On the grain, competition between species reigns supreme. Many species appear to be capable of inhibiting L. kefiranofaciens, which keeps its abundance in check. Meanwhile, Lactococcus lactis, another member of the core community, produces toxins known as bacteriocins that target and strongly inhibit the growth of other members of the community.
Although the community on the grains remains stable throughout the fermentation process, the surrounding milk sees increases and declines in different members as the microbes move from a solid to a liquid environment. The researchers described the kefir grains as a "basecamp" from which the different microbes "colonize the milk in an orderly fashion." This migration happens in a set order of species, which appears to have a lot to do with the preferred diet of each group.
Next stop: Cooperation Station
Unlike the grain environment, the complex nutritional landscape of the milk pushes the microbes to cooperate rather than compete. First to colonize the milk is L. kefiranofaciens, which, as on the grain, is the most abundant species throughout the fermentation process. Surprisingly, despite its dominance, L. kefiranofaciens can't grow in milk on its own. Its growth has been suggested to be supported by rare species, many of which can grow in milk alone. These species break down proteins and sugars in the milk to produce smaller molecules, generally referred to as metabolites, that L. kefiranofaciens could use to grow.
The analysis of these metabolites, using several techniques collectively known as metabolomics, was crucial for resolving how and why all these microbes cooperate. By measuring the concentrations of key metabolites throughout the fermentation process, it became apparent that some of their patterns match the growth patterns of key kefir species. For example, the concentration of a key intermediate molecule that cells use to produce energy, called citrate, drops suddenly in the early stages of fermentation. This drop correlates with the growth of two kefir species, L. lactis, and Leuconostoc mesenteroides, which suggests that they could be using citrate to grow.
In the milk, cooperative interactions between species are far more common than competitive ones, indicating that there are benefits to be gleaned from the presence of others. For example, L. kefiranofaciens and L. mesenteroides share a mutually beneficial relationship in which the presence of one promotes the growth of the other. This partnership seems to be centered on cross-feeding between the two. L. kefiranofaciens breaks up proteins into amino acids that can be accessed by L. mesenteroides. In return, L. mesenteroides, now able to carry out fermentation, produces lactate which L. kefiranofaciens can consume.
The acid test
The production and accumulation of major fermentation products, including lactate and acetate, acidifies the milk and gives kefir its distinct, slightly sour taste. However, these products also play a role in regulating the growth of microbes in the process. They inhibit the growth of many species that are important in the early- to mid-stages of fermentation, including L. lactis, L. mesenteroides, and several rare species.
Meanwhile, other species appear to benefit from the accumulation of lactate and acetate. Metabolomics measurements reveal that different species of yeasts and Acetobacter bacteria begin to grow during a favorable window of lactate and acetate concentrations in the milk, indicating accumulation of these metabolites clear the way for late-growing species. Although, high concentrations of lactate and acetate would be unfavorable for everyone.
Like many of the other core species, Acetobacter fabarum cannot grow in milk on its own. Here, another beneficial cross-feeding interaction appears to be at play, with L. lactis, an earlier-growing species, providing lactate and specific amino acids for A. fabarum to consume. However, whether A. fabarum provides anything in return is not clear. In contrast to the mutualism between L. kefiranofaciens and L. mesenteroides, this interaction could be described as commensalism: one partner benefits, and the other is seemingly unaffected.
Studying interactions between microbes presents a near-limitless well of discovery, precisely because these interactions are everywhere and occur in many flavors: from cooperation to vicious competition, and everything in between. Humans also have the potential to leverage microbial communities for our benefit: for example, understanding how microbial communities associated with crop plants function could help us devise ways to increase hardiness and yields under environmental stress. One longer-term goal is to develop a comprehensive-enough understanding that we can build communities to perform specific tasks, whether that be degradation of pollutants in the environment, producing new chemical compounds, or improving our health.
Can we slow or even reverse aging? The good news is, slowing aging and gaining more than ten years is absolutely possible and doesn’t cost you anything except some discipline (yeah, I know, that’s the bad news here). However, to keep you reading, I’ll tell you a little later how that works. Whether it is possible to slow or even reverse aging is currently the topic of a lot of research.
But let’s start at the beginning. If you want to treat something, you first need to define it clearly. The most obvious definition for aging is chronological. However, changing the actual flow of time falls more into the realm of physics and is probably not very practical. What we want to influence is the biological age. To measure this, we use a lot of different methods, called “clocks,” and they work with blood parameters, heart rate variability, epigenetics, simple photos of your face, or other data. Clocks are all somewhat linked to chronological age but can generally tell you how one (or several) aspects of your biological age compare to the average person your age. So they tell you if you’re younger or older than you actually are.
The specific unpleasant cellular effects of aging are summed up as the 9 Hallmarks of Aging that you see above. I won't go into detail, but they are all interconnected and lead to what we recognize as aging, like wrinkles, grey hair, loss of muscle mass, frailty, dementia, decreasing bone density, and all the other stuff that you're not keen on having.
Reading this list, you might already guess why treating aging might have other perks than just living longer. The biggest deal, not only for the individual but also for society, would be increasing the so-called healthspan. It can be argued that while in the last 100 years we have already more than doubled the average life span, the healthspan, the time lived in good health, hasn't grown accordingly. Our current medicine has become very good at treating most of the countless ailments that old age brings; however, many are more managed than cured. So wouldn't it be better (and cheaper, by the way) to treat the underlying cause of most illnesses instead of each of them at a time? The results of healthspan research could revolutionize medicine and bring us from fixing what's broken to preventing the breaking.
But how far along are we? Will we still get old like our grandparents? That depends. To cite one of the leading minds in this field of science, Professor David Sinclair: "It's easy to expand your lifespan. […] If you do the right things, which is: Don't overeat, eat less often during the day, do some exercise, don't smoke, don't drink! That alone gives you, compared to people who don't do that, 14 extra years. So living longer isn't hard, it just takes some discipline." Well, I told you, it's not too easy, but it's doable. However, there is obviously more to aging research than the typical advice on living more healthy.
First of all, there are drugs and supplements that (at least in animal models) show a huge potential to give another few healthy years like Nicotinamide Mononucleotide (NMN), α-Ketoglutarate (AKG), Resveratrol, Metformin, and Rapamycin. I won’t go into detail on those now, but I’ll write some more articles about that on my blog soon.
Most of these, however, seem to work mainly as a prevention and not a cure. But there are other measures in the pipeline. An interesting idea is the so-called “Senolytics.” Instead of killing themselves as damaged cells normally do, some become senescent. Senescence occurs when cells sense an instability of their chromosomes after having divided a certain number of times or because of high stress (due to their Telomeres), so they permanently stop dividing. Senescent cells also secrete signals that lead to inflammation, changing the development of their surrounding cells and the extracellular matrix.
The more senescent cells in an organ, the less vital and functional the organ becomes. Senolytics like Dasatinib and Quercetin are substances that target and remove these senescent cells to rejuvenate the organ. There are ongoing clinical studies on human patients with these substances on several age-related diseases, and they show some promise, but there is still a lot of research to do.
The idea that sounds probably most impossible but has the potential to slow the clock and actually reverse aging is cellular reprogramming. Each cell in our body has basically the same genetic information, the same construction plans packed into our DNA organized in chromosomes. But how does a cell in your brain know that it’s not in your foot and has to behave differently? And, even more important, how does a cell know that it’s not supposed to copy itself as often as possible or try to build a new complete clone of you? The answer is epigenetics (mostly). Epigenetics is quite a young field that has made huge progress in the last 15 years. Epigenetics determines which of the genes of a cell’s genome are switched on and switched off by modifying the DNA or proteins associated with the DNA. These bookmarks make a cell behave as it does. They are changed by environmental influences like sunshine, smoking, food, no food, or a thousand other things. Most of these factors and time itself lead to an overall decrease in these bookmarks, although certain areas of the genome also acquire more of them with time. So the idea is to reset these bookmarks to a “younger” state.
In 2006 a set of four transcription factors (regulators for genes) were identified that can reset a differentiated cell into part of a certain tissue to a very similar state to that of the cells you find in an embryo. The cells treated with the transcription factors become stem cells and can be reprogrammed into almost any cell type within the body. These transcription factors are called Yamanaka Factors after one of the authors of this study from 2006. Using the Yamanaka Factors, there have been successful studies on animals. The aim is to reset the epigenetics of cells to young without dedifferentiating the cells, making the tissues they form fall apart. This technique is currently tested to restore vision in primates after successful tests on mice that have gone blind because of glaucoma. It is expected to be ready for human clinical trials next year. If this is successful, it would be a new hope for many blind people and be a proof of concept for rejuvenating a tissue by epigenetic reprogramming.
A possible future application of this could be to treat a patient's cells outside the body to become stem cells and then inject them to regenerate damaged tissue or to rejuvenate the patient as a whole.
Much is unclear about reversing aging. Many studies in the field show contradicting results, but what would have seemed impossible 20 years ago is rapidly evolving from promising basic research to clinical trials. Currently, you still need some discipline and changes to your lifestyle if you want to increase your lifespan and healthspan. However, the more life and health you win through your life choices, the closer scientists might be to real solutions to all the unpleasant effects of aging and maybe to aging itself.