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:
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.