August 07, 2022 6 min read
When considering the function of the immune system, many have focused on its ability to eradicate infections by attacking and neutralizing invading microbes. Increasingly, however, the conversation is shifting towards a discussion about the extensive cooperation and crosstalk between our immune cells and the trillions of microbes that live in and on us.
Indeed, the development, regulation, and function of the immune system is now known to be inextricably linked to and dependent upon the presence of microorganisms with the ecosystem of the body. Moreover, shifts in both immune cell populations and the composition of the microbiome have been identified throughout the aging process, with these shifts corresponding to increased susceptibility for infectious and chronic diseases.
In this article, we will dive into a 2021 Nature Review entitled “The aging gut microbiome and its impact on host immunity” , which explores observations and conclusions around this burgeoning area of research.
To this end, we will cover three primary focuses:
There are two primary hallmarks associated with an aging immune system:
Immunosenescence is the degradation of immune function and impairments in appropriate immune responses that are frequently observed in the elderly. These changes in the extent and efficacy of immune-mediated activities result in dampened protection from infectious diseases, cancers, and autoimmune disorders in older adults. Although there is no scientific consensus as to the precise causes of senescence, some of the factors believed to contribute are:
These factors, in combination with genetics, stress, and metabolic dysfunction, can all contribute to declines in immune system efficacy throughout the aging process.
Inflammaging describes the heightened levels of sub-clinical, chronic inflammation at the whole-body level that are frequently observed in older populations. This inflammation both contributes to and is the result of immune dysregulation, and is known as a major risk factor for disease and death. There are a variety of factors that may contribute to the onset and persistence of this inflammation, including:
Chronic stress is known to interfere with innate immunity and lead to the over-production of inflammatory mediators like C-reactive protein and the cytokines IL-6 and TNF-a.
Additionally, gut permeability and microbiome composition heavily influence inflammatory status through immunomodulation and regulating the passage of potentially harmful molecules like bacterial endotoxin through the gut barrier into the circulation (leaky gut). The diseases that are fueled by inflammaging include metabolic syndrome, cardiovascular disease, sarcopenia (i.e., muscle loss), cancer, and neurodegeneration. Thus, alleviating chronic inflammatory signatures in the body is crucial acutely to support immune function and chronically to prevent disease.
Microbial colonization of the gut begins while the infant is still in utero. From birth through to around age 3, the microbiome is extremely labile after which its composition stabilizes and is largely maintained into adulthood. The nascent microbiome of the infant is greatly influenced by access to breast milk, the genetics and diet of the mother, antibiotic exposure, and the environment in which the child is raised. Moreover, vaginal birth is associated with enrichment of beneficial bacteria including lactobacilli, bacteroides, and Prevotella in the infant, whereas Cesarian born babies carry lower levels of bifidobacteria, lactobacilli, and enterococci.
In the one to two years following birth, the consumption of breast milk versus baby formula is the predominant force driving microbiome composition. The microbiomes of breast-fed babies are enriched in bifidobacteria and lactobacilli, while those of formula-fed babies possess high amounts of Bacteroides, clostridia, and proteobacteria . Following this stage of life, the variety and quality of solid foods consumed becomes the major determinant of microbiome composition.
Figure 1. The transformation of the microbiome over the course of a lifespan 
Figure 1 depicts the factors that affect microbiome diversity and composition over the course of a lifetime. Alpha diversity, which is a measure of the number of different types of bacteria in the gut, increases from gestation through adulthood. The development of immunity tracks closely with alpha diversity, suggesting that the health of the immune system is linked to high levels of alpha diversity. Conversely, beta diversity, which is a measure of how variable the microbiome is, drops from gestation to adulthood, indicating that the composition of the microbiome becomes more stable over time. Immunosenescence begins in adulthood and ramps up into old-age, corresponding to decreases in microbiome stability, species richness (i.e. alpha diversity), and immunity.
Throughout the lifetime of an individual, the gut microbiome changes dynamically in response to environmental exposures such as:
Dysbiosis is said to occur when the microbial communities within the gut become imbalanced; this imbalance can both contribute to and result from age-related diseases. The function and composition of the microbiome is highly regulated by interactions with immune cells surrounding the gut, which provides a permissive environment for the growth of commensal bacteria while inhibiting the growth of pathogens. In this way, the decline of immune function over time is believed to result in the gradual loss of these regulatory mechanisms and the development of dysbiosis. Namely, this age-related dysbiosis is characterized by a surge in the populations of Proteobacteria and potential pathogens like E. coli, and the loss of two categories of bacteria:
While immunosenescence contributes to the development of dysbiosis, dysbiosis can also contribute to deficits in immune function. However, dysbiosis can also occur early in life following repeated exposures to antibiotics and diets rich in ultra-processed foods that lack the prebiotics necessary to feed commensal species in the gut. This dysbiosis can promote inflammatory activity in the body, which accelerates aging and cellular senescence over time. In other words, the interplay between the microbiome and the immune system is a two-way street, and dysregulation in one can result in deleterious effects to the other. Despite this interplay, the literature suggests that improving the health and quality of the microbiome may directly improve healthspan and longevity.
Figure 2. The interplay between gut dysbiosis and immunosenescence in aging 
In the elderly, levels of commensal microbes like bifidobacteria and lactobacilli are depleted while levels of opportunistic pathogens like enterobacteria and C. difficile increase. Researchers believe that geographical location may play an important role in whether these deleterious changes in microbiome composition occur as readily. For example, elderly Italian individuals have been shown to possess two to three times more bifidobacteria compared to elderly individuals from France, Germany, and Sweden .
In addition to changes in microbial diversity, changes to microbial metabolism also occur throughout the aging process. Specifically, the microbiomes of the elderly have been shown to produce less short chain fatty acids (SCFAs) which can result in:
SCFAs are produced by bacteria including Clostridiales, Bifidobacteria, Akkermansia, and others, and play crucial roles in immune regulation, cognition, gut motility, and more.
Given food’s potent ability to shape gut microbial communities, targeted nutritional protocols can reasonably be prescribed to mitigate declines in microbiome health and immunity during aging. Prebiotics are the major determinant of which bacteria can thrive in the gut ecosystem. Prebiotics are ingested molecules that pass through the digestive system intact where they can reach to the colon and feed key species of bacteria. Both dietary and supplemental prebiotics can be effectively used to promote the growth of commensals, while inhibiting the growth of opportunists. These include:
The incorporation of these sources of prebiotics into one’s daily diet can encourage the development and maintenance of a healthy and diverse gut ecosystem that is robust to infection and inflammation. In turn, the functioning of immune cell populations will be supported which decreases whole-body inflammatory status and wards off immunosenescence. Thus, despite the interplay between aging, immune function, and the microbiome, we can leverage the diet’s unique ability to potently modulate the microbiome in order to promote both longevity and immunocompetence.
Written by: Dr. Alexis Cowan, a Princeton-trained PhD specializing in the metabolic physiology of nutritional and exercise interventions. Follow Dr. Cowan on Instagram: @dralexisjazmyn
 Bosco N, Noti M. The aging gut microbiome and its impact on host immunity. Genes Immun. 2021 Oct;22(5-6):289-303. doi: 10.1038/s41435-021-00126-8. Epub 2021 Apr 19. PMID: 33875817; PMCID: PMC8054695.
 Nagpal R, Mainali R, Ahmadi S, Wang S, Singh R, Kavanagh K, Kitzman DW, Kushugulova A, Marotta F, Yadav H. Gut microbiome and aging: Physiological and mechanistic insights. Nutr Healthy Aging. 2018 Jun 15;4(4):267-285. doi: 10.3233/NHA-170030. PMID: 29951588; PMCID: PMC6004897.
 Mueller S, Saunier K, Hanisch C, Norin E, Alm L, Midtvedt T, Cresci A, Silvi S, Orpianesi C, Verdenelli MC, Clavel T, Koebnick C, Zunft HJ, Doré J, Blaut M. Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study. Appl Environ Microbiol. 2006 Feb;72(2):1027-33. doi: 10.1128/AEM.72.2.1027-1033.2006. PMID: 16461645; PMCID: PMC1392899.
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