Senoinflammation or Inflammaging or …???

The below concerns very complex knowledge development but also represent a very fast knowledge development, where we can extract some superior information which has been known for some time. Important is to extract such knowledge in a concrete useful way individuals can “tailor” based on reasonable understandable information. Autophagy is one of the cornerstones as well as mitochondria funtitonality.

Most of the below is from different references and finally some of my own conclusions

Inflammaging: A chronic pro-inflammatory status is a pervasive feature of ageing. This chronic low-grade inflammation occurring in the absence of overt infection has been defined as “inflammaging” and represents a significant risk factor for morbidity and mortality in the elderly. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850851/
(Febr. 2018)

Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457053/ (April 2019)

Age-associated chronic inflammation is characterised by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the ageing process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the ageing process:

1. Molecular inflammation of ageing and
2. Inflammaging.

However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research.

3. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required. In this review, we discuss newly emerging data on multi-phase inflammatory networks and proinflammatory pathways as they relate to ageing. We describe
(a) the age-related up regulation of nuclear factor (NF)-κB signalling, cytokines/chemokines,
(b) endoplasmic reticulum (ER) stress,
(c) inflammasome, and
(d) lipid accumulation.

The later sections of this review present our expanded view of age-related senescent inflammation, a process we term “senoinflammation”, that we propose here as a novel concept. As described in the discussion, senoinflammation provides a schema highlighting the important and ever-increasing roles of proinflammatory senescence-associated secretome, inflammasome, ER stress, TLRs, and microRNAs, which support the senoinflammation concept. It is hoped that this new concept of senoinflammation opens wider and deeper avenues for basic inflammation research and provides new insights into the anti-inflammatory therapeutic strategies targeting the multiple proinflammatory pathways and mediators and mediators that underlie the pathophysiological ageing process.

  1. Causes. As inflamm-aging (https://en.wikipedia.org/wiki/”Inflammaging) is a complex and systemic issue, it is likely that inflammaging is a result of several factors. It seems that the major cause of inflamm-aging is accumulation of misplaced and misfolded self-molecules from damaged cells”. …. “As inflamm-aging is a complex and systemic issue, it is likely that inflammaging is a result of several factors. It seems that the major cause of inflamm-aging is accumulation of misplaced and misfolded self-molecules from damaged cells.[10] These molecules are recognized by receptors of innate immune cells which leads to their activation and consequently to inflammation. Cell components which can stimulate innate cells include microRNAs, mitochondrial DNA or histones.
    Senescent cells increase with aging, and senescent cells secrete a pro-inflammatory cocktail of chemicals, a condition known as senescence-associated secretory phenotype (SASP).[11]  (from https://en.wikipedia.org/wiki/Senescence-associated_secretory_phenotype) SASP expression is induced by a number of transcription factors, including C/EBPβ, of which the most important is NF-κB.[6][7] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4 *.[8] GATA4 is activated by the DNA damage response factors, which induce cellular senescence.[8]Inflamm-aging has been also associated with persistent Cytomegalovirus infection. Cytomegalovirus drives up production of a variety of inflammatory cytokines and also results in expansion of CMV specific memory T cells.[12] Other possible factors that may lead to inflamm-aging include overnutrition, altered gut microbiome, impaired intestinal epithlial barrier, and chronic stress occurring in any stage of the individual’s life.[13][14][15] Cytokines with inflammatory properties can also be secreted by fat tissue”
  2. Metformin Enhances Autophagy and Alleviates Inflammaging https://www.lifespan.io/news/metformin-enhances-autophagy-and-alleviates-inflammaging/
    A recent study published in Cell Metabolism has shown that metformin, a drug that has been previously shown to be effective against some aspects of aging, ameliorates inflammaging by promoting autophagy, the cellular recycling of damaged components.Mitochondrial dysfunction, autophagy, and TH17Mitochondrial dysfunction is one of the hallmarks of aging, the root causes that cause us all to age. The mitochondria are the powerhouses of the cell, but as we age, our mitochondria have their DNA damaged by sources such as reactive oxygen species, harming their ability to perform their fundamental job. This gradual increase in dysfunctional mitochondria causes our cells to lose their ability to utilize energy, leading to a panoply of age-related diseases.Autophagy is the consumption of damaged or dysfunctional organelles by intracellular processes. Through autophagy, cells are able to recycle and renew their internal components, and, as the researchers of this paper explain, CD4+ (helper) T cells that do not properly perform autophagy behave like older cells.Cytokines are known for causing inflammation, and, as the researchers demonstrate, the TH17 subset of cytokines is strongly associated with the chronic, age-related inflammation known as inflammaging, a key driver of multiple age-related diseases.

    In order to demonstrate the relationship between autophagy, mitochondrial dysfunction, and TH17, the researchers used RNA silencing to disrupt the ability of cultured cells to engage in autophagy. Such cells that were taken from a young subject had their mitochondrial function decreased to the level of an older person. This RNA silencing also set the TH17 cytokine profile of these cells to become one associated with age and diabetes.

    Obviously, what we want is the reverse of this process, and the researchers found that metformin, a commonly researched drug in the rejuvenation biotechnology field, was able to accomplish this in human cell cultures, spurring autophagy and reversing the TH17 cytokine profile.

    Summary Age is a non-modifiable risk factor for the inflammation that underlies age-associated diseases; thus, anti-inflammaging drugs hold promise for increasing health span. Cytokine profiling and bioinformatic analyses showed that Th17 cytokine production differentiates CD4+ T cells from lean, normoglycemic older and younger subjects, and mimics a diabetes-associated Th17 profile. T cells from older compared to younger subjects also had defects in autophagy and mitochondrial bioenergetics that associate with redox imbalance. Metformin ameliorated the Th17 inflammaging profile by increasing autophagy and improving mitochondrial bioenergetics. By contrast, autophagy-targeting siRNA disrupted redox balance in T cells from young subjects and activated the Th17 profile by activating the Th17 master regulator, STAT3, which in turn bound IL-17A and F promoters. Mitophagy-targeting siRNA failed to activate the Th17 profile. We conclude that metformin improves autophagy and mitochondrial function largely in parallel to ameliorate a newly defined inflammaging profile that echoes inflammation in diabetes

    Conclusion: This is a cell culture study, not a human trial, so the usual caveat applies: it may fail in this respect for reasons as of yet unknown. However, as metformin has a well-known safety profile and is already approved by the FDA for other conditions, including diabetes itself, conducting a human trial to assess its effectiveness in stimulating autophagy is easier than testing a novel drug would be. We look forward to such a trial and hope for its success.

* Autophagy concerns cells own sel-reparing proxess, which can be part of self-care program in terms of starvation 14-18 hour each day.

 

 

https://www.hindawi.com/journals/jir/2016/8426874/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348477/
https://www.cell.com/trends/endocrinology-metabolism/pdf/S1043-2760(16)30125-4.pdf