Killing off cells that refuse to die on their own will be powerful for antiaging

Clearing old zombie cells in mice has been shown to restore fitness, fur density and kidney function. It has also improved lung disease and even mended damaged cartilage. And in a 2016 study, it seemed to extend the lifespan of normally aging mice.

Biotechnology and pharmaceutical companies are keen to test drugs — known as senolytics — that kill senescent cells in the hope of rolling back, or at least forestalling, the ravages of age. Unity Biotechnology in San Francisco, California, co-founded by van Deursen, plans to conduct multiple clinical trials over the next two-and-a-half years, treating people with osteoarthritis, eye diseases and pulmonary diseases. At Mayo, gerontologist James Kirkland, who took part in the 2011 study, is cautiously beginning a handful of small, proof-of-concept trials that pit senolytic drugs against a range of age-related ailments.

This is a summary of the Megan Scudellari Nature article. Nature – To stay young, kill zombie cells

The US Food and Drug Administration has not labelled aging as a condition in need of treatment.

Unity’s president, Ned David, there will be a massive push to develop treatments and to better understand the fundamental process of aging if there is any hint of success in the upcoming trials. Nir Barzilai, director of the Institute for Aging Research at the Albert Einstein College of Medicine in New York City. “I think senolytics are drugs that could come soon and be effective in the elderly now, even in the next few years.”

Senescent cells are slightly different in each tissue. They secrete different cytokines, express different extracellular proteins and use different tactics to avoid death. That incredible variety has made it a challenge for labs to detect and visualize senescent cells. “There is nothing definitive about a senescent cell. Nothing. Period,” says Campisi.

In fact, even the defining feature of a senescent cell — that it does not divide — is not written in stone. After chemotherapy, for example, cells take up to two weeks to become senescent, before reverting at some later point to a proliferating, cancerous state, says Hayley McDaid, a pharmacologist at Albert Einstein College of Medicine. In support of that idea, a large collaboration of researchers found this year that removing senescent cells right after chemotherapy, in mouse models for skin and breast cancer, makes the cancer less likely to spread.

The lack of universal features makes it hard to take inventory of senescent cells. Researchers have to use a large panel of markers to search for them in tissue, making the work laborious and expensive, says van Deursen. A universal marker for senescence would make the job much easier — but researchers know of no specific protein to label, or process to identify. “My money would be on us never finding a senescent-specific marker,” Campisi adds. “I would bet a good bottle of wine on that.”

Earlier this year, however, one group did develop a way to count these cells in tissue. Valery Krizhanovsky and his colleagues at the Weizmann Institute of Science in Rehovot, Israel, stained tissues for molecular markers of senescence and imaged them to analyse the number of senescent cells in tumours and aged tissues from mice11. “There were quite a few more cells than I actually thought that we would find,” says Krizhanovsky. In young mice, no more than 1% of cells in any given organ were senescent. In two-year-old mice, however, up to 20% of cells were senescent in some organs.

But there’s a silver lining to these elusive twilight cells: they might be hard to find, but they’re easy to kill.

Researchers identified six signaling pathways that prevent cell death, which senescent cells activate to survive.

In early 2015, the team identified the first senolytics: an FDA-approved chemotherapy drug, dasatinib, which eliminates human fat-cell progenitors that have turned senescent; and a plant-derived health-food supplement, quercetin, which targets senescent human endothelial cells, among other cell types. The combination of the two — which work better together than apart — alleviates a range of age-related disorders in mice.

14 senolytics have been described in the literature, including small molecules, antibodies and, in March this year, a peptide that activates a cell-death pathway and can restore lustrous hair and physical fitness to aging mice.

Unity maintains a large atlas documenting which senescent cells are associated with which disease; any weaknesses unique to given kinds of cell, and how to exploit those flaws; and the chemistry required to build the right drug for a particular tissue.

There’s no need to kill every senescent cell in a tissue: mouse studies suggest that dispatching most of them is enough to make a difference. Finally, senolytic drugs will clear only senescent cells that are already present — they won’t prevent the formation of such cells in the future, which means that senescence can continue to perform its original tumor-suppressing role in the body.

Killing off senescent cells in normally aging mice delayed the deterioration of organs associated with aging, including the kidney and heart. It extended the animals’ median lifespan by about 25%.

Side effects include delays in wound healing.

11 thoughts on “Killing off cells that refuse to die on their own will be powerful for antiaging”

  1. Even cheaper is intermittent fasting, eat nothing and drink only water for 24 hours. The result is natural apoptosis and damaged cell death. At your first meal thereafter you may experience digestive irregularity, the result of naturally detoxifying your body. Immune function will remain normal throughout fasting and substantially increase after 18-24 hours of fasting. Of course you could wait for the feverish effects of influenza to accomplish this for you, but why not nip that in the bud as well?

    Reply
    • @Kevin ” Even cheaper is intermittent fasting, eat nothing and drink only water for 24 hours. ”

      Please prove that causes apoptosis of senescent cells.

      Reply
  2. Am I to understand that somebody marked my mention that I’d used quercetin as spam? What’s the matter, I shouldn’t have posted a link to Amazon, to show how affordable it was?

    Or am I just paranoid, and this site is buggy?

    Reply
  3. Anecdotally, I’ve actually tried high dose quercetin, and saw some interesting effects. It has seemed to at least partially reversed my baldness, and some troublesome thin patches on the backs of my hands became inflamed, and then gradually reverted to something more like normal skin. I was trying 6 grams once a month, orally. I guess I’m going to continue it. As experimental supplements go, it’s fairly cheap.

    Reply
    • How’d you come up with taking a single dose of 6 grams once a month?
      I’ve read recommendations of 250-500mg once or twice a day.
      Is there a reason for the high dose for it to be effective as a senolytic?

      Thanks,

      Reply
      • A fair question.

        Start with the fact that the acute toxic dose for quercetin is
        absurdly high; You’d likely die of choking if you tried to consume
        enough in once dose to poison yourself. So you don’t have to worry
        (Too much!) about acute effects from doses in the 1-10 gram range.

        On the other hand, quercetin has a low clearance rate from the
        bloodstream, which means that if you keep up high doses day after day
        that don’t have acute effects, you can eventually accumulate enough in
        your bloodstream to become toxic. Risk of kidney damage, I understand.

        And clearance of senescent cells looks like a threshold effect; You
        need to achieve a high enough concentration in the blood to actually
        kill those cells, or they may just recover and stick around.

        All that combines to suggest that the optimum schedule is one big dose
        with enough time before the next for you to clear it from your
        bloodstream. Which is exactly what they did in the research.

        I just scaled up the amount from 4 to 6 grams, because I’m a bit on
        the heavy side. And chose once a month because it was easy to
        schedule.

        But, seriously, this is self-experimentation, nobody actually knows
        what the best dose schedule would be. You’re just groping around in
        the dark trying to get the good effects without poisoning yourself.

        Like I said, I had some senescent skin patches that I could monitor
        easily, which was a help. I don’t know how somebody younger, without
        that issue, could get immediate feedback on whether it was working, at
        least without expensive lab work.

        Reply

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