Zombie Cells. The Race To Beat The Walking Dead

Richard Bradbury: If you could turn back time. If you could find a way… I’m not doing this. I’m happy to talk about aging today, but I won’t quote Cher.

Richard Bradbury: What’s up? 200 episodes and you’re feeling old?

Matt Armitage:

• I guess there’s some serendipity in celebrating a milestone in the number of episodes and then talking about age.

• This actually comes from a story we didn’t have time to cover on the most recent WS ep a couple of weeks back.

• Various tests on mice over the past decade have indicated that infusions of young blood reverse some of the effects of ageing in their cells.

• These stories have been widely reported. And the FDA in the US put an end to some of the tests.

• But despite the results and the continuing interest, scientists were unable to come to any firm conclusions as to why this might be the case.

• Until now, that is.

• New research from a team at the University of Valencia led by Consuelo Borras suggests may have uncovered the links.

• According to NS - Their research suggests that certain packages of RNA and proteins branch off in buds from certain cells and travel through our blood to other cells.

Richard Bradbury: So, essentially they’re transmitted?

Matt Armitage:

• It’s at times like this I wish I was better acquainted with cellular biology.

• I say better acquainted – I mean had the most basic of knowledge.

• If I’ve understood correctly, these things are known as extracellular vesicles.

• NS also mentions a study from the University of Pittsburgh last year that suggests these extracellular vesicles can help muscle tissue regenerate in mice.

• The same piece likens them to a form of communication – like an intravenous internet.

• The proteins and RNA these buds carry can switch genes off and on and alter the behaviour of the cells.

• A bit like the description of CRISPR I didn’t give on last week’s show.

Richard Bradbury: What kind of results did the Spanish research show?

Matt Armitage:

• They took fat stem cells from young and old mice and extracted the extracellular vesicles.

• These were then injected into old mice in two doses a week apart.

• There were three groups. One that received doses from young mice, another that received nothing but saline and a third that received doses from old rats.

• After a month, as you might expect, there was no change in the group that received saline.

• Nor those that received extracellular vesicles from old mice.

• But in the group that received the young cells, they exhibited improved motor function, grip strength and NS reports they could exercise for longer.

Richard Bradbury: How permanent do the changes seem to be?

Matt Armitage:

• The effects seem to have faded after a couple of months.

• So the next test is to give the mice the mice the cells on a monthly basis to see if it has any effect in terms of extending their lifespan.

Richard Bradbury: Are they confident that these tests will apply to humans?

Matt Armitage:

• There’s never any certainty.

• Consuelo Borras has stated that they plan to do clinical trials with humans using dermal applications of the extracellular vesicles.

• They hope that they will prove effective against conditions like pressure sores for people who are bedridden.

• And they suspect that there may be some cosmetic uses as well.

Richard Bradbury: That takes us into the broader topic for today, which is that wider expanse of anti-ageing science.

Matt Armitage:

• Yes. So, anti-ageing is an area where there is a huge overlap of real research and pseudo-science.

• To the point where it can be hard to distinguish one from another.

• People still spend hundreds of thousands of dollars to have their bodies – or if they’re on a budget – just their heads.

• Cryogenically frozen, despite concerns that the freezing process destroys many of the body’s cells, making it impossible to revive you.

• No matter how good technology gets.

• And there are always the folk and most likely untrue tales –

• like the one about Rolling Stone Keith Richards:

• which states that he owes some of his longevity to regular transfusions of young blood he once received at a Swiss clinic.

Richard Bradbury: Is longevity – extending our lifespans – the aim of most of the research?

Matt Armitage:

• That’s something we should clear up from the start.

• This isn’t about living forever.

• While we know that some of the private funders of these bio-tech companies have expressed the desire to live until they’re 120.

• Like Paypal and Palantir founder Peter Thiel.

• The main thrust of the research is that kind of 90 is the new 50 ethos.

• It’s more about extending our quality of life.

Richard Bradbury: Is that partly because – as a species – we’re already living longer?

Matt Armitage:

• Partly – better healthcare is extending lives in most developed nations.

• One of the downsides to that is that we’re living longer with infirmities and disabilities.

• Successful Anti-ageing therapies could stave off middle age and prolong it into old age,

• as well as finding ways to combat or prevent degenerative diseases like Parkinson’s and Alzheimer’s.

• And as we’ll detail as we go along, extending life is much more difficult than improving it.

• If an organ fails we can replace it. The better scenario is to treat it early to prevent that failure.

• We do seem to have a finite limit. There’s only so much you can do before the system fails and you die.

Richard Bradbury: Is this where we go off on a tangent into one of your consciousness in a box theories?

Matt Armitage:

• No. I’m the lucky human with a cloud consciousness.

• I do think that advances in BCI will eventually allow us to have our intelligence augmented by cloud processing.

• As a combined entity? Unlikely.

• That little computing chip will offload the heavy work and deliver the answer.

• I don’t think it will be part of you in that sense.

• We did some machine intelligence shows a few years ago where I asked the question regarding machine sentience.

• If you had a sentient machine on a chip in your brain, would you be one person or two?

• But no, we aren’t mining that seam today.

• As far as I’m aware, no one is really making any headway with the idea that you could upload someone’s memories…

• Or that essence of who they are, as a way of extending, if not their life, then at least their existence.

Richard Bradbury: Before we go into the science of anti-ageing, let’s look at the business side of it.

Matt Armitage:

• Sure. As I mentioned, anti-ageing is one of those areas where there’s a lot of pseudo-science.

• So it’s often been regarded as a little bit fringe.

• But over the past decade or so, the science part of the industry has become a bit of a silicon valley darling, with lots of companies raising hundreds of millions or even billions of dollars.

• Altos Labs, a biotech company dedicated to cellular rejuvenation programming, launched at the start of the year with an investment war chest of $3bn.

• Investors in the company include Jeff Bezos, and Yuri Milner, a venture capitalist and physicist whose company, DST Global has invested in Facebook, Stripe, Spotify, Alibaba, Airbnb, just to name a few.

• And who has personally invested in the DNA analysing startup 23andme.

• Altos Labs has embarked on a huge headhunting spree, signing up some of the top global talent in the field, including a number of Nobel prize winners.

• Altos is building a campus in Cambridge in the UK and plans two in the US with ancillary research teams in Japan.

Richard Bradbury: You mentioned Peter Thiel earlier…

Matt Armitage:

• Yes, so he’s funded a variety of anti-ageing projects, probably the most notable of which is the Methuselah Foundation.

• That’s the one with the mission to make 90 the new 50.

• As someone who hits 50 this year, I wish they’d chosen a younger number.

• I’d like to feel 30 again.

• The Foundation is an incubator that funds the work of other companies, including 3D bioprinting.

• I like that one – printing new tissue and organs.

• Research into senescent cells – more of which later.

• As well as companies working with degenerative brain diseases and technologies to match organ donors.

Richard Bradbury: Not to mention Unity Biotechnology…

Matt Armitage:

m in: 2016

• They seem to be having some success with trials of drugs they’re developing that flush out the senescent cells that cause aging

• They don’t cause aging exactly – more of that after the break.

• But tests at the Mayo clinic showed that the drugs did indeed flush out senescent cells in mice and improve their physical health and extend their lifespans.

• They have more than a dozen human clinical trials going on, as varied as osteoarthritis and Alzheimer’s.

• Unity Co-Founder Ned David has hopes that treatments the company develops could eventually wipe out up to a third of human diseases in the developed world.

• I’m sure the rest of the world will be happy to hear that…

• Incidentally, a lot of the background for today came from a Guardian article by Ian Sample called If they could turn back time.

• Links as usual in the shownotes, on the substack newsletter and on the kulturpop website.

• Then there’s Calico – the California Life Company…

Richard Bradbury: This is the one that Google founded?

Matt Armitage:

• Yes, they’re reported to have invested as much as a billion dollars in the company.

• Which is now a subsidiary of Alphabet.

• We haven’t seen any products, as Google likes to call its stuff, resulting yet.

• But according to its own website, the company is collaborating quite widely with teams and Harvard and MIT.

• On things like immunotherapy drug treatments, cancer and neurological treatments and tissue repair.

• By their own claim, they want to specialize in overlooked or unexplored areas of development.

• So there seems to be a broad correlation with the company’s wider activities where data is a priority.

• This really is an area that would have been derided or classified as quack science not that long ago.

• The quack science is still there – all too often advertising its wares on late night TV and social media.

• But, partly thanks to this influx of money, but also because of the breakthrough discoveries of dedicated researchers and tools like CRISPR.

• We are making genuine progress towards that goal of living well for longer.

Richard Bradbury: You heard it: Matt’s living his best life. More from the senescent guru after the break.

BREAK

Richard Bradbury: We’re talking about aging today. No, it’s not some late night TV, get rich quick scheme that Matt cooked up. It’s proper science.

Richard Bradbury: You used the word senescence a number of times in the first half of the show. Would you like to explain what it means?

Matt Armitage:

• Without going too far into the whole complexity of it – which is another way of saying I don’t really understand it.

• Senescence happens when cells stop dividing.

• The cells themselves don’t die, they remain active and mostly functional, but as these aging cells accumulate in your tissue,

• They can release harmful enzymes and inflammation causing proteins that damage the healthy cells around them.

• Which is why there’s a link between senescent cells and so many aging relating factors like arthritis and the cell mutations that cause cancer.

• As I mentioned before the break, a lot of these aging focused startups are working on methods to reprogramme senescent cells…

• …or to formulate drugs to essentially flush them out of the body.

Richard Bradbury: So we mentioned some of the studies and breakthroughs briefly before the break. Can we look at some of the work these start-ups are doing and what it might mean?

Matt Armitage:

• Sticking with those senescent cells. We mentioned those findings at the Mayo clinic earlier.

• That what have been termed senolytic drugs can flush out senescent cells in mice and improve their physical health and extend their lifespans.

rest in this area since about: 2015

• Scientists have since been working on ways to make those drugs more precise and effective.

• So that they only target those specific zombie cells and leave the healthy cells unharmed.

Richard Bradbury: How did you work zombies into this?

Matt Armitage:

• That’s what they’re calling senescent cells – zombie cells.

• Did I not mention that earlier? Not like me to miss a good zombie connection.

• A team at the UK’s university of Leicester published a study last Fall, showing breakthrough in targeted senolytics.

• Study author Dr Salvador Macip was quoted in New Atlas as saying that the first generation of senolytics are scattergun in their approach and have a number of side effects.

• Their breakthrough was to develop a drug that can identify the membrane marker of senescent cells.

• That way it would only deliver its payload of toxins to those zombie cells.

• In fact, they’re describing it as a smart bomb.

Richard Bradbury: A smart bomb to destroy zombies?

Matt Armitage:

• I know how it sounds. I’m not making this up.

• Their tests of cell cultures in the lab showed that the senescent cells were eradicated without damage to the healthy cells around them.

• Just a month before that study was published there was a breakthrough in managing age related back pain at the Thomas Jefferson University in Philadelphia.

• They were performing clinical trials with two senolytic drugs, dasatinib and quercetin which were developed to treat scarred lung tissue.

• They wanted to see what effect they would have on spinal degeneration.

• They tested the drugs on young, middle aged and elderly mice.

• And were surprised to find the results were most marked in the younger rodents.

• Along with the middle-aged mice, they found less degermation in the spinal discs as they aged compared with control groups of mice given a placebo.

• They expected to find the biggest difference in the elderly mice with the most senescent cells.

• Suggesting new pathways for preventive treatments.

Richard Bradbury: I think there was also a study related to diabetes…

Matt Armitage:

coming out at the tail end of: 2021

• Senescent cells play a role in type 2 diabetes because they can alter the way our cells process proteins and sugars.

• Using those same two experimental drugs, dasatinib and quercetin, the Connecticut team was able to clear senescent fat cells in obese mice and alleviate the insulin resistance it was creating.

• The hope is that the drugs could be used to make human fat healthy. Something that could help to prevent the development of type 2 diabetes

• And reduce the risks for those already suffering from it.

Richard Bradbury: All of this is making that US3bn in funding for Altos look like a smart investment…

Matt Armitage:

came out in the last half of: 2021

• So you can see how rapidly the sector is both innovating and progressing.

• And it isn’t all about senescence.

• An area that Altos will be focusing on is the body’s ISR – its immune stress response.

• It’s a bit like a command and control system that maintains equilibrium – homeostasis – in your body’s cells.

• Your body gets stressed when you have an infection, experience a shortage of oxygen, or the cells are deprived of amino acids or glucose.

• It’s a signaling system – which can reboot and reprogram your cells to better cope with those new threats.

• And in extreme cases it shuts the cell down – like a kind of auto-destruct mechanism.

• But ISR can itself contribute to conditions like Alzheimer’s.

• For example, if it triggers cells to respond to a virus or other emergency, it may then fail to return them to their normal state.

• In tissue like the brain, those misbehaving or wrongly functioning cells can wreak their own damage.

Richard Bradbury: In instances of conditions like traumatic brain injury?

Matt Armitage:

• Yes, that type of thing.

• One of the researchers that Altos has recruited to run its San Francisco unit is Peter Walter.

• He made a breakthrough in: 2020

• It showed the rapid restoration of cognitive abilities in elderly mice.

• It also demonstrated that some types of brain degeneration may result from a blockage in the cells,

• Rather than a complete loss of capacity.

• So, it suggests that the normal functioning of the brain is still possible

• but that the stress response has triggered changes that block the normal functioning of the cells.

• The hope is that breakthrough with ISRIB could eventually lead to treatments for conditions as varied as

• TBI, Down Syndrome, noise related hearing loss, alzheimer’s, prostate cancer and diabetes.

• So, those are areas we’re likely to see Altos researching and collaborating with partners on.

Richard Bradbury: But Altos Labs will still focus on cellular programming.

Matt Armitage:

• Yes – that’s part of its core vision.

• This is another example from the Guardian piece.

• Altos has also recruited Nobel prize winning stem-cells researcher Prof Shinya Yamanaka.

• Back in: 2006

• And in that embryonic state they could be used to grow different kinds of body tissue.

• So there was a hope that it could be harnessed to create spare parts.

Richard Bradbury: Is this another zombie reference?

Matt Armitage:

• Genuinely, I’m not making these up. And it isn’t pseudo-science.

• One of Yamanaka’s subsequent breakthroughs was in using the approach to create healthy muscle tissue to treat sufferers of muscular dystrophy.

• One of the drawbacks of the process, is that the reprogrammed cells can get confused about what they’re supposed to replicate.

• Leading to the growth of tumours.

• So a lot of the focus of Altos, and scientists like Prof Yamanaka and this dream team the company has assembled,

• Will be to develop drugs that dial back the clock on those cells, but not so far that they are likely to mutate.

Richard Bradbury: Medical research is expensive and the results are uncertain. Why do you think there is so much money flooding into this kind of research?

Matt Armitage:

• On the one hand, there are the personal obsessions of some very wealthy people to extend their lifespan, or improve their life into old age.

• If I was to become a billionaire, I’d be a pretty old billionaire.

• You want to be young to really enjoy that kind of money.

• But more than that, it’s for those very reasons you highlighted.

• Drug and treatment research is often very specific.

• You develop a coronavirus vaccine and it likely won’t treat anything else.

• It may not even be effective on mutations of the virus it was developed to fight.

• With approaches like cellular programming, targeting senescent cells.

• If they work in one disease, they’re likely to work on a number of other conditions.

• That’s a bit like having a universal patent for a cure-all medicine or treatment regime.

• Not only is it enormously beneficial, it’s enormously valuable.

• I’m not here to argue the toss between profit and societal benefit:

• I imagine different investors and operators will have different end goals.

• What we do have here, is the potential, within a relatively short space of time,

• To develop effective and safe treatments which can turn back time in terms of the effect it has on our bodies.

• Which should be Richard’s cue to play Cher’s horrifying power ballad as the Walking Dead swarm around us.

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