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A Short Tour of the Senescence-Associated Secretory Phenotype


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#1 reason

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Posted 02 September 2021 - 10:11 AM


Senescent cells accumulate with age, but are never more than a tiny fraction of somatic cells in most tissues, even in very late life. Senescent cells nonetheless cause considerable harm via the signals that they produce, the senescence-associated secretory phenotype (SASP). These signals provoke chronic inflammation, harmful remodeling of tissue, and dysfunctional activity in nearby cells. That comparatively few senescent cells can cause an outsized level of pathology simply by existing is why the strategy of selectively destroying senescent cells with senolytic therapies produces such impressive results in animal studies. Removing accumulated senescent cells turns back degenerative aging. A meaningful fraction of the inflammatory, disrupted state of aged tissue is actively maintained by the SASP generated by senescent cells.

A number of features of senescence have been characterized, which could be used as proper biomarkers or potential therapeutic targets. Senescent cells generally display dramatically morphological changes, increased β-galactosidase activity, stable cell cycle arrest, persistent DNA damage response, metabolic reprogramming, and significant chromatin remodeling. The secretion of senescence-associated secretory phenotype (SASP) factors change the tissue microenvironment and affect even remote tissue via paracrine mechanisms, which is believed to contribute to organ degeneration with aging.

The phenotypic manifestations of SASP are heterogeneous and induced by different internal and external stimulus including telomere attrition, DNA damage, oncogenic activation, mitochondrial dysfunction, or epigenetic alterations. The SASP factors are mainly made of different types of soluble components including pro-inflammatory cytokines, growth factors, chemokines, and extracellular matrix-degrading proteins. This particular combination of signaling factors and the proteases that degrade extracellular matrix (ECM) to facilitate signal transduction has made SASP a powerful mechanism to modulate intercellular communication. The secretion of SASP factors is considered as a major detrimental aspect of senescence because it promotes chronic inflammation, induces fibrosis, and causes stem cell exhaustion.

However, it has also been shown to favor embryonic development or wound healing, suggesting whether beneficial or detrimental effects the SASP exerts depends on the physiological and pathological context. For example, a recent study has shown that transiently exposing the primary mouse keratinocytes to SASP factors increased cell stemness and regenerative capacity in vivo, while prolonged exposure caused secondary senescence and hindered regeneration. This suggests senescence has more complicated physiological roles than currently understood.

Senescence and its secretion phenotype SASP are the most fundamental player that could systematically change physiological functions at the intercellular level and reshape the tissue microenvironment toward aging. They directly change compositions of cell population by arresting the proliferation of progenitor cells or release pro-inflammatory factors to chronically elevate basal inflammation level causing systematic inflammaging. The effects of senescence and SASP are "erosive." Once it starts, it has the potential to spread via the flowing cytokines to induce remote secondary senescence.

Elimination of senescent cells by senolytic drugs has been proven to be effective to counteract senescence in natural aging or age-related disease model. Recently, the first clinical trial of senolytic drug was conducted in human with idiopathic pulmonary fibrosis (IPF). Surprisingly, instead of rescuing lung functions, there was significant improvement in locomotor function such as walking distance or gait speed. Although it is a mystery why the drug failed to take effect in lungs where the most of senescent cells exist in IPF patients, it is still exciting to see the improvement in motor functions which proved senescence communicates at inter-tissue levels. In the future, increasing the specificities of senolytic drugs might help to better cure aging-related diseases.

Link: https://doi.org/10.3...hys.2021.702276


View the full article at FightAging
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#2 Steve H

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Posted 02 September 2021 - 02:10 PM

Today, we want to highlight a recent review that charts the pro-inflammatory signals produced by senescent cells [1].

What is the senescence-associated secretory phenotype?

As we grow older, an increasing number of aged cells in our body enter a state called senescence. At this point, the cells no longer divide and, under normal conditions, should initiate a self-destruct sequence known as apoptosis. The immune system then disposes of these old cells, allowing fresh replacement cells to take their place.

Unfortunately, like many things in our bodies, this disposal process breaks down and starts to grind to a halt. This results in an increasing number of senescent cells evading apoptosis and remaining at large in the body. Cellular senescence is one of the reasons that we are thought to age.

The problem is that these cells don’t just hang around taking up space that could be used by healthy new cells, they also cause inflammation. Senescent cells secrete a mixture of pro-inflammatory cytokines, chemokines, and extracellular matrix proteases, which, together, form the senescence-associated secretory phenotype, or SASP.

The SASP contributes to the smoldering background of chronic inflammation that typically accompanies aging and can cause many problems.

 

 

Disrupting the lines of communication

Not only does the SASP cause inflammation and disruption to various cellular processes, it can also mess up cell-to-cell communication, leading to things like the immune system going haywire and triggering other cells exposed to the SASP to become senescent. Altered intercellular communication is also a proposed reason we age.

It doesn’t take many senescent cells at all to create this pandemonium. Even by the time we reach advanced age, only a small percentage of the total cells in our body are senescent. This means that a relatively small amount of these cells can create a problem many times greater than their number.

 

 

Reviewing the senescence-associated secretory phenotype

This review takes a look at the SASP and how its influence contributes to systemic aging in the context of altered intercellular communication and cellular senescence. The review explores the mechanisms of how senescent cells and their secreted SASP, NAD+ metabolism, and circulating factors regulate systematic aging.

It also takes a look at some of the potential solutions to these problems using various therapies for age reversal.

Abstract Conclusion

With 100% incidence rate and individualized symptoms, aging is a highly complex process which simultaneously affects multiple organ systems (Ahadi et al., 2020). In addition to probing for the cell-autonomous mechanisms of aging, there is growing awareness of that deregulated intercellular communication contributes to decline in tissue/organ health with aging (Lopez-Otin et al., 2013). Intercellular communication refers to both direct interactions between neighboring cells and indirect cell communication via various message signals. A harmonious intercellular communication system is very important for organ development, stress response, cell survival and etc. In contrast, a disordered intercellular communication can be detrimental in aging progression and promote aging-related diseases (Fafian-Labora and O’Loghlen, 2020).

The best-known means of regulating intercellular communication are soluble factors in blood or extracellular matrix that can easily cross cell membrane to take effect through autocrine or paracrine signaling (Acosta et al., 2013). These soluble factors exist in various forms including proteins, metabolites or nucleic acids. Protein factors are the most well-studied, with the proactive secretome of senescent cells, known as senescence-associated secretory phenotype (SASP) factors, accounting for the vast majority. Senescent cells amass with age and secret more and more SASP factors into extracellular matrix, resulting in chronic low-grade immune response activation, or “Inflammaging,” which systematically compromise physiological functions and contribute to age-related dysfunctions in different organs or tissues such as neurodegeneration (Frederiksen et al., 2019; Ogrodnik et al., 2021), atherosclerosis (Childs et al., 2016), osteoarthritis cancer (Jeon et al., 2018), and kidney dysfunction (Valentijn et al., 2018), etc. Apart from SASP factors, non-SASP circulating protein factors and metabolites, particularly NAD+, have been extensively researched in recent years for their roles in aging development. Studies designed to counteract the change of these factors or metabolites caused by aging have shown that they are promising targets for anti-aging interventions. Moreover, recent studies have accumulated evidence that non-coding RNA molecules are linked to several biological aspects of aging such as senescence or autophagy, indicating more research attention needed.

Here, we review some major means of intercellular communication that affect aging such as senescence and senescence associated secretion phenotype (SASP) in the context of physiological or pathological scenario. We also go over the regulatory mechanisms of circulating aging-related factors including proteins factors, NAD+ and non-coding RNAs, as well as potential anti-aging strategies that target them. In light of the close tie of NAD+ metabolism with aging, we discuss how different organs use this highly mobile cofactor to shape cellular microenvironment. In light of the close tie of NAD+ metabolism with aging, we-discuss how different organs use this highly mobile cofactor to shape cellular microenvironment.

While we are still some way from a more complete understanding of aging and how the nine reasons we age are linked and regulated, that knowledge is growing. We are much further down the road to understanding and ultimately bringing aging under medical control than we were just ten years ago. This review collates a great deal of that knowledge and helps order it in a logical way that makes for a worthwhile read.

One of the urgent needs for our field is moving toward a unified theory of aging that puts all the pieces of the puzzle together. Reviews like this help to consolidate what we have learned and contribute towards that unified theory of aging.

That said, while it is certainly true that we do not yet understand aging fully, we know enough to start testing interventions against aging. Therapies such as senolytics as well as those that seek to restore metabolic homeostasis, such as NAD+ repletion, are likely near-future prospects and could significantly change how we age. This review does a good job of discussing these and other potential solutions.

 

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Literature

[1] Tan, Q., Liang, N., Zhang, X., & Li, J. (2021). Dynamic aging: channeled through microenvironment. Frontiers in Physiology, 12.


View the article at lifespan.io


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#3 Kentavr

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Posted 03 September 2021 - 06:23 AM

It is necessary to distinguish between the processes of "aging" and "decrepitude".
 
"Aging" is an increase in the PROBABILITY of DIE with age. In the process of "decrepitude" it is not directly related.
 
Senescence is the destruction of the extracellular matrix, aging of cells, the occurrence of age-related diseases. Reducing decrepitude, we only CURE age-related diseases, and DO NOT EXTEND the maximum life expectancy.
All the increase in lifespan does not exceed the threshold of life of mice sitting on a diet.
 
(!) A decrease in the number of senescent cells (and SASP) DOES NOT GIVE AN OPPORTUNITY to reduce the likelihood of death in LONG-LIVING mice. Decreasing SASP DOES NOT INCREASE maximum life span. This means that it is at least incorrect to say that reducing the amount of SASP heals "aging". It only heals "decrepitude".

Edited by Kentavr, 03 September 2021 - 06:27 AM.

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#4 Kentavr

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Posted 03 September 2021 - 06:36 AM

Drugs that destroy senescent cells only stop the aging process and reduce the development of cancer. That is, they, in fact, simply improve the quality of life.
 
Improving the quality of life can be achieved with the help of diet - the effect will be about the same.
 
Drugs that kill aging cells will not decrease the likelihood of death for dieters.
 
You are looking in the wrong direction. You have to look at stem cells and extracellular matrix.
 
Metformin prolongs the life of diabetics because it increases the number of stem cells in the body. This effect was shown in mice: metformin increased the number of stem cells in the hippocampus of the mouse brain.
 
This is why metformin prolongs human life: it increases the number of stem cells. And then the stem cells provide an epigenetic rollback, and also enable organ regeneration, and the person / animal lives longer.
 
You are looking in the wrong direction!

Edited by Kentavr, 03 September 2021 - 06:39 AM.

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