Understanding Why the Immune System Fails to Destroy Lingering Senescent Cells May Lead to New Senolytic Therapies

The accumulation of lingering senescent cells in all tissues is one of the causes of aging. Even in very late life, senescent cells are thought to account for only a few percent at most of all cells in any given tissue, but they cause great disruption to tissue structure and function: chronic inflammation, impaired regeneration, fibrosis, and other unpleasant outcomes. This is accomplished via an as yet incompletely cataloged mix of secreted molecules known as the senescence-associated secretory phenotype, or SASP. Acting via secretions allows a small number of cells to have large effects.

When present for a limited period of time, senescent cells are helpful, a necessary part of wound healing, embryonic development, and suppression of cancer. Cells become senescent in response to the circumstance, the SASP assists in calling in the immune system to help, or in spurring growth, or in instructing nearby cells to also become senescent. Then the senescent cells self-destruct or are destroyed by the immune system once their contribution to the task at hand is complete. It is only when senescent cells linger for the long term that the SASP becomes dangerous, corrosive to tissue function.

Why do some senescent cells fail to self-destruct? Further, while we know that the immune system declines with age, becoming less effective in all of its tasks, why specifically do immune cells fail to identify and destroy some senescent cells? Progress towards more complete and detailed answers these questions may open the door to new classes of senolytic therapy, capable of purging senescent cells from old tissues. While a variety of senolytic treatments are either available or under development, none are capable of destroying more than about half at best of these cells, and then only in some tissues. Combinations of different therapies, and more efficient therapies will be needed in the years ahead.

Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition

Cellular senescence is an evolutionarily conserved mechanism with beneficial effects on tumour suppression, wound healing and tissue regeneration. During ageing, however, senescent cells accumulate in tissues and manifest deleterious effects, as they secrete numerous pro-inflammatory mediators as part of a senescence-associated secretory phenotype (SASP). The elimination of senescent cells in mouse models was shown sufficient to delay the onset or severity of several age-related phenotypes. This has prompted the development of senolytic drugs that selectively target senescent cells. Despite successful reversal of age-related pathologies in animal models, the use of senolytic drugs in humans may be hampered by their lack of specificity for senescent cells, leading to the risk of toxicity. Therefore, alternative approaches that can be used in isolation or in combination with senolytic drugs to improve the elimination of senescent cells in humans should be explored.

Senescent cells can be recognised and eliminated by the immune system. Different immune cell types including macrophages, neutrophils, natural killer (NK) cells and CD4+ T cells have been implicated in the surveillance of senescent cells, depending on the pathophysiological contex. Senescent cells become immunogenic by expressing stimulatory ligands like MICA/MICB that bind to NKG2D and activate their killing by NK cells. Moreover, by secreting chemokines and cytokines, senescent cells can recruit immune cells into tissues that enable senescent cell clearance. However, this secretory process may perpetuate a low-level chronic inflammatory state that underlies many age-related diseases.

Despite the evidence for senescent cell clearance by the immune system, it is not yet clear why senescent cells accumulate during ageing and persist at sites of age-related pathologies. A decline in immune function may contribute to incomplete elimination of senescent cells with age. Ageing has a great impact in both innate and adaptive immune systems, a process known as immunosenescence. Alternatively, changes in major histocompatibility complex (MHC) expression can lead to escape from recognition by the immune system as previously described in cancer and virally infected cells in vivo. Nevertheless, the effects of senescence on MHC expression are not fully understood.

Here, we show that senescent primary human dermal fibroblasts express increased levels of the non-classical MHC-class Ib molecule HLA-E. HLA-E inhibits immune responses against senescent cells by interacting with the inhibitory receptor NKG2A expressed on NK and highly differentiated CD8+ T cells. Accordingly, we find an increased frequency of HLA-E expressing senescent cells in the skin of old compared with young subjects. HLA-E expression is induced by SASP-related pro-inflammatory cytokines, in particular IL-6 and regulated by p38 signalling in vitro. Lastly, we show that that blocking HLA-E/NKG2A interactions in cell culture enhances NK and CD8+ T cell-mediated cytotoxicity against senescent cells. Taken together, these findings suggest that HLA-E expression contributes to the persistence of senescent cells in tissues. HLA-E may therefore represent a novel target for the therapeutic elimination of senescent cells in age-related diseases.

Comments

Aside from mitochondrial dysfunction, is it possible that aging may be due to nothing more than immune system dysfunction?

Posted by: Abelard Lindsey at June 12th, 2019 4:13 PM

@Abelard Lindsey
It seems there is more to aging than immune system corruption and dysfunction. We can design an experiment with immuno compromised move who are never exposed to any biological pathogens and love on sterile environment. I guess they will still age...

Posted by: Cuberat at June 12th, 2019 9:37 PM

@August
Fasting has a lot of beneficial effects. In some cases it can even shrink tumors, sometimes better and faster then chemo. Doesn't cure cancer on its own, though. Fasting forces autophagy and intra and extracellular recycling. In fact, periodic fasting used to be the norm for most of the people for many millennia and our bodies are not made (didn't evolve) for unlimited food supply.

I think that the body waits for the lean times to do the maintenance which is postponed in the time of plenty, so we can be more active for mating or some other expansion activities. When the lean times come, we can( and have to ) slow down, and the body does the cleanup and repairs. It is like a seasonal business where all the maintenance is postponed for low seasons and during the high season all the resources are allocated to serve/accommodate more clients, catch more fish, cut more trees, etc...

The article mentions 72 hours fasting. I would not call those prolonged, though. For the mice and the rats that is a very long period. For a human, someone with BMI over 18, not so much. It might not be enough to deplete the glycogene stores in the liver and muscles. In water fasting one needs at least 3 days to hit keto mode . In many cases even 7 days. From day 7 to 14-17 the body is in a ketosis mode. After that, it passes through usually an unpleasant transition to more energy efficient mode. I would call prolonged fasting from 14 days. From 14 to 21-28 days, depending on one's BMI. After 28 days it becomes extreme. Still doable, but requires the right motivation and techniques.

I , personally, will try to do 3 to 7 days next week. Depending how much will power I could muster. Subjectively, the effects of fasting are good. However, I don't have good objective measures.

Posted by: Cuberat at June 12th, 2019 10:06 PM

@Cuberat: after 14 days it's not fasting but starving. And with a BMI of 18 after 21 days you are likely dead.

Posted by: Barbara T. at June 13th, 2019 12:48 AM

@Cuberat Google "fasting glycogenesis" and look at the picture search. There are several graphs showing glycogene stores depleted at approx 24h.

Posted by: m. at June 13th, 2019 1:51 AM

Hi Abelard! Just a 2 cents.

Me too, I wondered such, it aging really just an immune system become dysfunctional. What is most likely sure is that the immune system is very important to safeguard health and keep above low-health threshold (which compromise your life). You can continue functioning but can suffer frailty/loss of fitness as seen as cancer patients that lose fitness and lose body mass, either/both by cancer itself, immunity loss or by chemotherapy and radiation. Immunity loss or hyperactvation has vast effects from atherosclerosis, cancer, fibrosis to autoimmune diseases, etc..and even a bit aging, itself. But, not as much, that is the epigenetic part of aging. A compromised immune system, in cancer, causes accumulation of mutations (mostly, deleterious), this in turn, causes loss of epistasis/it causes transcriptome drifting and thus demthylation; which means True advancement of aging (as shown measuring blood clock by Horvath epiclock measure), the clock 'needle' is pushed forward, thus you are accelerating in aging 'ahead of your time'. Oncogene-senescence was shown to advanced the clock. The immune system is in communication with oncogenes, oftenly, recruiting them to mitigate cancer invasion (TNF, INF, p53...).

Just a 2 cents.

Hi Cuberat! Just a 2 cents.

Yes be careful, CR or worse, fasting, is not something to take lightly. Although water fasting is feasible, you ahve to be in overall good shape already with enough flesh on...
I practically have this bmi of 18...I would not tough that, 3 days is already too much (when I was younger I could have done it/I did sort of like 3 days water fasting or so (it was hard), but after my disease it 'totalled' me and made me much weaker/frailer. So I would most likely be gone by the 4th day). If you are low BMI, be Very Careful...of doing famine like 'water fasting', humans can tough 30 days, but *can* tough, is not assurance, you may not reach that. It's excrutiating (stomach pangs) and as you said, you becmoe ketotic, but if you have no flesh/fat...then you realize how harder it will be, so it depends as said on BMI and your health prior to doing that. Otherwise, if unhealthy, fasting will terminate you after amount of days and just water; you can lose conscience and your body will become a skeleton, you could lose up to 30lbs, even 40+ lbs...it's that bad (ahteroscleoris made me go from 150lbs to 100lbs at 5'10''...starvation does the same/you burn all the fat WAT/BAT tissue, no carbs anymore, become hypoglemic and can brain lethargy. With taht said, water fasting is powerful for toxin/detoxification of liver ..etc and by a certain amount of days..you will feel euphoric like a 'eureka' in the brain/vivid feel...it means its cleansing and doing autophagy (people must remember that CR and fasting is undernourishment/lack of nutrient and that can have plethora of consequences depending of the body response (I guess you are more experienced and so adapted..that may be much more feasiable as the body was already prepped/experienced that). Jsut be careful (being someone of older age is more need of care to not push body too much to point of (nutrient) 'exhaustion'). Sticking to one day or 2 is better, and still has an effect; while less risky.

Just a 2 cents.

Posted by: CANanonymity at June 13th, 2019 2:11 AM

My BMI is much higher than 18, so I have quite a room. I never had the euphoria. The closest thing was on day 3 that I stopped feeling like crap, but probably not better than when breaking the fast. Fasting over 3 days requires experience and correct techniques to start and break, that is for sure. Otherwise you can get nasty constipation and even poisoning. The gut Flora might get impacted too...

Some 13 years ago I did 22 days and know people who have done 28. Last year u did 8 days and a couple of mini first of 2-3 days . That's why I don't consider 72h "prolonged". Of course, it is highly individual. On top of that I have no subjective way to measure the effects of fasting. Is fasting 3 days better or worse than taking 2g of fisetin? What about 7 or we days versus Dasatinib plus quercetin ? Can senolitics be engaged by fasting? What is the optimal protocol?

Posted by: Cuberat at June 13th, 2019 5:36 AM

Per this topic, here is my recent interview with Professor Shai Shen-Orr PhD., Associate Professor at Technion - Israel Institute of Technology, and Founder and Chief Scientist of CytoReason, discussing AI and machine learning tools to speed up our understanding of the complex labyrinth that is the immune system, and enhancing related drug and bio-marker discovery:

https://www.youtube.com/watch?v=NvGxC1i4IS4

Posted by: Ira S. Pastor at June 13th, 2019 7:39 AM

Aubrey de Grey in his latest interview says that the magnitude of the benefits of senolytics were much greater than he would have expected: https://www.youtube.com/watch?v=zYs8iqZpZKU

Posted by: John S at June 13th, 2019 7:54 AM

@John
Honestly, after so many years of research and basically nothing to slow aging it is about time to find something that works works.

Posted by: Cuberat at June 13th, 2019 8:29 AM

You would think if fasting actually targeted rejuvenation, most old people wouldn't look so weak and frail. Cancer patients lose tons of weight and don't eat for weeks on end. Wouldn't this spur cell regeneration and fight the tumors?

Posted by: Person1234 at June 13th, 2019 8:57 AM

@Cuberat

If you take a look at celebrities like Jared Leto and Shemar Moore. Leto especially remains extremely youthful for being almost 50. He could easily pass for 25-30. He is on a vegan diet, and I don't believe he has had any work done.

Posted by: Person1234 at June 13th, 2019 8:59 AM

@Person1234
If the effects was that strong it would be obvious since the humanity had to fast, albeit involuntarily, so often. The benefits we can get from fasting ate more about to countering the calorie bonanza we are exposed to. So it will increase the health span, reduce morbidity but will not get you pay 125. But with the right protocol you might get a good shot at reaching 110. Ironically before senolitics fasting was the best if not the only option available. I hope they can have synergy and be used together.

Posted by: Cuberat at June 13th, 2019 9:28 AM

As for how the celebrities look. While some of them do drugs and abuse their bodies others are taking extreme care. And usually good looks , which help becoming a celebrity, are evidence of good health and good genes.

So good genes, coupled with good care can get you far at looks, especially if you do minor
Treatments (no plastic surgery, just skin peeling, soon care make up and haair dye). In this light it is surprising how some actors don't agree gracefully...

Posted by: Cuberat at June 13th, 2019 9:33 AM

"It seems there is more to aging than immune system corruption and dysfunction."

Yes, of course. I meant that, in addition to mitochondrial dysfunction, that immunosenescence is the primary cause of aging. I still maintain that mitochondrial dysfunction (mtDNA damage, etc. there are several different mechanisms involved here) is the fundamental cause of aging.

It was a book written by an astrophysicist/astrobiologist (Nick Lane and his story of mitochondria), not a life extension guy, that convince me of this.

Posted by: Abelard Lindsey at June 13th, 2019 10:26 AM

I firmly believe that our body has built-in mechanisms that can keep us strong and healthy up to the end, which I hope is not death but LEV. However, that demands that we treat our body well, which requires a lot of will power, commitment and a positive attitude.

The way it works for me is diet, exercise and CR ( time restricted feeding, intermittent fasting, fasting) in some unusual combinations to achieve homeostasis.

If there is interest, I can provide more detailed information. BTW, I'm 64.

Posted by: Stephan at June 13th, 2019 2:39 PM

We will reach LEV ... or die trying :)

Posted by: cuberat at June 13th, 2019 4:56 PM

I think if immune system dysfunction was the major cause of immune senescence, then there would be a notable correlation become super centurions and some autoimmune conditions. I am aware of only type 1 diabetes as an aging correlation, and that does not cause immune hyper function, and is likely related to insulin control. But I am open to the possibility that the stress of the auto immune conditions result in them killing them selves.

Posted by: JohnD at June 13th, 2019 6:00 PM

@Cuberat : I've fallen into a monthly habit of 4 day water fasts with 10 grams of Fisetin a day during those 4 days. The first day I drink a solution of 3 heaping tablespoons of psylium husk powder - 1) It makes you full/bloated 2) The epic bowl movement that follows the next morning is the opposite of "constipated". The 2nd day (morning, afternoon, and before bed) I take 6 capsules of Dr. Group's "Oxi-Powder" (18 total). Whatever might have remained in your guts after the blunt force of the psylium log is chemically removed. I too feel better on day 4.

On Wednesday evening when I broke my June fast, I went to "Texas Roadhouse" for an 1,100 calorie 24 ounce sirloin. I could only eat half, and enjoyed the leftovers this morning :) . BTW: High-end Curcumin does a pretty good job of easing the muscle pain during the fasts.

Posted by: Tom Schaefer at June 14th, 2019 9:32 AM

@Tom Schaefer
10 grams a day is 5 be times the human equivalent dose determined to simulate the mouse study

You might be overtime the laxatives but if that works for you and you can do fasts each month it's very good.

I think (that's my personal pet theory) that fasting will tone down the inflammation pathways, and many cells that world have died from fisetin can survive during fasting. Some of them repair well enough not to be senecent. Some might go to senility a few weeks after breaking the fast. I would rather use fisetin+qercetin before the fast. I might be wrong, though.

BTW, where do you get your fisetin supplies. Doctors best are 20 $ a bottle, and the bottle had 30 pills of 100mg, so it would be about 7 to 20 bottles.

Posted by: Cuberat at June 14th, 2019 1:06 PM

@Tom Schaefer
Btw, if you take fisetin alone. What effects do you experience ?

Posted by: cuberat at June 14th, 2019 2:10 PM

@Tom Schaefer
May I ask about your age?

Posted by: Stephan at June 14th, 2019 4:52 PM

If I take fisetin alone, the general muscle soreness (concentrated in the large muscles in the front of the thighs and butt), makes it impossible to sleep. I'm 58. Anecdotally: I had a dental procedure that the dentist assumed might have residual pain, so she gave me permission to buy a tylenol-opiate combination. I took one during the 4 days of my fast 3 months ago and experienced no pain and slept like a baby. Curcumin (apparently an Indian festival of Tumeric ongoing) is a second best.

Posted by: Tom Schaefer at June 17th, 2019 9:24 AM

@Tom Schaefer, My husband has a neurological problem causing pain and twitching in his legs, especially when he goes to bed at night. He uses CBD oil - 5% or up to 8% - and applies it generously to his legs. The pain and twitching will disappear instantly, and he can sleep during the night. Be careful, it will stain the bed sheets! But that is a minor problem.
We also use high dose Curcumin, but it is the CBD oil that works.

Posted by: helga at June 17th, 2019 1:23 PM

You can establish and confirm that there is some effect during the treatment do you experience any effects afterwards. for now on you can confirm that you are not wasting the fisetin. But are there any benefits or improvements you can see?

Posted by: Cuberat at June 17th, 2019 2:52 PM

@Cuberat: If I had an evil and undisciplined twin, I suppose I could compare notes with him. Regrettably, I'm doing so much to fight aging, hard workouts and drinking an absolutely disgusting stack of endocrine enhancers (it's the macca root extract that's the worst in it), that I can't isolate any benefits to the fisetin. This much has not changed: I'm exhausted at the end of my eliptical workouts and my recovery time is consistent with the time 15 years ago. Comparing the discomfort felt after my weight lifting routines (every 3 days) vs. eliptical (the other 2 days)is a close call, but I don't dread the aftermath of the weight lifting as much. I've adapted to a normally lower energy life with almost no sugar and very few carbs for over 6 months now. I realize now that processed sugar is used as an amphetamine.

Posted by: Tom Schaefer at June 19th, 2019 7:46 AM

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