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An Attempt to Attenuate the Bad Behavior of Senescent Cells

In the paper linked below, the authors report on an attempt to make senescent cells less damaging to surrounding tissues and overall health by modulating their behavior via inhibition of TNF-α, a signaling molecule involved in inflammation. Senescent cells accumulate with age and secrete a mix of molecules - the senescence-associated secretory phenotype (SASP) - that cause all sorts of harmful effects. The more senescent cells there are in any given part of the body, the worse the outcome: chronic inflammation, tissue dysfunction, and raised cancer risk are among the consequences. Accordingly, the presence of senescent cells is known to contribute to the development and pathology of most of the common age-related conditions. Removal of senescent cells has been shown to extend life in mice, but among the researchers who work in this field, there is in fact no great consensus that removal is the best approach. This approach is being taken nonetheless, and two startups, Oisin Biotechnologies and UNITY Biotechnology, are working on commercial development of their approaches to selective destruction of senescent cells. Still, there are those who would rather aim at using pharmacology to adjust the behavior of senescent cells to suppress the worst aspects of their behavior.

For my money, I want to see destruction rather than manipulation. It absolutely and definitely gets rid of whatever bad things senescent cells might be doing, including all the bad things that the research community is still the process of cataloging, or don't yet know about. The recent life span study in mice gives us a good assurance that the useful contributions that senescent cells may be making to our health, such as their roles in wound healing and reduction of cancer risk when they are few in number, are not going to be impacted significantly by periodic clearance. Manipulation of cell behavior, on the other hand, doesn't have an auspicious history of producing more than incremental gains. The way things tend to work is that researchers find a mechanism, often via gene engineering in mice, that produces some beneficial outcome. They then dig through the catalog of approved medicines, herbs, and other odds and ends in search of something that adjusts the same gene or protein level to some degree, while causing side-effects that are not unbearable. At the end of the day, a very diluted effect is the median outcome, achieved at great cost.

So given the option between (a) a straightforward effort that can rid of senescent cells and their effects near-entirely, and which already has methods under development, and (b) the standard lengthy and expensive drug development process that in the end may produce a modest reduction in the harmful output of senescent cells, and which currently has no good drug candidate in the works, the first of those choices sounds a lot better to me. Still, as I mentioned, a fair number of researchers are focused not on removal of senescent cells but rather on tinkering with adjusting the metabolism of senescent cells so as to reduce the impact of the senescence-associated secretory phenotype. Here is one example:

Anti-TNF-α treatment modulates SASP and SASP-related microRNAs in endothelial cells and in circulating angiogenic cells

The senescence status of stromal cells, including endothelial cells (ECs), plays a major role in inflammaging, the low-grade, chronic, and systemic inflammatory condition associated to aging. Cellular senescence is related to the acquisition of a discrete phenotype, the so called senescence-associated secretory phenotype (SASP), characterized by the activation of a pro-inflammatory transcriptional program. Accordingly, the pathways involved in SASP acquisition, as the NF-kB and the IL-1/NLRP3 inflammasome pathways are master modulators of the aging rate. Notably, removal of senescent cells in animal models, is able to prolong lifespan and healthspan. Evidence that the number of senescent dermal fibroblasts correlates with the presence of some age-related diseases has also been reported in humans.

Interventions directed at preventing the adverse effects associated with the SASP are being explored The most promising strategies involve delaying cellular senescence; SASP switch-off; and selective removal or killing of existing senescent cells. Even though SASP involves the release of hundreds of molecules, like interleukin (IL)-1, IL-6, IL-8, tumor growth factor (TGF)-β, and tumor necrosis factor (TNF)-α, the most common and best characterized. Some of these cytokines can induce or reinforce the senescent phenotype by acting in autocrine and paracrine manner, spreading senescence via a "bystander effect." However, TNF-α inhibition in relation to EC senescence and SASP acquisition has not been already extensively explored yet. TNF-α can promote senescence in endothelial progenitor cells and human umbilical vein endothelial cell (HUVEC) cultures, and it has well-known adverse effects on endothelial function in vivo. However the molecular basis for these effects has not been fully elucidated yet.

Here we tested whether TNF-α blockade can reduce the acquisition of the senescent phenotype and/or the SASP by HUVECs, an in vitro EC model. We documented that inhibition of TNF-α activity in ECs undergoing replicative senescence attenuated the SASP. Importantly, anti-TNF-α treatment also induced eNOS up-regulation, suggesting an enhanced endothelial function. Interestingly, these significant effects induced in HUVECs undergoing replicative senescence were not associated with significant decrease of classic senescence biomarkers, such as SA-β-Gal, p16/Ink4a, and PAI1.

Some studies have described the possibility of dissociating experimentally the SASP from senescence. Although a number of reports have shown that SASP modulation influences the rate of senescence, differences have been observed depending on the cytokines involved. In our experimental model, i.e. HUVECs undergoing replicative senescence, the number of senescent cells was not significantly affected by continuous anti-TNF-α treatment, suggesting that TNF-α is not closely associated with the arrest of replicative growth. Although it has been demonstrated that IL-1 or TGF-β blockade can attenuate SASP spread in different senescence models, data on anti-TNF-a treatment were scarce and inconclusive. The present findings now indicate that anti-TNF-α treatment can restrain the SASP without significantly affecting senescence signal transmission, either autocrine or paracrine.

In conclusion, anti-inflammatory treatments capable of restraining the SASP could contribute to delay age-related disease onset and progression, especially in patients with an established chronic inflammatory background. Clearly, TNF-α inhibition has too many side effects to be administered as a clinical anti-aging treatment in old patients. However, the present findings are in line with earlier reports that it is possible to dissociate the SASP from senescence, and encourage the search for substances, synthetic or natural, that not only suppress but also restrain the SASP. Our data adds a piece to the complex puzzle of inflammaging, furthering our knowledge of the mechanisms controlling the SASP in ECs and the associated chronic inflammation that can promote the development and progression of the major age-related diseases.

Comments

In a study in humans, polypodium leucotomos, the sun screen pill, decreased TNF-alpha by 53%, IL-2 by 24%, INF-gamma by 72% and the inflammatory cytokine IL-6 by 100%. Besides attenuating the rate of skin aging it seems like it may be a helpful addition as an intermediate measure while we wait for a more advanced method of senescent cell clearance in humans.

Posted by: Santi at March 16th, 2016 7:23 PM

Yes I agree with Reason, removal is the best solution.

We are looking at ABT-199 in our first MMTP testing phase and potentially ABT-199 + Dastatinib as there is synergy potential there.

The key is to raise the funds to robustly test this, we begin in April on lifespan.io please support us!

http://www.majormouse.org

Posted by: Steve H at March 17th, 2016 7:17 AM

@Santi: the study to which you refer was not a study in humans, but a study in human cells in culture — specifically, a study in peripheral blood mononuclear cells. The cells were simply bathed in Polypodium leucotomos extract, bypassing the real-world questions of absorption, metabolism, distribution, and excretion, which could nullify any such effects. Moreover, even in this artificial model, they didn't demonstrate a reduction in baseline cytokine production, but from the artificially-inflated levels generated by riling them up with phytohaemagglutinin, a lectin found in uncooked beans that stimulates inflammation in white blood cells. It tells you exactly nothing about the real-world effects of oral consumption of P. leucotomos pills.

Posted by: Michael at March 17th, 2016 9:04 PM

@Michael any thoughts on ABT-199 and its potential as a Senolytic?

Posted by: Steve Hill at March 18th, 2016 6:33 AM

Why would you want to use this agent? ABT-199 was designed explicitly as a BCL-xL-sparing BCL-2 inhibitor, because BCL-xL was shown to be critical to platelet survival and its inhibition by Navitoclax the reason for its thrombocytopenia, which latter has likely tanked its further development. But Zhang's group showed with siRNA that dual inhibition of both antiapoptotic proteins was necessary to compromise the survival of senescent cells, and reports explicitly that selective “Inhibition of BCL-2 or BCL-xL function alone by treating cells with ABT199 (ref. 21) or WEHI539 (ref. 22), respectively, did not selectively kill [senescent cells]; however, treatment with the combination of ABT199 and WEHI539 did so.”

On that basis, I can see no reason to expect that it will work, and having now seen the context from your earlier comment I would want to understand your rationale for bothering with it, and no matter how strong that rationale is I would still discourage you from using it unless you have the resources to do a series of detailed in vitro studies in a wide range of cell types and modes of senescence induction to support its efficacy before going to the time and expense of animal studies

Posted by: Michael at March 18th, 2016 11:30 AM

It was a lead given to us by a company working on Senolytics. We were looking at Navitoclax but are aware there was no additional synergy shown when combined by Scripps with Dasatinib. ABT199 was a suggestion to test perhaps in combinaton with Dasatinib.

Posted by: Steve Hill at March 18th, 2016 7:33 PM

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