Aging, Inflammation, and the Failure to Clear Senescent Neutrophils

Can Turning Off the Prostaglandin E2 EP2 Receptor on Macrophages Rejuvenate Aging Tissues?

Cellular senescence is probably a term you’re familiar with if you’re interested in longevity science. It’s the zombie-like state when cells are at the end of their life and can be cleared out by the immune system. While cellular senescence is a normal process that happens all of your life, in aging, senescent cells start to pile up. The problem with excess senescent cells is that these cells secrete inflammatory cytokines as signals that they need to be killed off and removed from the body — leading to chronic low-grade inflammation in aging. Inflammaging.

For a number of years, longevity research focused on senolytic compounds, like quercetin + dasatinib, as a way to clear out excess senescent cells. While this works well in cell cultures, it doesn’t quite cut it as far as moving the needle in aging (and new studies show possible negative long-term side effects).¹²³

A new study shows an alternative to senolytics: Prompt our own immune system to kick it back into gear to clear out the senescent cells.

Some background first:
Neutrophils are a type of white blood cell that circulate in the bloodstream, looking for pathogens or foreign particles. When they encounter something ‘bad’, they basically squirt out poison and release their cellular content in a way that forms a net to trap the pathogen.

Neutrophils are the most abundant white blood cell, and your bone marrow cranks out up to 100 billion a day (which is kind of mind-boggling). They are short-lived cells that only circulate for about a day, and then they end up needing to be cleared out of the spleen, liver, and other tissues by another type of immune cell — macrophages.

Tissue-resident macrophages are constantly clearing out the dying or senescent neutrophils, which release signals to the nearby macrophages that they are ready to be cleared. Macrophages then tether and engulf the neutrophils, which are then digested. This is called efferocytosis. Think of them as acting like garbage collectors, taking out the cellular trash. You don’t want the garbage collectors to go on strike or get slowed down.

So all day long your macrophages are clearing out billions of senescent neutrophils. When the ability to clear out neutrophils slows in aging, these cells can quickly accumulate, giving off their inflammatory signals and also inducing neighboring cells, such as fibroblasts, to become senescent. Thus, neutrophils are disproportionately important in aging because of production scale, rapid transition to senescence, and ability to promote nearby cells to become senescent.

New paper, new insight into aging:
A new paper in Science (Tan et al., July 2026) explains how macrophages lose their ability to clear out senescent neutrophils efficiently in aging.

The study found that the prostaglandin E2 receptor EP2 is key here. In aging, that receptor is activated and, in turn, blocks the ability of macrophages to tether to the senescent neutrophils and clear them out.

Most importantly, blocking that PGE2-EP2 signaling on the macrophages restored their ability to clear senescent neutrophils in multiple organs, reverting the organs to a more youthful state. In mice.

What is prostaglandin E2 and the EP2 receptor?

Prostaglandin E2 (abbreviated PGE2) is a lipid signaling molecule made from arachidonic acid. It’s generated with help from the COX1/2 enzymes from arachidonic acid (omega-6 PUFA stored in cell membranes). PGE2 is produced by many different cell types (immune cells, endothelial cells, fibroblasts, etc) during inflammation or injury. If COX1 and COX2 sound familiar, they are the enzymes that NSAIDs and aspirin act on, reducing pain and inflammation by blocking prostaglandin production.

Prostaglandin E2 is completely necessary in acute inflammation - when you cut yourself, PGE2 is essential in recruiting immune cells to the wound in the initial response. You don’t want to block it all the time. However, PGE2 signaling also can dampen the macrophage response when it is chronically available.

Prostaglandin E2 binds to four different receptors, called EP1, EP2, EP3, and EP4. EP2 is the one that is important in the context of macrophages clearing out senescent neutrophils. On macrophages, the EP2 receptor is abundant. When activated by prostaglandin E2, it causes a signaling cascade that restrains macrophage activation, shifting them away from the activated phenotype that clears senescent neutrophils. This can be beneficial for limiting damage during an acute situation, keeping the immune system from being overly aggressive. However, it becomes problematic in aging if prostaglandin E2 is chronically slightly elevated, essentially causing macrophages to be less efficient in clearing out senescent cells at the same time that the aging body is producing a lot of senescent cells.

It’s like a never-ending loop of low-grade inflammation causing an increase in prostaglandin E2 due to COX2 activation. I mentioned above that aspirin blocks COX2 activation, and this inhibition of prostaglandin E2 synthesis is likely one way that aspirin has beneficial effects for aging. (Yes - there are drawbacks too; this isn’t a blanket endorsement that everyone should take aspirin…)

Why is this new study important?

It may seem like I’m rehashing old science here - arachidonic acid, inflammation, prostaglandin E2, etc. These players have been talked about for decades for their role in cardiovascular disease, arthritis, and aging.

This new study⁴ showed that blocking one specific prostaglandin E2 receptor, the EP2 receptor, on tissue-resident macrophages was effective for jump-starting the macrophages to clear out senescent cells. This reduces inflammation and partially turns back the clock in tissues, especially in the liver. Yes, it was done in mice, but these same EP2 and neutrophil signatures exist in aged human tissue.

Reducing EP2 signaling in macrophages improved mitochondrial fitness and immune system fitness. It improved frailty, cognitive decline, and cardiac dysfunction - moving them toward a more youthful state.

The organs of older mice lacking EP2 in their tissue-resident macrophages had lower neutrophil numbers, similar to youthful mice. The mice looked younger, were more physically fit, and had younger organ function -compared to the control group that didn’t have EP2 inhibited.

Importantly, the researchers were able to do this both through genetic editing and through pharmacological inhibition of the EP2 receptor on the tissue-resident macrophages.

There are still a lot of unknowns and questions on this new research…

The prostaglandin E2 EP2 receptor has been studied for decades for its role in asthma, fertility, and neurodevelopment - and for its problematic role in tumor growth. There’s a lot of research on inhibiting the receptor for cancer and for pain syndromes, so this pathway has potential drugs in the pipeline, with a lot of testing still needed.⁵

So what can you do in the meantime?

Reducing prostaglandin E2 overproduction is the first thing that comes to mind. This goes back to what has long been known - reducing overall inflammation, eating a healthy diet that doesn’t contain a lot of omega-6 PUFAs, and possibly considering a COX2 inhibitor.

PGE2 is made from omega-6 fatty acids, so avoiding omega-6 seed oils in large quantities may also make a difference. A somewhat famous study from a few decades ago in mice showed that a diet high in corn oil (omega-6) increased prostaglandin E2 levels by 6-fold. ⁶

Supplementing with DHA and EPA (omega-3 fatty acids found in fish or krill oil) can also decrease PGE2. DHA and EPA increase pro-resolving mediators to reduce inflammation, and they also shift the omega-6 to omega-3 balance a bit. ⁷⁸

Natural COX2 inhibitors include:

• Polyphenols and plant compounds, such as berberine or kaempferol, which specifically inhibit COX2-mediated PGE2 production. (Amazon links are examples and not a brand recommendation, per se.)

• Curcumin also reduces COX2 expression and decreases PGE2 in macrophages.⁹

However, it is really important here to note that reducing PGE2 in macrophages is likely to help a little bit, but it’s nowhere near the same as selectively blocking the EP2 receptor on tissue-resident macrophages. Shifting away from dietary omega-6s and popping a curcumin pill isn’t likely to be enough to fully restore the macrophages’ ability to remove the senescent neutrophils. Think of it more as a way to reduce some of the negative impacts of aging.

Silymarin has been studied for inhibiting EP2 activation, but not to the same extent as EP2 inhibitors used in research studies.¹⁰ Silymarin is found in milk thistle seeds.

Wrapping up…
Promoting the body’s natural clearance of senescent cells makes a lot of sense, and this new study gives us a big leap forward in understanding how to do that. We need a lot more research on the pros and cons of blocking the EP2 receptor, since it is found in tissues throughout the body and plays a role in things like bone healing, vasodilation, and fertility. This will be a nuanced pathway for researchers to figure out how and when to modify EP2 with antagonist drugs without negative side effects.

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Side note for my paid subscribers: I wanted to let you know that I’ve updated my article about my experiment with a DIY topical supplement for reversing age spots. Check it out if you’re interested.

References:

1. https://lifespan.io/a-popular-senolytic-treatment-causes-brain-damage-in-mice/

2. https://www.biorxiv.org/content/10.1101/2024.10.22.619522v1

3. https://www.aging-us.com/article/205581/text

4. https://www.science.org/doi/10.1126/science.aea3075

5. https://www.sciencedirect.com/science/article/pii/S0968089626000969

6. https://pubmed.ncbi.nlm.nih.gov/2770427/

7. https://www.sciencedirect.com/science/article/pii/S0271531726000254

8. https://pmc.ncbi.nlm.nih.gov/articles/PMC12087734/

9. https://pmc.ncbi.nlm.nih.gov/articles/PMC6137277/

10. https://onlinelibrary.wiley.com/doi/abs/10.1002/mc.22092