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Is Aging a Gut Instinct?


The levels of circulating inflammatory cytokines and other signaling factors increase with age, contributing to the loss of tissue maintenance, wound healing difficulties, immune system dysfunction, loss of stem cell mobility and a host of other problems.

However, it remains a subject of much debate as to what starts the cascade of inflammation that drives the aging process and the progression of age-related disease. A recent study suggests that the initial source of age-related inflammation could be microbial burden originating in the gut microbiota.

The microbiota and inflammaging

The microbiota describes the community of symbiotic and pathogenic microorganisms found in and on all multicellular organisms studied to date, from plants to animals. The microbiota includes bacteria, archaea, protists, fungi, and viruses, which are present in all living things exposed to a normal environment.

Research suggests that as we age, the gut microbiota increasingly favors pro-inflammatory activity, as a lifetime of exposure to pathogens tips the delicate balance from a pro-youthful to a pro-aging nature.

Microbial burden, cell debris, crosslinks, the immune system, and senescent cells all contribute to a collective chronic, low-grade background of age-related inflammation known as ‘inflammaging’, though the hierarchy of these sources has yet to be established[1].

It has been suggested that inflammaging is focused around the macrophages and involves a number of tissues, organs, and the gut microbiota; there is a complex interplay between these elements that creates a balance between pro-inflammatory and anti-inflammatory responses[2].

We have talked about the importance of macrophages in tissue repair and how they can become dysfunctional when exposed to inflammation and cease to function in a number of articles.

Could the initial inflammatory stimuli not begin with the immune system, as some researchers suggest, but originate in the gut microbiota that then goes on to generate that first inflammatory immune response? This new study suggests it does.

A germ-free environment means no inflammation

The researchers in this new study found that, when kept in a germ-free environment, their mice did not show any increase in age-related circulating pro-inflammatory cytokines[3].

They also found that a higher number of the germ-free mice lived significantly longer than mice exposed to a normal environment, which would naturally contain pathogens, bacteria and so on. In addition to this, they observed that in the germ-free mice, macrophages maintained their antibacterial activity compared to the control group.

When the research team mixed the germ-free mice with aged mice from a normal environment, they observed an increase of pro-inflammatory cytokines in the blood of the germ-free mice.

They observed that mice deficient in tumor necrosis factor (TNF) are protected from age-related inflammation, and the usual age-associated changes to microbiota do not occur. Also, these age-associated changes to the microbiota can be reversed by reducing the level of TNF circulating in the system using therapies that block or reduce it.


It is an intriguing suggestion that the microbiota may potentially be the source of the initial cascade that drives inflammaging. The idea that a lifetime of accumulated harmful bacterial burden eventually tips the balance in the microbiota to favor a pro-aging one is a compelling one.

The world beyond the sterile lab environment is filled with bacteria and all kinds of microorganisms that can potentially invade our body. Obviously, living in a germ-free bubble is completely impractical, so what is the solution?

The researchers here suggest that the microbiota promotes age-related inflammation and that reversing these changes is a potential strategy for reducing age-related inflammation.

Certainly, managing age-related inflammation at various checkpoints is the focus of much recent research, including senescent cell removal and immune system modulation to favor an anti-inflammatory profile. The microbiota is a complex system that is not well understood at present, so perhaps at this point in time, the most direct solution is to manage inflammation at the nearest checkpoint.

Regardless of if the microbiota is or isn’t the origin point of age-related inflammation, its role in inflammaging is without a doubt and, therefore, makes it a potential therapeutic target. The study results here represents a step forward in our understanding of the interplay between the various forces that collectively make inflammaging, and controlling them could help prevent or even reverse some age-related diseases.


[1] López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.

[2] Franceschi, C., Garagnani, P., Vitale, G., Capri, M., & Salvioli, S. (2016). Inflammaging and ‘Garb-aging’. Trends in Endocrinology & Metabolism.

[3] Thevaranjan, N., Puchta, A., Schulz, C., Naidoo, A., Szamosi, J. C., Verschoor, C. P., … & Schertzer, J. D. (2017). Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction. Cell Host & Microbe, 21(4), 455-466.


About the author

Steve Hill

Steve serves on the LEAF Board of Directors and is the Editor in Chief, coordinating the daily news articles and social media content of the organization. He is an active journalist in the aging research and biotechnology field and has to date written over 600 articles on the topic, interviewed over 100 of the leading researchers in the field, hosted livestream events focused on aging, as well as attending various medical industry conferences. His work has been featured in H+ magazine, Psychology Today, Singularity Weblog, Standpoint Magazine, Swiss Monthly, Keep me Prime, and New Economy Magazine. Steve is one of three recipients of the 2020 H+ Innovator Award and shares this honour with Mirko Ranieri – Google AR and Dinorah Delfin – Immortalists Magazine. The H+ Innovator Award looks into our community and acknowledges ideas and projects that encourage social change, achieve scientific accomplishments, technological advances, philosophical and intellectual visions, author unique narratives, build fascinating artistic ventures, and develop products that bridge gaps and help us to achieve transhumanist goals. Steve has a background in project management and administration which has helped him to build a united team for effective fundraising and content creation, while his additional knowledge of biology and statistical data analysis allows him to carefully assess and coordinate the scientific groups involved in the project.
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