Many mechanisms of aging are two-way streets: A accelerates B, but B also makes A worse. Or A leads to B that causes C which aggravates A. Chronic inflammation, a persistent and damaging activation of the immune system, is a player in many of these sorts of circular relationships and feedback loops. The open access paper noted here briefly covers some of the known contributions to increased inflammation in aging. Inflammation is a vital part of the way in which the immune system coordinates with tissues in order to repel invaders and respond to injury; it is beneficial when temporary. When inflammation is constant, however, regeneration and tissue maintenance start to run awry, cancer rates rise, and many disease processes accelerate. Among the inflammatory conditions of aging are found osteoarthritis, the many forms of fibrosis, near all neurodegenerative diseases, atherosclerosis, and more.
What causes the raised level of chronic inflammation found in older people? Well, at root the forms of molecular damage outlined in the SENS view of rejuvenation biotechnology, but the line between root cause and age-related inflammation is only clear and direct in a couple of cases. Aging is a spreading, vastly complex network of many layers of cause and effect, branching out from the few fundamental forms of tissue damage, influencing one another along the way. So there are few simple answers when it comes to the proximate causes of chronic inflammation - they are very complicated in their details. It is easy enough to say that a part of it is the signaling of senescent cells, and a part of it is particular to the way in which the immune system runs down and malfunctions in later life. But those short sentences cover a ferociously complex biochemistry that is only partially understood.
There are a few simple ways forward towards effective control of some of the sources of inflammation in aging, however. Selectively destroying senescent cells removes their inflammatory influence without having to understand the details. Similarly, clearing out all immune cells while using cell therapy to speed their replacement is a viable approach to some of the issues in the aged immune system that result in higher levels of inflammation. Restoring the ability of the thymus to produce a larger supply of new immune cells is probably also useful. These and a few other plausible approaches don't require a great deal of new knowledge and largely bypass the state of ignorance regarding the biochemical details of inflammatory aging. Sometimes it doesn't matter why something takes place, given a comprehensive enough approach to removing it or otherwise dealing with it.
At present, chronic inflammation is thought to be a risk factor for a broad range of age-related diseases such as hypertension, diabetes, atherosclerosis, and cancer. The burdens of unhealthy aging associated with lifestyle are increasing, both in developed and developing regions. Therefore, the elucidation of the sources and cellular pathways/processes of chronic inflammation is an urgent task.
There are several possible factors that initiate and maintain a low-grade inflammatory response. These include aging, unbalanced diet, low level of sex hormones, and smoking. In contrast to young individuals, aged individuals have consistently elevated levels of inflammatory cytokines, especially interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which may induce muscle atrophy and cancer through DNA damage. Visceral fat tissue from obese individuals can also produce both IL-6 and TNF-α, affecting systemic metabolism. The accumulation of macrophages in visceral fat seems to be proportional to body mass index and appears to be a major source of low-grade persistent, systemic inflammation and insulin resistance in obese individuals. Chronic smoking increases production of several pro-inflammatory cytokines such as IL-6, TNF-α, and interleukin-1β (IL-1β), increases systemic inflammation and is an independent risk factor for several lifestyle-related diseases.
Acute inflammation is indispensable for immune responses to invading pathogens or acute traumatic injuries. This process enables repair and cell turnover in multiple tissues. In contrast, chronic inflammation normally causes low-grade and persistent inflammation, leading to tissue degeneration. Chronic, low-grade inflammation is a crucial contributor to various age-related pathologies and natural processes in aging tissue, including the nervous and the musculoskeletal system. Many tissues in the elderly are chronically inflamed, and inflammatory cytokines such as IL-6, IL-1β, and TNF-α are known to weaken the anabolic signaling cascade, including insulin and erythropoietin signaling, leading to the development of sarcopenia.
Debris and immunoglobulin accumulation due to inappropriate cell elimination systems in aging trigger the innate immune system activation leading to persist inflammation. Among the complex determinants of aging, mitochondrial dysfunction has attracted attention for some time. The consequences of age-related failing mitochondrial quality control include the release of mitochondria-derived damage-associated molecular patterns (DAMPs). Mitochondrial DAMPs, especially cell-free circulating mitochondrial DNA, have recently become the subject of intensive research because of their possible involvement in conditions associated with inflammation, such as aging and degenerative diseases. Through their bacterial ancestry, these molecules contribute to increasing an inflammatory response by interacting with receptors similar to those involved in pathogen-associated responses.
The barrier of the oral and gut mucosa against bacterial invasion deteriorates with age. Periodontal disease has also demonstrated to cause chronic low-grade inflammation. The gut microbiota of elderly people displays decreased diversity. The abundance of anti-inflammatory microbiota are diminished in aged individuals. Conversely, inflammatory and pathogenic microbiota are increased with age.
Cellular senescence is defined as irreversible cell cycle arrest driven by a variety of mechanisms. It is evident that the number of senescent cells in several organs increases with age; these cells secrete multiple inflammatory cytokines, generating low-grade inflammation. This phenotype of senescent cells is termed the senescence-associated secretory phenotype or SASP, which recently has been proposed as the main origin of inflammaging in both aging and age-related diseases such as atherosclerosis, cancer, and diabetes. Increasing evidence has suggested that the clearance of senescent cells in animal models attenuates the progression of age-related disorders, including atherosclerosis and osteoarthritis. These data strongly support the hypothesis that senescent cell clearance, reprogramming of senescent cells, and the modulation of pro-inflammatory pathways related to the acquisition of SASP might be pursued as potential anti-aging strategies for combating age-related diseases and expanding the health span of humans.
"Immunosenescence", which is the age-related dysregulation of an innate immune system, is characterized by persistent inflammatory responses. Immunosenescence increases the susceptibility to malignancy, autoimmunity, and infections; decreases the response to vaccinations; and impairs wound healing. Conversely, chronic inflammatory disease can accelerate the "immunosenescence" process. The mechanisms that underlie this persistent aging-associated inflammation remain incompletely understood but seem to involve changes in the numbers and functions of innate immune cells. Changes in the expression of pattern recognition receptors (PRRs), activation of PRRs by endogenous ligands associated with cellular damage, and unusual downstream signaling events of PRRs activation have been implicated to induce chronic cytokine secretion. Thus, together with cell senescence, dysregulation of immunological imprinting mediated by trained innate immunity might also contribute to persistent low-grade inflammation that occurs even after the initial stimulus has been removed.