Today, we are going to take a look at the emerging theory that inflammaging, a chronic, age-related background of inflammation, is caused by alterations to the populations of intestinal microbes.

What is inflammaging?

Inflammaging is a term coined to describe the chronic, smoldering background of inflammation that accompanies the aging process. It is constant, low-grade inflammation that interferes with stem cell mobility, cellular communication, and the immune system’s ability to operate correctly.

There are a number of known sources of inflammaging, including senescent cells, cell debris, immunosenescence, and microbial burden. Inflammaging precedes many age-related diseases, including atherosclerosis, arthritis, hypertension, and cancer [1-3]. This persistent background of inflammation also leads to increasingly poor tissue repair and degeneration as we grow older [4].

This chronic inflammation likely contributes to the development of age-related diseases and to the aging process in general [5]. Aged tissues have high levels of inflammatory cytokines, such as IL-6, IL-1β, TGF-b, and TNF-α, which are known to interfere with anabolic signaling, including insulin and erythropoietin signaling, thus contributing to the development of sarcopenia. This is part of the aging hallmark known as deregulated nutrient sensing [6].







This inflammation also plays a key role in reducing the level of NAD+ and sirtuin activity by increasing CD38 in tissue, which is linked to the development of sarcopenia and other age-related diseases [7-9].

Research efforts have attempted to discover an origin point that sets this downward spiral of increasing inflammation and decreasing tissue repair in motion.

An emerging theory

An increasing number of researchers are suggesting that inflammaging is caused by changes to the intestinal microbiome, the communities of microbes that live in the gut and perform a variety of functions.

The microbiome is not a static thing; it changes in response to a variety of stimuli, such as diet, lifestyle, infection, immune response activation, and IgA-producing B cells in the intestine. In humans and rodents, the composition of the gut microbiome differs significantly between young and aged individuals, and, in humans, the microbiomes of centenarians compared to frail, aged people with histories of cancer [10-11].







Age-related gut dysbiosis, the microbial imbalance in the gut, favors a shift towards proinflammatory microbes and a decline of beneficial microbes such as those responsible for creating butyrate, a compound vital for creating the energy that colonocytes feed on. These changes lead to inflammation and impair the intestinal barrier, causing it to leak, hence the common name for the condition being “leaky gut” [12].

The result of microbial lipopolysaccharide and other microbial contaminants leaking from the gut is an increased activity of interferons, TNFα, interleukin-6, and interleukin-1 in the blood, which contributes to chronic systemic inflammation. This constant background of low-grade inflammation is also a strong predictor of the decline of health and fitness in older people [13-14].

Immune system dysfunction, which is partly encouraged by dysbiosis, also interferes with the ability of myeloid cells to remove senescent cells [13]. The myeloid cell family includes a wide range of cells, including monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, megakaryocytes, and platelets.

Therefore, in a very real sense, the inflammation from dysbiosis interferes with the immune system and its ability to remove unwanted and harmful senescent cells, which secrete the senescence-associated secretory phenotype (SASP), which, itself, is a major source of inflammaging. This creates an environment conducive to cancer and other age-related diseases.

It is not yet clear if inflammaging is then sustained by the continual stimulation of the immune system or via the intrinsic dysregulation of that system. Studies that are investigating the targeting and effective management of inflammaging may make this clear in the near future and determine if decreasing inflammaging may benefit overall health and reduce the risk of age-related diseases.







The gut microbiome and systemic inflammation

The gut microbiome is an ever-changing environment populated by vast numbers and types of archaea, eukarya, viruses, and bacteria. Four microbial phyla, Firmicutes, Bacteroides, Proteobacteria, and Actinobacteria, make up 98% of the intestinal microbiome.

The microbiome is a complex ecosystem that regulates various aspects of gut function along with the immune system, the nutrient supply, and metabolism. It also helps to control the growth of pathogenic bacteria, protects from invasive microorganisms, and maintains the intestinal barrier.

The gut microbiome is essential for normal immune function and development, and the immune system is impaired by its absence [15]. Bacteria such as Candida albicans and Citrobacter rodentium facilitate pathogen control by activating T helper-type 17 cells and recruiting neutrophils and other immune cells. Bacteroides fragilis and Clostridium regulate inflammation by inducing the differentiation of regulatory T cells (FoxP3-positive) and the production of interleukin-10 and transforming growth factor β [16].

The microbiome is also critical for energy production and metabolism to function correctly. The processing of fibers into short-chain fatty acids (SCFAs) and their conjugate bases (acetate, propionate, and butyrate) is conducted by various bacteria (see table below), which provide an energy source for the microbiota and colonocytes, support the intestinal barrier, and stimulate the inflammasome pathway in gut homeostasis [17].







Microbe Associated with Function Age-related change General bacterial diversity Unknown Unknown Decreased Firmicutes phylum MAMPs and PAMPs Potentially pathogenic Increased Ratio of Firmicutes to Bacteroidetes phyla MAMPs and PAMPs Potentially pathogenic Increased Alistepes genera Unknown Unknown Increased Oscillibacter genera Unknown Unknown Increased Eubacteriaceae family Unknown Unknown Increased Faecalibacterium prausnitzii SCFAs Affects metabolism and immune cell activity. Decreased Roseburia faecis SCFAs (butyrate) Ferments prebiotics, plant products that contain dietary fiber, into butyrate, which is used by gut microbes and colonocytes as energy. Butyrate is also a histone deacetylase inhibitor; induces generation of colonic regulatory T cells; induces antimicrobial peptide production of colonocytes; prevents expansion of pathogenic commensals; and inhibits toll-like receptor 4 signaling. Decreased Anaerostipes butyraticus SCFAs Affects metabolism and immune cell activity Decreased Ruminococcaceae SCFAs (butyrate) See above description of butyrate. Decreased Christensenellaceae SCFAs Affects metabolism and immune cell activity Decreased Verrucomicrobia phylum Outer membrane protein Possibly causes the loss of Akkermansia bacteria and is potentially involved in metabolism. Decreased Akkermansia muciniphila Amuc_1100 protein Activates colonocyte toll-like receptor 2, produces the immunoregulatory SCFA propionate, induces mucus production and thus supports growth of other beneficial bacteria, such as producers of SCFAs, and improves metabolism and insulin sensitivity. Decreased Bifidobacterium animalis subspecies lactis Polyamines, including putrescine, spermidine, and spermine. Scavenges reactive oxygen species, activates the stress-response gene, regulates the activity of nuclear factor κB, and inhibits the production of pro-inflammatory cytokines from macrophages. Decreased

Table: SCFAs=short-chain fatty acids. MAMPs=microbe-associated molecular pattern molecules. PAMPs=pathogen-associated molecular pattern molecules.

Short-chain fatty acids also bind the metabolite-sensing G-protein-coupled receptors (GPR)43 and GPR109A which then blocks the creation of inflammatory cytokines and chemokines produced by dendritic cells [18].

The SCFA butyrate is estimated to be responsible for approximately 70% of the energy created by colonocytes, making it the most important SCFA in colon homeostasis [19]; butyrate controls the growth of pathogenic bacteria by activating the peroxisome proliferator-activated receptor-γ-dependent β-oxidation metabolic pathway and oxygen consumption in colonocytes [20], which stabilizes hypoxia-inducible factor and, in turn, intestinal barrier protection [21]. Butyrate also regulates inflammation via blocking histone deacetylases and toll-like receptor 4 (TLR4) signaling [22] and encourages the creation of FoxP3-positive regulatory T cells [23].

Faecalibacterium prausnitzii and Akkermansia muciniphila produce the SCFA propionate, which increases the activity of epigenome-modifying enzymes, including histone deacetylases 3 and 5, and influences gene expression linked to lipid metabolism [24]. Faecalibacterium prausnitzii also has anti-inflammatory activity. It is able to trigger the production of interleukin-10, inhibits antigen-specific interferon γ-positive T cells, and protects the intestinal membrane against dysbiosis [25].

Akkermansia muciniphila and its outer membrane protein Amuc_1100 activate toll-like receptor 2 to support the intestinal barrier [26]. It also improves conditions at the intestinal barrier by maintaining the mucus layer, which supports other SCFA-producing bacteria, such as bifidobacterium animalis subspecies lactis, which uses mucus to adhere to the gut wall.







Bifidobacterium animalis subspecies lactis produces the polyamines putrescine, spermidine, and spermine, which scavenge reactive oxygen species, activate stress response genes, regulate the activity of the nuclear factor κB activation protein complex, which is itself a major regulator of inflammation, and block the production of inflammatory cytokines created by macrophages [27].

The health of the immune system is supported by a healthy gut, which includes a complex interplay of symbiotic relationships between the various bacteria that make up its microbiome. The loss of bacterial diversity and the decline of beneficial bacteria species during aging lead to a compromised gut barrier and dysbiosis, which, in turn, increase bacterial infiltration into the body and trigger chronic inflammation.

Conclusion

While it is not yet certain that the gut microbiome is the origin of inflammaging, there is an increasing amount of evidence that this is the case. If so, the effective management of the microbiome and its resulting inflammation could be an important key to increasing healthy lifespans and preventing age-related diseases.

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