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Aging and Lifespan

Clearing Cellular Dead Wood

For many years now, the topic of “senescent cells” has been the subject of plenty of research work. Back in the 1960s the “Hayflick limit” was noticed in cell culture: there was an apparent limit to the number of cell divisions that could take place before the cells just sort of stalled out. For human fibroblasts, that kicks in at around fifty divisions. Over time it was worked out that a primary mechanism involved is the shortening of telomeres with each cell division, specialized nucleotide sequences out at the ends of the chromosomes, and this cellular clock phenomenon has been making its way into the public consciousness ever since.

It’s strange to think, but before these experiments human cells were considered to be more or less immortal and capable of unlimited numbers of divisions. Now, there are cells like that, but that (outside of some stem cell populations and a few other special cases) is a very short working definition of cancer. Those cells do indeed seem to be able to carry on for as long as conditions permit – which in the artificial world of cell culture labs, means apparently forever. Henrietta Lacks died in 1951, but HeLa cells are still with us, and can be all too vigorous when they contaminate other lines. Tumor cells can pile up mutations that will make them die off, but short of that the jams have indeed been kicked out.

It’s gradually become apparent that many aging or damaged tissues have a (sometimes substantial) population of cells that have reached their limit. They’re alive and metabolically active but not really contributing much, in a stage of permanent growth arrest. Cellular senescence is a complex phenomenon, but its importance in aging, cancer, and tissue damaged by other factors (radiation, oxygen stress, etc.) is by now undeniable. Many of these non-aging states can be traced back to early telomere damage by other mechanisms, emphasizing that as a key countdown mechanism. But it’s clear that senescent have a different secretory profile (cytokines, growth factors and more) from the more vigorous cells around them and a number of other protein expression differences that can be used the characterize them.

Naturally enough, thoughts have turned to targeting such cells for therapy. There are a couple of very easy-to-picture hypotheses: first, could you keep telomeres from shortening (or shortening so much) and therefore keep cells in a non-senescent state for longer, potentially delaying biological aging? And second, could you somehow target cells that have already become senescent, and would doing so improve the health of the surrounding tissue? Though pretty obvious ideas, both of these are still very much in play. For now, I’m going to talk about the second one, in light of a new paper.

That one’s on the kidney. Younger people can regain some kidney function after an injury, but that ability goes down with aging, as you’d imagine. It also goes down in states of chronic kidney disease, or after radiation damage. This new paper shows that targeting and removing senescent cells actually starts to reverse this phenotype – once you’ve done that, the kidney tissue after injury shows increased function, increased regenerative ability, and less development of fibrosis. This is demonstrated both in aged tissue and in younger tissue exposed to radiation damage, in human cell culture and in mouse animal models.

You may well ask: how exactly does one target senescent cells? That takes us to ABT-263 (navitoclax), shown at right. This rather hefty molecule is part of a series of AbbVie protein-protein inhibitors for the Bcl-2 (B-cell-lymphoma) family. There are several of those, and navitoclax inhibits the function of Bcl-2, Bcl-xL, and Bcl-w. All of these proteins are intimately tied up in the pathways of apoptosis, programmed cell death, which is another monstrously huge pathway all its own. But one of the questions about senescent cells is why they don’t go down some apoptotic pathway and just fall on their on cellular swords, instead of hanging around forever gumming up the works.

This one, like the others in its class, was developed to cause this to happen to tumor cells as an adjunct to other types of chemotherapy, but these have also turned out to be useful against senescent cells (although not all types of them). Similar to the kidney results reported in the new paper linked above, there have been reports in lung, CNS, muscle and other tissues of broadly similar enhancements (many of these summarized in this paper). So at this point you might be wondering why we don’t just go ahead and put these things into the water supply already.

There’s a problem, unfortunately. It was clear from the clinical studies of the AbbVie compounds that platelet effects were dose-limiting. Cells in that pathway are sensitive to messing with these apoptosis pathways, and while you might be able to deal with that side effect in a chemotherapy situation, it doesn’t exactly make for a good-for-what-ails-you drug. Navitoclax has also recently been shown to have profoundly bad effects on bone density and deposition, which is the exact opposite of what you’d want for an aging population.

AbbVie’s next generation of such compounds, though, includes venetoclax, at right, also a lunker of a molecule and now approved for several types of leukemia. It still has platelet effects, but they aren’t nearly as disastrous as with navitoclax, thanks to deliberately lower binding to Bcl-xL.  That also makes it a bit less of a mighty sword across senescent cell types – for example, it appears that you need that pathway for activity against glioblastoma cells. But it has been reported to show strong protective effects against the development of Type I diabetes through the elimination of senescent cells in the islets of Langerhans. Meanwhile, other groups are looking at turning these ligands into targeted protein degraders, which (at least in some cases) seems to decrease the platelet problems and increase senolytic activity.

And before leaving the topic, it has to be noted that there are plenty of other ways to target these cells other than the Bcl pathway (although that one seems to be one of the most developed so far). What can I say? I’m 59, and I doubtless have more senescent cells than I want or need, so I (and plenty of others) are interested in the idea. The whole cellular senescence pathway presumably developed as a way to avoid slipping into a tumor phenotype – the more cellular divisions, the greater the chance of something going wrong along the way. It’s a tradeoff, and evolution seems more than willing to shortchange older members of the species who have generally passed on their genes to all the offspring that they’re going to. But humans have other goals. We are looking at a rather rapidly aging planet, if current demographic trends hold up, and it would be extremely desirable to have that associated with less of a disease burden. Can we split the difference?

 

 

 

36 comments on “Clearing Cellular Dead Wood”

  1. lizzy says:

    Valter Longo’s Fasting mimicking diet seems to be an excellent way of getting rid of senescent cells. Look it up.

    1. bodrell says:

      Totally agree about Valter Longo’s work. But after watching David Sabatini’s lectures about autophagy, I think Longo’s diet needs some tweaks: more fat, less carbohydrate. It’s all about mTOR, and there are two inputs to that pathway: protein and carbohydrates. Reduce those, and the mTOR pathway turns on and senescent cells start getting gobbled up. Also, the fasting mimicking diet is a whole lot easier to maintain than actual fasting.

      1. Skeptical says:

        I hope you’re right, because I occasionally fast, which means that while I am, my body is running on the only thing it has an ample supply of.

  2. If history is any guide I’m sure David Sinclair will be right on it, with Christoph and Michelle back at his side.

  3. David E. Young, MD says:

    For what it’s worth, Venetoclax is a very well tolerated medication. Very patient-friendly.

  4. Not a Doctor says:

    I follow longevity news, but it’s a big treat to get one of your articles on the topic, getting perspective from someone outside the cult. More often than not it’s a sobering reminder (see: every Alzheimer’s announcement ever), so talking about a credible approach with known failings is great.
    I did notice that every longevity-associated mention of the senescence-associated secretory phenotype tends to come along with the implication that those secretions damage nearby cells into senescence, but that didn’t stand out to you. Wonder if that’s one of those “facts” that showed up in an early study and hasn’t been explored since. (I recommend looking up the history of the “90% of the cells in your body are bacteria” claim.)

    It makes perfect sense in retrospect that cancer drugs are senolytic, with the theory that senescence is a cancer-like state.

    1. Patrick Farrell says:

      “ It makes perfect sense in retrospect that cancer drugs are senolytic, with the theory that senescence is a cancer-like state.”

      Can you talk about this a little more? This doesn’t make any intuitive sense to me at all – for example, they don’t replicate uncontrollably. I’m wondering what link/similarity you’re getting at.

      1. steve says:

        Yes, in fact it’s just the opposite. Cancer cells do not senesce. They turn on telomerase and other pathways. That statement should be corrected.

        1. Not a Doctor says:

          To clarify – my mental model is that cancer cells need 5-6 things to all go wrong at once (extend telomeres, ignore signals moderating division, prevent apoptosis, escape immune attention…). Usually cell damage results in apoptosis or is noticeable enough for the immune system to clear the dysfunctional cells out when only one or two things go wrong. However, if the damage neatly knocks out everything that would clear away the cell but not quite the other problems that lead to uncontrolled division, then you get a senescent cell.

          Under this mental model, cancer cells are different behaviorally but share a couple of key properties in the sense that they persist in the body when they really shouldn’t. Any technique that interferes with these survival strategies in the senescent cell then has a chance of messing with cancer cells, as the cancer might keep proliferating but suddenly start undergoing apoptosis or become immune targets.

          Of course, this mental model could be flawed. The obvious prediction is that senescence should then increase risk of cancer, as you have cells that are already halfway there… But this isn’t obvious, and senescence is more of a safeguard against cancer, as the damaged cells stop replicating and thus lose their primary source of mutations to explore for the cancer phenotype. It also depends on whether the loss of cell division is an active difference in senescent cells (cell has mutated to not divide) or a safeguard present in all cells that only kicks in when there’s enough damage to turn the cell senescent. In the latter case, you could also have regular cells that lost their senescent fallback strategy and you only notice when they pick up the other 4-5 cancer problems all at once.

  5. luysii says:

    I think that senescent cells are at the root of some cases of chronic fatigue syndrome (CFS). Senescent cells secrete a bunch of mediators called the Senescence Associated Secretory Phenotype (SASP) which produce fatigue. I got the idea after reading a big review on cellular senescence 4 years ago by Norman Sharpless [ Cell vol. 169 pp. 1000 – 1011, 2017 ].

    I thought patients with chronic fatigue syndrome should be tested for SASP, with subsequent senolytic treatment of those with high SASP levels.

    I wrote Sharpless who liked the idea. Great, I thought, he has a lab able to measure SASP, and all that was needed were CFS patients which I didn’t think would be a problem.

    Then, 8 days later, fate in the form of Donald Trump, intervened, putting Sharpless at the head of the National Cancer Institute. Of course he then had to sever connections with his lab. I subsequently tried to interest others in testing the idea, including a national organization of CFS sufferers, but to no avail.

    Senolytics could also be tried on postCOVID19 patients with severe fatigue as well.

    Why don’t one of you do it?

    For the whole sad story, see — https://luysii.wordpress.com/2017/09/04/is-the-era-of-precision-medicine-for-chronic-fatigue-syndrome-at-hand/

  6. sgcox says:

    The standard regiment of Venetoclax is 400 mg per day for one year. This is probably max toler. dose. By now thousands of people went through this. Is there are, by any chance, a way to access if there are any signs of reduced senescence cell numbers or some relevant markers ? I guess it is too much to ask cancer patients for biopsies but if some happened during disease monitoring can it be studied for senescent cells count and matched to similar aged people or if possible, controls like people on different treatments?
    Just to get some idea if it might work or just another hokum.

  7. Marcus Theory says:

    That upside-down chlorine atom is crucial to Venetoclax’s activity — we need more methodologies that can install such functionality!

    1. David E. Young, MD says:

      Good one!

    2. Derek Lowe says:

      Oy. Hadn’t noticed that – everything else had rotational symmetry! Fixing now. . .

      1. David A. Van Baak says:

        Too bad — I had thought that was the crucial ‘chiral chlorine’!

      2. Sue says:

        And now the joke is lost! _À bas_ any editing powers! Unintentional humor for the win! 🙂

    3. eub says:

      That’s the proverbial Tasmanian Chlorine.

  8. Jonathan B says:

    On paper I must have even more of a vested interest in this topic than Derek, presumably because of my somewhat higher age more of my cells will probably be senescent.

    What interested me (and I admit to little knowledge of the area other than serendipitous reading/attending talks) was the fact that using these drugs to remove cells that were already senescent allowed their non-senescent neighbours to regenerate. I had always assumed that finding a way to block senescence would only work clinically if the drug was taken constantly from a point in one’s life before senescence became a significant problem. In that case of course one would have to have immense confidence that the drug had no unwanted consequences.

    In that regard, does anyone here know if the block on cell division in terminally differentiated cells such as neurons resembles senescence? If so there are several neurodegenerative diseases where these drugs might be worth exploring, in model systems at least. If damaged cells could be selectively removed in a way which allowed previously suppressed regenerative ability to be expressed in the tissue, might new growth and innate plasticity allow some regain of function?

  9. Christophe L Verlinde says:

    I take issue with your statement that cells capable of unlimited numbers of divisions are a very short working definition of cancer. Stem cells in the bone marrow and the lining of the gut keep dividing indefinitely, yet they are not cancer cells.

    1. Derek Lowe says:

      True, I should have excepted stem cells! I’ll make a note in the post.

      1. steve says:

        Nope, sorry. Stem cells do not have unlimited division. In fact, this is probably why we age. https://www.nature.com/articles/s41580-018-0020-3

  10. vida says:

    After taking resveratrol for a few months, my graying hair turned dark brown. Except for the completely gray hair. It’s still completely gray 🙁 Looks odd.

    1. base651 says:

      Did you take the resveratrol orally or apply topically? 🙂

      1. Shandyman says:

        …and or take that with Zinc.

  11. Rhenium says:

    This post is not relevant to the above post, I simply include it here for the chemistry. Short version there is a somewhat incredible ship fire going on right now. Website link in name.

    “The Sri Lankan Navy previously said the ship is loaded with 1,486 containers, including 25 tons of Nitric Acid and other chemicals which it had loaded at the port of Hazira, India on May 15. Preliminary investigations indicate the fire started due to a chemical reaction of the hazardous cargo.”

    https://gcaptain.com/wp-content/uploads/2021/05/X-press-pearl_fire.jpeg
    I saw the photo with the classic nitrogen yellow fumes appearing and though, “that’s not good”. Now it’s way worse. Oh nitric acid, you never disappoint. One can’t even use water because it will flood and thereby eventually sink the sink

    1. myma says:

      Oh, goodness. That … that doesn’t look like it is going to end well.

  12. Yuri Kudinov says:

    Here is an interesting fact. Senescent cells can disappear from the liver of aged mice without the use of senolytic drugs. All you have to do is to induce Yamanaka factors in every mouse cell for a very short period [pubmed 27984723, Figure 5E]. A note of caution. Normal macrophages can look like senescent cells but, unlike fibroblasts or fat cells, macrophages can lose and re-acquire p16 and beta-galactosidase depending on a stimulus [pubmed 28768895]. What type of cells does navitoclax kill? Senescent adipocytes or M2-polarised macrophages? Or both?

    PS. I am 55 and I watch two senolytic companies: Cleara Biotech and Oisin Biotechnologies.
    Cleara Biotech design cell penetrating senolytic peptides made entirely of D-amino acids.
    https://www.google.com/patents/WO2016118014A2?cl=en
    http://www.sciencemag.org/news/2017/03/molecule-kills-elderly-cells-reduces-signs-aging-mice
    Oisin Biotechnologies design senolytic DNA plasmids delivered by fusogenic liposomes
    https://scienceofsingularity.files.wordpress.com/2019/02/80376-oisinslidedeck2018.07.11c28icsa2018293.pdf
    https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1000016

  13. steve says:

    Interesting that you failed to mention one of the big names in the field, Unity Bio. Their Ph2 trial of their p53/MDM2 interaction inhibitor tanked for osteoarthritis and they cut 30% of their staff. The field is a lot more complicated than would appear at first blush. (Yeah, I know – surprise!)

  14. TallDave says:

    senescence has so many prongs, to make real progress we may need our own designer mitochondria, something less prone to replication errors than anything in human cells today

    unlike Nature we don’t have to worry about the energy budget trade-offs — as we get better at protein folding we can eventually code for a unnaturally ridiculous number of error checks, just because we decided want to live longer/better lives

    serolytic drugs seem promising on the surface but in terms of actual effect on longevity I worry they’re like trying to install an enlightened, tolerant democracy using only JDAMs and cruise missiles

  15. Jeff says:

    Does anyone know if any of the parabiosis “fountain of youth” studies showed declines in senescent cells?

  16. Another Idiot says:

    Can’t recall who said it, but it was a leading researcher into senescence and the quote was “The first person to live to 200 years is alive right now.”

    Initial reaction: No way.
    Later reaction: Likely to be correct.

    1. Dave says:

      That sounds like something Aubrey de Grey said. Though in his case he said 1,000 years.

      1. Someoneelse says:

        I hope it’s not me.

  17. truthortruth says:

    “A good-for-what-ails-you drug”

    Why don’t you just put some cream on it??

    Always enjoy your writing Derek!

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