Immune defense/background
This second Genomics of Aging series edition explores the role of the immune system and chronic inflammation in aging, age-related diseases, and proposes approaches to support appropriate gene expression and healthy immune system response. As a first line of defense to pathogens, toxins, or allergens, the immune system engages in short-term inflammation coordination of immune cells, endogenous anti-inflammatory agents, and tissue remodeling to eliminate infected cells and pathogens and repair tissue damage. However, if this phase fails to resolve, long-term immune response known as chronic inflammation ensues. This chronic phase leads to further engagement with macrophages, lymphocytes, chemokines, and cytokines, leading to oxidative stress and cell death signaling. Although age-related chronic inflammation has been described as molecular inflammation, microinflammation, pan-inflammation, gero-inflammation, and inflammaging the phenomena remain poorly defined (Chung et al., 2019). The aging process as a result of inflammation has been described as molecular inflammation of aging: inflammaging (i.e., an increase in the body's proinflammatory status with advancing age) and a new concept of senescent inflammation (senoinflammation). Senoinflammation refers to the accumulation of senescent cells and resulting activation of proinflammatory secretomes. Over a lifetime of accumulating damage to DNA and changes in gene regulation in aging cells, transcription factors, including AP-1, p53, STAT, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-[kappa]B), become overactivated in a proinflammatory state. In a vicious cycle of secretome activation, chemokines and cytokines further stress intracellular organelles, tissues, organs, and systems contributing to metabolic disorders and insulin resistance in a cascade of events leading to age-associated diseases (Chung et al., 2019). Senoinflammation blends the evidence of systemic inflammation caused by chronic inflammation, identifies the interactions of inflammatory pathways and mediators, and provides potential therapeutic targets to reduce or reverse this process and in turn delay aging.
Unregulated inflammation
Regulated inflammation to injury or infection promotes protection and healing, whereas unregulated inflammation can lead to further tissue injury and damage. Chronic infections and underlying chronic inflammation left unchecked can lead to DNA mutations and reduced repair. With the accumulation of DNA alterations such as point mutations, deletions and insertions, and rearrangements (i.e., somatic mutations) coupled with erroneous DNA repair and replication degeneration and functional decay ensues leading to aging, cancer, and degenerative diseases (Vijg & Montagna, 2017). Age is recognized as a risk factor for cancer. As an example of an immune system gone awry, cancer has been associated where inflammation-related DNA damage accumulated from exposures such as Helicobacter pylori in the stomach, hepatitis B virus and hepatitis C virus in the liver, human papillomavirus in the cervix, Epstein-Barr virus in the lymph nodes and nasopharnyx, Schistosoma haematobium in the bladder, and Opisthorchis viverrini in the bile duct, as well as asbestos in the mesothelium and lung (Kawanishi et al., 2017). Cancer has also been associated with other noninfectious chronic disease such as oral lichen planus, leukoplakia, Barrett esophagus, and inflammatory bowel disease (Kawanishi et al., 2017).
Mediators involved in the pro-inflammatory immune response include transcriptional factors, peptides, cytokines, chemokines, complement, enzymes, lipids, coagulation factors, and adhesion molecules, and if the immune system can be neutralized, immune cells shift their activity to anti-inflammatory signaling, including lipoxins and cytokines (Chung et al., 2019). The transcription factor, NF-[kappa]B, is most associated with aging, especially in brain, cardiac muscle, kidney, and skin, and genetic blockade of this factor has been shown to reverse the aging process (Adler et al., 2007). Although medications are able to block portions of the NF-[kappa]B pathway (i.e., aspirin, salicylate, PS-34, lactacystin, tacrolimus, glucocorticoids, and protease activated receptor agonists), research continues to determine efficacy and safety because NF-[kappa]B is also required for normal immune responses and cell survival (Liu et al., 2017).
Microbiome and inflammaging
The gut microbiome contains billions of bacteria, fungi, viruses, archaea, and parasites that support digestion, metabolism, nutrition, development, and immunity and protect us from pathogens. The low-grade inflammation of inflammaging is underscored by the microbiome. The term microbiota-associated proteopathy and neuroinflammation describes the process of microbial amyloid misfolding and other configurations on the nervous system that contributes to Alzheimer disease and Parkinson syndrome (Friedland & Chapman, 2017). There are many factors associated with the development of Alzheimer disease and Parkinson syndrome, but evidence is suggesting that proinflammatory gut microbes inhibit recovery in the postinflammatory phase delaying removal of cellular debris and return to homeostasis contributing to increased tau phosphorylation, tau tangles within the brain, and motor and cognitive impairment (Chung et al., 2019). Oral Streptococcus mutans (linked to stroke and cerebral microbleeds) and the trigeminal nerve and autonomic nervous system have both been suggested as routes of microbial amyloid access to the central nervous system (Friedland & Chapman, 2017). Proposed microbiota prevention and therapy includes prebiotics, probiotics, antibiotics, and dietary intervention; but no clear therapeutic approach has yet been recommended in the management of either Alzheimer disease or Parkinson syndrome.
It has been suggested that to reduce overall inflammation and disease risk and promote healthy DNA and immune response, regularly taking a probiotic, treating any underlying microbe disorder, and supporting healthy microflora by increasing dietary fiber, fruits, and vegetables while avoiding red meat, processed foods, high-fructose corn sugar, and refined carbohydrates (Lockwood & Green, 2020).
Clinical approaches to reversing chronic inflammation
Healthy lifestyle choices may help avoid age-related chronic disease and promote a healthy life span. As the evidence links chronic inflammation to premature aging, there is increasing support for the use of anti-inflammatory medications (e.g., aspirin, COX2 inhibitors, omega-3) and antioxidants because these substances seem to be effective in decreasing inflammation and slow down overall aging. Research continues to explore the effects of medications and supplements in reducing/reversing chronic inflammation without totally shutting down important inflammation required in immune defense. Support gut microbiota by cutting out processed foods high in sugar content and unhealthy trans fatty acids and increasing foods (like fruits, vegetables, fish, and chicken) that promote beneficial microbes that "soothe" our immune system. Microbe diversity can also be supplemented by consuming probiotic foods such as yogurt, kefir, and fermented vegetables or a balanced probiotic capsule. The key to supporting healthy DNA aging starts with improving health maintenance, restoring body homeostasis after inflammatory flares, and turning down pathways in chronic inflammation.
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