in the study? There was a control group, as you just mentioned. Then just one other group or was it multiple groups?
Susan Westfall:	09:40	We studied multiple groups. We had a control group which had no treatment and we also had a group that had one probiotic by itself. Mainly the alphamentum bacteria. It’s a control to see is a combination of bacteria better or is it only this one bacteria that is implementing the longevity effects. Now, we also had a group that had Triphala alone, the polyphenol rich prebiotic. Building on that, we had a group of just the three probiotics without the Triphala and then finally the symbiotic groups that contain both the Triphala and the three probiotics.
Dan Pardi:	10:13	Simple study in terms of its implementation, but the results were quite remarkable. What were the different areas that you investigated in terms of the health impact?
Susan Westfall:	10:22	I really wanted to look into the different axes of the gut brain access and just see which one of these axes are primarily being effected by a symbiotic treatment. So the first one we looked at was metabolism. We wanted to look at different markers of both lipogenesis and fat accumulation and also diabetic markers including insulin resistance and different insolent mediators in the flies. Then we also looked at the inflammatory pathways in Drosophila, so we looked at different legs of the inflammatory pathways and finally the accumulation of oxidated stress. This was a main pathway to look at as oxidative stress is one of the most accepted models of aging that we know today. So we looked at how the gut microbiota or the symbiotic formulation was impacting the oxidative status of the flies.
Susan Westfall:	11:07	We actually saw benefits in all three of these main pathways that we looked at, which really brought us to the conclusion of the paper. Efficacy of this symbiotic formulation isn’t due to it acting through one pathway, but it’s actually the combination of pathways. The fact that it has this overall beneficial effect on the physiology of the fly, which is giving us such a drastic impact on the longevity.
Dan Pardi:	11:30	I think we can generally say that even though you looked at different groups, one probiotic by itself, just the Triphala than the symbiotic, which is the combination generally across all measures, the symbiotic perform better. Is that true?
Susan Westfall:	11:44	That is true. However, if you look at the individual studies, you’ll see that sometimes Triphala alone works as well as a symbiotic. In other cases, the probiotic formulation works as well as the symbiotic formulation. However, when you put everything together, you can see that the symbiotic consistently has the best ability to reduce each of these risk factors of aging. So sometimes it works just as well as Triphala, maybe you can say for inflammation. However, when you look at everything in combination, the metabolism, the inflammation and the oxidative stress, the symbiotic formulation consistently and simultaneously benefits each of those independent axis.
Dan Pardi:	12:22	So there was no situation where the symbiotic underperformed one of the other groups, and so for the most part here, we’ll talk about the symbiotic since that had as powerful of effect or more powerful than everything else on the different factors that we’ll discuss. Let’s talk more about fatty acid metabolism. What did you see there?
Susan Westfall:	12:40	Overall, the triglyceride levels of the flies was reduced. As in general levels, triglycerides are going to increase as flies age, so that increase was prevented by the symbiotic formulation. What we also saw on a fundamental level that the genes that control lipogenesis were reduced by the symbiotic formulation as well as the factors that control gluconeogenesis and basically any accumulation of energy regulating molecules. So this is really exciting, especially in the context of obesity because you could see that by taking this symbiotic that you can prevent basically deterioration of our fatty acid metabolism.
Dan Pardi:	13:15	Let’s talk more specifically about oxidative stress.
Susan Westfall:	13:18	We looked at two different angles of oxidative stress, both the accumulation of oxidants, total oxidants and also lipid oxidation. We also looked at the activity of the specific antioxidant enzymes. It’s not only the accumulation of oxidants that creates this aging phenotype, but it’s also a reduction in the activity of the antioxidants clearance enzymes. So we wanted to see that whether or not the symbiotic formulation was actually physically reducing the level of oxygen by sequestering them or just preventing them from being developed or are they actually increasing their elimination by increasing the activity of the enzymes.
Susan Westfall:	13:58	This was actually very interesting because we were able to see that the symbiotic formulation, reduced the oxidants much more than it increased the antioxidant enzyme activity. So we went a little bit deeper and we actually looked at the production of the different oxidants in the electron transport chains as mitochondria and we indeed did find that the symbiotic formulation greatly rescued the activity of the electron transport chain complexes in the mitochondria. This is another mechanism of aging slowly over time out mitochondria lose their integrity and when they lose their integrity, you’re going to get an increased production of oxidants lead to aging. Another nice mechanistic point that we got from the paper.
Dan Pardi:	14:37	A while back I interviewed Bruce Hay and his work on mutant mitochondria and as we age, due to damage of living and energy production, we produce more mutant mitochondria. Once we get to a place where there’s about 70% mutant mitochondria, you see a was a pretty significant loss of function and he’s doing some work to try to reduce through genetic modification, the amount of mutant mitochondria back down to a level of let’s say 4% where we start. He was able to show that there was a maintenance of function. He wasn’t able to show that the fruit flies that he looked at a return to youthful levels, but there’s potential there, real potential there. In this case, it looks like if you can maintain mitochondrial function across the lifespan, that could lead to the extension of health span and also longevity as well.
Susan Westfall:	15:17	Yes, it is. It’s a very nice angle to look at, so you’re happy to see that result.
Dan Pardi:	15:21	So far, we’ve discussed that there was significant changes on fatty acid metabolism. In the control group, you saw an elevation and things like triglycerides over the period of time studied in the group that was receiving the symbiotic. They had a maintenance of triglyceride levels and that correlated or corresponded with activation of certain genes. Similarly, looking at oxidative stress again, there was a loss of function over time in the control group where they had a reduction in both the levels of certain antioxidants and their activity, and there was a preservation of these antioxidants that are produced by the body with the groups that received the symbiotic. So overall we see a decrease in markers of insulin resistance and a decrease in inflammation and oxidative stress. Wow.
Susan Westfall:	16:05	There is definitely a lot going on. That is the beauty of the gut microbiota because it basically impact most of our physiological systems, which then gives it the angle to have preservative effects against multiple chronic diseases.
Dan Pardi:	16:17	Right now, my feeling has been that with increasing appreciation, we understand that the microbiome is an important source for human health. How exactly we intervene though is still a bit of the wild west. We know that our gut bugs need prebiotic foods, one sources, fibers and other sources, polyphenols. We can affect the composition through adding probiotics to our diet. Do you have any plans to take this research and doing work in humans where you would test a similar composition to see if there are similar effects?
Susan Westfall:	16:48	Yes, we do have plans to move forward with these studies in mammalia and hopefully in human models. I don’t want to give too much away, but there are going to be some studies coming out with some more disease specific effects of this formulation. We have filed a patent for the IP for this formulation. So that’s a work in progress.
Dan Pardi:	17:05	We know that the gut microbiome is important and this gives us some more insight into how we might be able to intervene and it goes back to eating a good fiber rich diet with lots of polyphenols, a lot of plants. At minimum that seems to be something that you could take from this work to affect your diet right now if that were to hold up in humans. Thank you so much Susan. I really appreciate your time and coming onto the show.
Susan Westfall:	17:25	Thank you for having me. It’s been a pleasure.