Mice Raised in a Germ-Free Environment Exhibit Less Age-Related Inflammation and Longer Average Lifespans

The research I'll point out here is an interesting data point to add to what is known of the impact of a life-long exposure to pathogens on aging and longevity. Researchers raised mice in a germ-free environment, and found that they did not suffer anywhere near the same age-related increase in inflammation, and the average life span increased. You might compare it with another recent study in which germ-free mice developed less metabolic waste in brain tissues over a lifetime. The research here focused on the interaction between gut microbiota and the immune system over the course of aging, a topic that has been explored to an increasing degree in recent years. The influence of the microbial populations of the gut on long-term health appears to be of around the same order of magnitude as that of other prominent environmental factors, such as level of exercise, though no-one has yet demonstrated as large an effect as that of calorie restriction via manipulation of gut microbes.

The high level summary is simple to outline, but the picture is a complicated one under the hood. Even given just the three broad categories of (a) immune cells, (b) gut microbes, and (c) pathogens - a dramatic oversimplification of the real picture - we can still argue about the direction of causation. Does exposure to pathogens cause malfunctions in the immune system, that in turn leads to changes in the gut microbe populations, that in turn feed back to cause further immune issues and other problems in intestinal function? Or are direct effects of pathogens on gut microbes more important? Or are other bodily systems involved in a significant way? There is much work yet to be accomplished in this part of the field. Further, the usual caveats apply here despite promising supporting evidence from other parts of the field: mice are not people, and the interactions with pathogens that are important over a mouse life span are unlikely to be the same as those that are most important over a human life span.

That said, there is a good deal of evidence for the aging of the immune system over a normal human life span to be accelerated by exposure to persistent pathogens like cytomegalovirus. An ever increasing fraction of immune cells are dedicated, uselessly, to this class of invader, while other activities are neglected. The immune system malfunctions in ways that promote ever greater inflammation, but with ever less of the usual benefits in terms of increased beneficial immune activity. Transient inflammation in younger people is useful, a necessary part of the way in which the immune system functions. Chronic inflammation in the old, on the other hand, is essentially a form of damage that contributes to the progression of many age-related diseases. Further, we can look at recent human history to see the effects of reduced exposure to infectious pathogens on long-term health and average lifespans. Older people in a given age group today are considerably less physically aged than was the case for that age group a century ago. Further again, there is a fair amount of research in shorter-lived species to suggest that declining intestinal function is an important component of degenerative aging. In flies, for example, it might be the most important component, though in mammals that is probably not the case. That decline is linked, separately, to immune function and the microbes of the gut.

More than a 'gut feeling' on cause of age-associated inflammation

Gut microbes cause age-associated inflammation and premature death in mice. The research shows that imbalances in the composition of gut microbes in older mice cause the intestines to become leaky, releasing bacterial products that trigger inflammation, impair immune function and reduce lifespan. Humans with high levels of inflammatory molecules are more likely to be frail, hospitalized, and less independent. They are also more susceptible to infections, chronic conditions such as dementia and cardiovascular disease and death. Up until now, the cause of the relationship between the composition of gut microbes and inflammation and poor health in the elderly has not been determined.

"To date, the only things you can do to reduce your age-associated inflammation are to eat a healthy diet, exercise and manage any chronic inflammatory conditions to the best of your ability. We hope that in the future we will be able use drugs or pre- or probiotics to increase the barrier function of the gut to keep the microbes in their place and reduce age-associated inflammation and all the bad things that come with it."

In contrast to conventionally raised mice, germ-free mice did not show age-related increases in inflammation and a higher proportion of them lived to a ripe old age. Age is associated with an increase in levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF), in the bloodstream and tissues. It was found that germ-free mice did not have increased TNF with age. In addition, TNF-deficient mice that did not develop age-associated inflammation or conventional mice that were treated with an anti-TNF drug approved for humans had reduced age-related changes in the microbiome. "We assume that if we reduce inflammation, we improve immune function. If we improve immune function, we maintain the ability to farm a healthy gut microbiota, but we don't know for sure yet. We also believe that targeting age-associated inflammation will improve immune health and we are investigating repurposing drugs that are already on the market and developing novel strategies or therapeutics to this effect."

Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction

Levels of inflammatory mediators in circulation are known to increase with age, but the underlying cause of this age-associated inflammation is debated. We find that, when maintained under germ-free conditions, mice do not display an age-related increase in circulating pro-inflammatory cytokine levels. A higher proportion of germ-free mice live to 600 days than their conventional counterparts, and macrophages derived from aged germ-free mice maintain anti-microbial activity.

Co-housing germ-free mice with old, but not young, conventionally raised mice increases pro-inflammatory cytokines in the blood. In tumor necrosis factor (TNF)-deficient mice, which are protected from age-associated inflammation, age-related microbiota changes are not observed. Furthermore, age-associated microbiota changes can be reversed by reducing TNF using anti-TNF therapy. These data suggest that aging-associated microbiota promote inflammation and that reversing these age-related microbiota changes represents a potential strategy for reducing age-associated inflammation and the accompanying morbidity.

Although manipulation of the microbiota may improve health in the elderly, until now it has not been clear whether microbial dysbiosis is a driver of immune dysfunction. For example, it has been demonstrated that gut microbial composition correlates with levels of circulating cytokines and markers of health in the elderly and that intestinal permeability and systemic inflammation increase in old mice, but not whether the microbiota drive these changes. Our data demonstrate that microbial dysbiosis occurs with age, even in minimal microbiota, and these changes are sufficient to promote age-associated inflammation, although we have not determined whether this is due to enrichment of specific species, changes in microbe-microbe interactions, alterations in the functional capacity of the aging microbiota (e.g., changes in short-chain fatty acid production), or loss of compartmentalization of the microbiota as is found in Drosophila.

Although there were significant changes in the composition of the microbiota with anti-TNF treatment, we have not yet identified which members of the microbial community alter barrier function with age. Further experiments will need to be performed to determine if it is the loss of beneficial members of the microbial community, overgrowth of harmful members, or a shift in metabolism that contributes to this phenomenon.

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