Immunotherapy for senescent cell removal – lessons from human embryo development and other species

Immunotherapy for senescent cell removal - lessons from human embryo development and other species

For a long time I had this simplistic view that senescent cells accumulate with age, contributing to many age-related degenerative diseases through the sterile inflammation and regeneration impairment they cause. I also thought their removal with the help of drugs is the only  possible solution to get rid of them.
Destroying senescent cells shouldn’t be as difficult as killing cancer cells, hence the immediate focus is on testing a multitude of chemotherapy options in different doses to remove senescent cells from the aging body. Just like there are several clinical protocols in oncology, in the next decades I expect to see the same depending on the type of senescent cells to be removed, their location, additional pathology of the patient, gender, age, risk factors and so on.
But although using chemotherapy which already exists on the market is the low-hanging fruit of bringing senolytics to the clinics, I wondered whether senescent cell removal could be achieved any other way.
If you are an adult reading these lines, then you already removed a bunch of senescent cells during your development as an embryo and most probably you had no idea you were capable of that.
Although in gerontology we are used to view senescent cells as the enemy of youth, there are many types of cellular senescence – both physiological and pathological ones. Mammalian life wouldn’t even be possible without the physiological ones appearing during embryo development and placenta formation. Depending on the species and type of cellular senescence, different immune cells remove these ‘zombies’ either during embryo development or as adults (macrophages in salamanders, allowing the latter to undergo complete limb regeneration after reaching maturity; NK cells in mice).

 

What happens if you inhibit senescent cells from developing?
In embryos, you would prevent tissue remodeling and the embryo may not look and/or function normally. The same would happen if you put a 100% halt on apoptosis in an embryo.
In wounds you could end up with fibrosis as the formation of senescent cells is necessary for starting regeneration. In salamanders this fibrosis would be the equivalent of incomplete regeneration and the limbs would not be regenerated properly.
In tumors you could accelerate their growth.
In stress-induced premature senescence the result would be positive as the individuals would live longer, healthier lives.
In fusion-induced senescence you would inhibit normal mammalian placental formation hence the pregnancy would end as miscarriage. Aging pathology of the placental syncytiotrophoblast layer may lead to restricted fetal growth and early – but not late-onset – pre-eclampsia since the nutrition exchange between mother and fetus would be impaired. Aging pathology of the amniotic sac could lead to pre-term birth. Finally, fetal membrane senescence may determine the duration of pregnancy in humans – I have no additional data right now, but I wonder whether different rates of cellular senescence and mTOR signaling determine the different gestation durations in other mammals.

Fusion-induced senescence can occur in many other situations where cells are made to fuse such as in certain viral infections. In this case, preventing the infection would obviously be good for the host  – at least I can’t think of any commensal virus that does this.

At this point you may think that in gerontology the problem doesn’t lie in the formation of senescent cells, but in their lack of removal. Yet I chose to mention all these types of cellular senescence as in some cases their removal is the rule and we could learn something from this. There are two situations from which we could adapt this more elegant manner of removing senescent cells:
-normal embryo development – in humans and other species
-cleanup in species able to undergo complete regeneration as adults such as salamanders

For the first case, I found a couple of papers where this process was studied in human, mice and chick embryos. By reactivating early developmental programs, it could be possible to detect and remove senescent cells as adults as well.

The responsible cell doing the cleanup for the second case is the macrophage as shown in the axolotl (Ambystoma mexicanum) and the newt (Notophtalmus viridescens) in this paper and a couple of others seen below in the references section. When the macrophages in these animals were destroyed with the help of toxic substances, complete limb regeneration was impaired. This is similar to adult humans – we also have macrophages, but ours do not detect and ‘eat’ the accumulating senescent cells in case of injuries so we form scars. Unlike humans and other mammals, salamanders do not accumulate senescent cells with age – at least in heart, spleen and liver. After multiple limb amputations their regeneration abilities do not decrease either. While senescent cell accumulation is a part of human aging, here are two types of salamanders that use their immune system to get rid of these ‘zombies’. Aging may be inevitable in humans, but that is not the case in all species. And this is only the beginning, as the salamander immune system is barely researched and only two species are mentioned for the time being – it may well be that other phagocytic cells are just as important for senescent cell removal. Besides, salamanders are not the only species capable of complete regeneration as adults, but that’s all I could find for now regarding senescent cell removal.

If the next step in cancer treatment is immunoterapy, then I see no reason to turn back the clock and use chemotherapy – even in low doses – to remove senescent cells from aging bodies. Immunotherapy for treating metastasized tumors is not part of the regular oncology treatment regimen, but it shows promise. Could the same method be one day used to genetically edit immune cells so they’d detect senescent cells and remove them once not needed anymore?

 

References

Cox, L. S., & Redman, C. (2017). The role of cellular senescence in ageing of the placenta. Placenta, 52, 139-145.

Menon, R., Bonney, E. A., Condon, J., Mesiano, S., & Taylor, R. N. (2016). Novel concepts on pregnancy clocks and alarms: redundancy and synergy in human parturition. Human reproduction update, 22(5), 535-560.

Jun, J. I., & Lau, L. F. (2010). The matricellular protein CCN1 induces fibroblast senescence and restricts fibrosis in cutaneous wound healing. Nature cell biology, 12(7), 676.

Muñoz-Espín, D., Cañamero, M., Maraver, A., Gómez-López, G., Contreras, J., Murillo-Cuesta, S., … & Serrano, M. (2013). Programmed cell senescence during mammalian embryonic development. Cell, 155(5), 1104-1118.

Storer, M., Mas, A., Robert-Moreno, A., Pecoraro, M., Ortells, M. C., Di Giacomo, V., … & Keyes, W. M. (2013). Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell, 155(5), 1119-1130.

Sagiv, A., Burton, D. G., Moshayev, Z., Vadai, E., Wensveen, F., Ben-Dor, S., … & Krizhanovsky, V. (2016). NKG2D ligands mediate immunosurveillance of senescent cells. Aging (Albany NY), 8(2), 328.

Yun, M. H., Davaapil, H., & Brockes, J. P. (2015). Recurrent turnover of senescent cells during regeneration of a complex structure. Elife, 4.

Godwin, J. W., Pinto, A. R., & Rosenthal, N. A. (2013). Macrophages are required for adult salamander limb regeneration. Proceedings of the National Academy of Sciences, 110(23), 9415-9420.

Dall’Agnese, A., & Puri, P. L. (2016). Could we also be regenerative superheroes, like salamanders?. BioEssays, 38(9), 917-926.

McCusker, C., & Gardiner, D. M. (2011). The axolotl model for regeneration and aging research: a mini-review. Gerontology, 57(6), 565-571.

 

Immunotherapy for senescent cell removal - lessons from human embryo development and other species

Anca Ioviţă is the author of Eat Less Live Longer: Your Practical Guide to Calorie Restriction with Optimal Nutrition ,The Aging Gap Between Species and What Is Your Legacy? 101Ways on Getting Started to Create and Build One available on Amazon and several other places. If you enjoyed this article, don’t forget to sign up to receive updates on longevity news and novel book projects!

Don’t miss out on the Pinterest board on calorie restriction with optimal nutrition where she pins new recipes every day.
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7 thoughts on “Immunotherapy for senescent cell removal – lessons from human embryo development and other species

  1. Hi, I’m wondering whether salamanders’ abillity to remove their senescent cells is responsible for their longevity. A quick google research gives that they live around 20 and some 50 years — I thought that’s impressive for these “simple” creatures. Moreover, according to https://www.livescience.com/9973-long-lived-salamanders-offer-clues-aging.html , blind salamanders / olms are documented to live at least 69 “with a predicted maximum age of more than 100 years, three times longer than related species”.
    Similar data in https://phys.org/news/2010-07-scientists-salamander.html

    Perhaps, this is another trove of longevity research clues. Same article: “Surprisingly, the long-lived amphibian doesn’t seem to have an especially low metabolism nor unusual levels of protective antioxidant molecules to explain why it lives so long. As such, this salamander could help uncover mechanisms that could help keep us young.”

    And some can be kept as pets too … perfect match for the longevity scientist that needs companion until he/she discovers their biology’s secrets 🙂

    1. Hi, I knew about axolotls and newts being raised as pets, but olms? I doubt it as these are animals threatened by extinction and they live in underwater caves anyway.
      As regards why salamanders live so long, I’d rather credit their lack of metamorphosis for that. Metamorphosis is energetically expensive and in harsh environments it is much better to avoid it. This is why salamanders have tails and gills just like juvenile tadpoles. Frogs – which undergo metamorphosis – lead much shorter lives.
      I disagree with the quote you provided stating that olms don’t have a low metabolism since they can survive for months without food. They had to adapt to this since there aren’t many nutrients to be found in underwater caves. Check out this paper, I think you’ll find it interesting: https://www.ncbi.nlm.nih.gov/pubmed/11136613

  2. – Hi, I should have been more specific: I meant salamanders in general as pets, as even 15..20 years is plenty of time.
    – But then, many other animals don’t undergo metamorphosis, and still die fast?
    – Well, then I trust you more than the random website I quoted, knowing all the research you do on these questions.
    – What I found curious is that the we humans (and I guess most mammals too) have a roughly similar response to starvation: first run out of stored carbs, then start ketosis and run on fats, and only in the end metabolizing our proteins in bulk (and die shortly after).

    1. Ok, I get it now. Axolotls are so cute, I saw one for sale in my last trip to Japan 🙂
      Indeed, many animals don’t undergo metamorphosis and the comparison was strictly among amphibians, but here is what I find interesting in the olm: it synthesizes thyroid hormones normally just like any other amphibian, but its tissues are insensitive to them.
      No need to trust me, that’s why I gave you the paper link 🙂
      Yes, that’s how it happens in humans. Many negligibly senescent species are extremely tolerant to starvation and anoxia. We are not.

  3. I know from my own hyperactive thyroid condition that I had treated several years ago that the thyroid gland can speed up the metabolism in all of the cells. The doctor told me that , if left untreated, it could potentially hurry my body to death sooner than later (among other inconveniences).
    So, yeah, these olms seem to be immune to such a thing. Yet another thing to potentially manipulate in humans in future…

    1. Hope you’re better now. Unfortunately, left untreated hyperthyroidism increases the risk of cardiovascular disease while subclinical hypothyroidism is a protective factor for longevity.

  4. Thanks, I’m good for several years now, but still checking the parameters every half a year.
    Everyone with his own luck…cruel non-discriminatory fate 🙂 … which I’m trying to control!

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