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A Problem Population of Monocytes are Found to be Senescent Cells

The Life Extension Advocacy Foundation volunteers here note an open access paper from earlier this year. The authors characterize a small, problematic population of the immune cells known as monocytes as being senescent cells, having the same character of inflammatory signaling and disruptive behavior as other types of senescent cell. This finding is one of many discoveries emerging from the great expansion of funding and interest in cellular senescence that has taken place in recent years. The accumulation of senescent cells is an important cause of aging and age-related disease, but broad recognition of this point has required a great deal of time and hard work. Now that research in this field has picked up, the consensus on a range of cell types and behaviors, those observed in age-related disease and known to be harmful, is likely to be revised in the direction of the involvement of cellular senescence.

Monocytes are immune cells that can differentiate into macrophages and are involved in the processes of both innate and adaptive immunity. There are three known types of monocytes: classical, intermediate, and nonclassical. The nonclassical ones are the most pro-inflammatory even though they express high levels of miR-146a, a microRNA that is known to limit inflammatory responses. This apparent contradiction is what led the authors of this study to discover if there is more to miR-146a than meets the eye.

Cellular senescence is a phenomenon by which normal cells stop dividing and begin secreting a highly inflammatory cocktail of chemicals known as the senescence associated secretory phenotype (SASP). In modest amounts, senescent cells have beneficial roles; however, they tend to accumulate as we age, which results in a constant, low-grade inflammation as well as a higher susceptibility to a range of age-related diseases, cancer included, in the elderly. Given that the elevated pro-inflammatory activity of nonclassical monocytes is rather reminiscent of the SASP and that they display such high levels of miR-146a, the scientists reasoned that nonclassical monocytes may well undergo senescence.

Scientists found that elderly patients display an accumulation of these cells compared to younger people. They collected samples from 30 healthy volunteers between the ages of 22 and 35 years and 30 healthy elderly people aged 55 and older. While there was no significant difference in the total percentage of any of the three monocyte types between the two groups, the researchers found out that the elderly had a higher monocyte count per volume of blood, especially nonclassical monocytes. Accordingly, the level of inflammatory cytokines in the blood of the elderly was significantly higher. This led the scientists to conclude that senescent monocytes do indeed accumulate in the blood of the elderly and may well contribute to inflammaging, which is the chronic, low-grade inflammation that is typical among older people.

The researchers suggest that nonclassical monocytes might be a viable target for treating age-related and chronic inflammatory conditions, even non-age-related ones. It may be possible to reduce the SASP secreted by nonclassical monocytes or reduce the number of circulating nonclassical monocytes.

Link: https://www.leafscience.org/type-of-human-monocytes-found-to-undergo-senescence/

Comments

Now we have to know how well do those senecent monocytes teaspoons to the well known senolitics.

Posted by: Cuberat at October 10th, 2018 6:50 AM

Do the current senolytic therapies under development target Monocyte senescent cells?

If not, Oisin might come out on top in this area as their DNA promoter targeting approach could be easier than trying to find a small molecule drug to bind to relevant proteins, whilst not having off target effects by binding to other proteins.

Posted by: Jim at October 10th, 2018 11:04 AM

It seems that a lot of conditions are either outright caused by or aggravated by done form of senecent cells. Looks the senolitics will be a neat hammer and all the diseases will look like nails.

Posted by: Cuberat at October 10th, 2018 1:16 PM

@Jim, like all senescent cells it would depend what pro-survival pathway it is using to evade apoptosis. It is for that reason that no single small molecule appears to be able to kill all senescent cells as they differ in which pathways they use to survive. Peter de Kezier mentions a senolytic "cocktail" as being a possible solution to this in the interview we did with him here:

https://www.leafscience.org/dr-peter-de-keizer/

Posted by: Steve Hill at October 10th, 2018 1:49 PM

@Steve Hill: Great interview, thanks for the link to that.

Posted by: Steven B at October 10th, 2018 3:04 PM

Steve, the interview was awesome, very detailed and candid, thank you for the link.

It seems for some us wanting to take the senolytic treatment, either have to wait at least 10 years, self experiment, or "hope" it will be available via medical tourism.

Anyone thinks it will be available in another country similar as stem cell treatments anytime soon?

Posted by: Robert at October 10th, 2018 7:45 PM

@jim

Fisetin doesn't appear to target macrophages or dendritic cells; two types of cells derived from monocytes. It may be possible that these senescent monocytes are not able to differentiate further into macrophages or dendritic cells and they have a pathway that is able to be targeted by another type of senolytic. It is highly likely nobody has looked at this as the published studies are pretty narrow in scope with respect to identifying target cell types.

Given that there have been a lot of promising results associated with different senolytics and there is some evidence to suggest that there is a decrease in systemic inflammation, I really would be interested in seeing a much more detailed study looking at the effects on the immune system. Not only looking at changes in immune cell subsets but also looking at how the immune system responds to different types of immune challenge.

Re: Fisetin: https://www.ebiomedicine.com/article/S2352-3964(18)30373-6/fulltext

In this paper they look a bit at how the immune system responds, but it would be nice to see more.

Posted by: Aaron at October 14th, 2018 12:59 AM

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