... is not Space.
It is of course, Death.
There is a convergence of science on the issue of life extension. This isn't the same as Death reversal, more like postponement. But there's a concept arising in longevity circles that sounds familiar to us spaceship junkies: "Escape Velocity".
This is a mathemathical concept, but it isn't hard:
Every year that passes, our tech allows us to extend our lives longer by a bit more on average. When that bit becomes bigger than 1 year, the continued advances will pile up faster than people can die. Theoretically this means we never die. At least those who can access and afford that technology will never die.
Of course, this is merely a mathemathical abstraction. It's just a graph function, and it isn't grounded in the real world.
Well great- but how well does he predict stuff then?
I'm no Ray Kurzweil, but even I can smell the changes coming.
If we want to really understand how things are likely to go within say the next 20 years, we'd probably be shocked if the things being researched now actually pan out. Most folks haven't got the time to dig into this material, as it's advanced science often hidden behind paywalls, and it's written in language that cannot be understood easily by laymen. Media reports generally misunderstand it. But let's look at the work of one guy.
This is Captain James Kirk.
The fictional captain of the starship Enterprise is well known to all on this forum, of all places surely. The actor is 90 years old, still active and likely to outlive some of us at the rate he's going.
He's just a mneumonic aid to the Mayo Clinic man, a Doctor James Kirkland. And a nod to the thread title.
KirkLAND is a Gerontologist.
That is he studies the illnesses and progress of the elderly. It used to be the most depressing thing to do in Medicine, maybe narowly beat out by Paediatric Oncology, but the last thing anybody I knew wanted to study in school. Why would anybody want to tackle the most hopeless thing, ageing and death? Isn't that inevitable? We'll look at his work in a second, but let's start with another scientist first.
This is Dr. Judi Campisi.
She works at a place called the Buck Institute.
She works on understanding and possibly disrupting a type of cell known as senescent cells, which appear to be a major component of the biology of ageing. It's tricky to even identify these cells. They stain bluish on microscopy, and have enlarged nuclei and fused mitochondria. Nobody paid them any attention for decades.
Dr Campisi's lab first determined that senescent cells are actually doing stuff, and are not just paralyzed zombie cells. It is not often that we credit a female scientist with groundbreaking science, so this lady ought to be recognised.
She's one of the scientists behind Unity biotech.
Unity's main idea is to oppose the secreting activity of senescent cells. As we age, the secretion makes more cells turn senescent. The hypothesis is that we clear these cells at a declining rate over time. At some point, enough of them appear, and they set off a cascade of senescence, causing catastrophic loss of homeostasis, and we get old.
In order to make the most money, they wanted drugs that work on specific targets so they have a wide product range.
Hence, they look for a "joint" drug, an "eye" drug etc.
The senescent cells don't work like that. They talk to the whole body by secretion that circulates like hormones. You therefore cannot "deage the left knee" by injecting it. Sure the drug failed, but the implication is this: It's going to likely be deageing the WHOLE human body at once. Bad for sales, good for us.
Ok, let's look at Kirkland's work: He has 200 papers, so let's just do one
Kirkland's group took senescent cells from the ear cartillage of an old mouse, and another whole healthy young mouse. They injected a young knee joint with the cells. A few days later, the joint developed arthritis.
Here's the kicker: mice don't get osteoarthritis. They had basically uncovered a mechanism that switches it on, that is connected to ageing. NOT wear and tear, as they lied to us in Med School. Senescent cell accumulation.
So now we can understand better what Judi Campisi and Unity was trying to do. Maybe they should have tried it in Kirkland's mouse.
In any case, senolytics is now a hot young field in Medicine. Senescent cells everywhere in our organs seem to be at least partly responsible for every chronic disease of ageing known to man.
There are a pile of approaches all with cumulatively billions behind them. People are shortsightedly looking to "get rich" primarily, but the implications of this research is profound. Arthritis is by no means the only thing attributed to senescent cells. They may underlie virtually every aspect of aging, including artherosclerotic disease, dementia, kidney failure, cataracts, muscle loss, infertility, diabetes, etc etc.
( Extra points if you noticed Dorian Theraputics. That's a Dorian Grey reference)
Kirkland's lab is at the forefront of the efforts:
At the moment, a bunch of his drug trials are in Phase 2. Some of the senolytic substances are very benign common substances found in food. Like Grape Seed Extract. Or Strawberries.
The first drug combination known to succeed was the DQ combo:
Dasatinib and Quercetin.
Here's the first trial in Humans:
Grape Seed Extract showed the ability to clock out 90% of senescent cells selectively, leaving the rest intact, in a Petri dish. Fantastic non toxic stuff that anybody can make with a bunch of grapes, brandy and a stove. Not that I'm proposing you do that. We might need a bit more than 10 percent of these cells- they are doing a lot of things that we might need. Also assuming that they are all the same is oversimplifying the truth. But that has not stopped scientists who really are convinced this is the path:
3 days ago this story appeared in STAT news feed:
Here's the relevant chunk from the actual journal publication:
Basically, the natural immune mechanism by which our Natural Killer cells remove senescent cells has been elucidated. If the mechanism can be adjusted in humans, we don't have to worry about targeting the right cells, the immune system has that covered. Invariant NK cells cruise the bloodstream, and they get activated by a lipid substance called ɑ-galactosylceramide, if it is attached to CD-1d. CD-1d is a protein expressed by senescent cells. This is a specific targeting system. Give an injection of ɑ-gal-cer, and the NK cells just home in and take out the senescent cells. And only those.
Ok, so this is just looking at ONE anti-ageing approach, out of many. The volume of research is staggering. Even specialized scientists in the field itself cannot keep up. But we can be certain of this: if the research proves to work in humans, medical textbooks are going to become museum artifacts, and we are going to live long enough to actually read some of the research papers.
It is of course, Death.
There is a convergence of science on the issue of life extension. This isn't the same as Death reversal, more like postponement. But there's a concept arising in longevity circles that sounds familiar to us spaceship junkies: "Escape Velocity".
This is a mathemathical concept, but it isn't hard:
Every year that passes, our tech allows us to extend our lives longer by a bit more on average. When that bit becomes bigger than 1 year, the continued advances will pile up faster than people can die. Theoretically this means we never die. At least those who can access and afford that technology will never die.
Of course, this is merely a mathemathical abstraction. It's just a graph function, and it isn't grounded in the real world.
Who's this guy, Kurzweil? He's one of the most interesting people alive today, IMHO. Ray Kurzweil appeared on TV to demonstrate a piano piece, composed by a computer. No big deal right? Well that was in 1968. And he'd written the program himself, as a teenager.
Well great- but how well does he predict stuff then?
Of the 147 predictions that Kurzweil has made since the 1990's, fully 115 of them have turned out to be correct, and another 12 have turned out to be "essentially correct" (off by a year or two), giving his predictions a stunning 86% accuracy rate.
I'm no Ray Kurzweil, but even I can smell the changes coming.
If we want to really understand how things are likely to go within say the next 20 years, we'd probably be shocked if the things being researched now actually pan out. Most folks haven't got the time to dig into this material, as it's advanced science often hidden behind paywalls, and it's written in language that cannot be understood easily by laymen. Media reports generally misunderstand it. But let's look at the work of one guy.
This is Captain James Kirk.
He's just a mneumonic aid to the Mayo Clinic man, a Doctor James Kirkland. And a nod to the thread title.
KirkLAND is a Gerontologist.
That is he studies the illnesses and progress of the elderly. It used to be the most depressing thing to do in Medicine, maybe narowly beat out by Paediatric Oncology, but the last thing anybody I knew wanted to study in school. Why would anybody want to tackle the most hopeless thing, ageing and death? Isn't that inevitable? We'll look at his work in a second, but let's start with another scientist first.
This is Dr. Judi Campisi.
She works on understanding and possibly disrupting a type of cell known as senescent cells, which appear to be a major component of the biology of ageing. It's tricky to even identify these cells. They stain bluish on microscopy, and have enlarged nuclei and fused mitochondria. Nobody paid them any attention for decades.
She's one of the scientists behind Unity biotech.
Unity's main idea is to oppose the secreting activity of senescent cells. As we age, the secretion makes more cells turn senescent. The hypothesis is that we clear these cells at a declining rate over time. At some point, enough of them appear, and they set off a cascade of senescence, causing catastrophic loss of homeostasis, and we get old.
In order to make the most money, they wanted drugs that work on specific targets so they have a wide product range.
Hence, they look for a "joint" drug, an "eye" drug etc.
...Unity announced that its lead drug candidate had failed to beat a placebo in reducing joint pain and stiffness, according to interim results from a trial of patients with osteoarthritis of the knee. The company’s stock plunged more than 60% on the news, nearly one-third of Unity staff were laid off, and its experimental drug UBX0101 — the first novel ‘senolytic’ agent ever to enter clinical testing — was swiftly abandoned.
The senescent cells don't work like that. They talk to the whole body by secretion that circulates like hormones. You therefore cannot "deage the left knee" by injecting it. Sure the drug failed, but the implication is this: It's going to likely be deageing the WHOLE human body at once. Bad for sales, good for us.
Ok, let's look at Kirkland's work: He has 200 papers, so let's just do one
Here, we present a novel senescent cell transplantation model involving injection of small numbers of senescent or nonsenescent cells from the ear cartilage of luciferase-expressing mice into the knee joint area of wild-type mice. By using bioluminescence and 18FDG PET imaging, we could track the injected cells in vivo for more than 10 days. Transplanting senescent cells into the knee region caused leg pain, impaired mobility, and radiographic and histological changes suggestive of OA.
Here's the kicker: mice don't get osteoarthritis. They had basically uncovered a mechanism that switches it on, that is connected to ageing. NOT wear and tear, as they lied to us in Med School. Senescent cell accumulation.
Here, we provide evidence that accumulation of senescent cells in and around previously healthy joints can actually cause an OA-like arthropathy in mice. This both provides a new model of OA and implies that clearing senescent cells with senolytics or interfering with their pro-inflammatory SASP could be a disease-modifying therapeutic option.
So now we can understand better what Judi Campisi and Unity was trying to do. Maybe they should have tried it in Kirkland's mouse.
In any case, senolytics is now a hot young field in Medicine. Senescent cells everywhere in our organs seem to be at least partly responsible for every chronic disease of ageing known to man.
Table 1 Selected biotech companies focused on senolytics
From: Send in the senolyticsCompany (year founded) | Business focus/technology |
---|---|
1E Therapeutics (2020) | Antisense oligonucleotide–based senolytics |
Atropos Therapeutics (2018) | Targeting transition between quiescence and senescence (senescence after growth arrest, or SAGA) |
Cleara Biotech (2018) | Targeting FOXO4 to release proapoptotic p53 |
Deciduous Therapeutics (2018) | Activating immune cells to clear senescent cells |
Dialectic Therapeutics (2018) | Systemic delivery of senolytic agents using proteolysis-targeting chimeras (PROTACs) |
Dorian Therapeutics (2018) | Targeting USP16, a deubiquitination enzyme, to reverse senescence |
Eternans (2017) | FOXO4-binding peptide |
FoxBio (2018) | Targeting p53/FOXO4 prosurvival pathways in senescent cells |
Genome Protection (2018) | Stimulating innate immunity to eradicate genome-compromised cells |
Geras Bio (2020) | SASP inhibitors |
Insilico Medicine/Taisho (2020) | AI target identification and generation/validation |
NRTK Biosciences (2020) | Synthetic optimization of approved drugs and supplements |
Numeric Biotech (2017) | Selective targeting of FOXO4-p53 |
Oisín Biotechnologies (2014) | Gene therapy with caspase-9 activated in p16-positive cells |
Oncosence (2019) | Monoclonal antibodies targeting tumor cells after inducing them to senescence |
OneSkin (2016) | Peptide that modulates senescence-related signaling pathways and enhances DNA repair |
Recursion Pharma (2013) | AI drug discovery platform |
Rejuversen (2020) | Antibody against PD-L2 that promotes immune-mediated clearance of senescent cancer cells |
Rubedo Life Sciences (2018) | Small-molecule senolytics |
Senisca (2020) | Antisense oligonucleotides against splicing factors |
Senolytic Therapeutics (2017) | Senolytic and senomorphic drugs to treat fibrosis |
SIWA Therapeutics (2006) | Antibody against glycation surface molecule |
Unity Biotechnology (2011) | Targeting various senescence-related proteins (Bcl-xL) |
There are a pile of approaches all with cumulatively billions behind them. People are shortsightedly looking to "get rich" primarily, but the implications of this research is profound. Arthritis is by no means the only thing attributed to senescent cells. They may underlie virtually every aspect of aging, including artherosclerotic disease, dementia, kidney failure, cataracts, muscle loss, infertility, diabetes, etc etc.
( Extra points if you noticed Dorian Theraputics. That's a Dorian Grey reference)
Kirkland's lab is at the forefront of the efforts:
Kirkland worked out why it is these senescent cells don't just die on their own. That means, he figured out the biochemistry of how to bypass that, and kill them.Dr. Kirkland’s laboratory published the first article about agents that clear senescent cells - senolytic drugs. Dr. Kirkland demonstrated that senolytic agents enhance healthspan and delay, prevent, or alleviate multiple age-related disorders and chronic diseases in mouse models. He published the first clinical trials of senolytic drugs and is currently conducting multiple clinical trials of senolytics. He has more than 200 publications and holds over 20 patents
At the moment, a bunch of his drug trials are in Phase 2. Some of the senolytic substances are very benign common substances found in food. Like Grape Seed Extract. Or Strawberries.
The first drug combination known to succeed was the DQ combo:
Here's the first trial in Humans:
Senolytics decrease senescent cells in humans: Preliminary report from a clinical trial of Dasatinib plus Quercetin in individuals with diabetic kidney disease
Senescent cells, which can release factors that cause inflammation and dysfunction, the senescence-associated secretory phenotype (SASP), accumulate w…
www.sciencedirect.com
The term "Hit and run" just means we only treat with one or two doses for a day. Short term treatment, that can be repeated say monthly. Low toxicity, easy to do. Cheap.“Hit-and-run” treatment with senolytics, which in the case of D + Q have elimination half-lives <11 h, significantly decreases senescent cell burden in humans.
Grape Seed Extract showed the ability to clock out 90% of senescent cells selectively, leaving the rest intact, in a Petri dish. Fantastic non toxic stuff that anybody can make with a bunch of grapes, brandy and a stove. Not that I'm proposing you do that. We might need a bit more than 10 percent of these cells- they are doing a lot of things that we might need. Also assuming that they are all the same is oversimplifying the truth. But that has not stopped scientists who really are convinced this is the path:
In 2017, a team led by Peter de Keizer, a researcher specializing on aging at University Medical Center Utrecht in the Netherlands, described a cell-permeable peptide comprising part of FOXO4 that could disrupt this process12. By freeing p53 to exit the nucleus and engage apoptotic pathways in the cytoplasm of senescent cells, the therapy, which incorporated right-handed amino acids for added potency, helped counteract frailty, hair loss and renal dysfunction in mice.
It was the first intentionally designed senolytic agent — and it attracted a lot of attention. One self-experimenter even started injecting himself with de Keizer’s peptide and chronicling his experiences online.
Reawakened immune cells show promise in mice against zombie cells tied to diseases of aging
If the results hold up, they could offer a promising alternative to “senolytics” — experimental drugs that destroy zombified senescent cells that pile up and pollute your tissues as you get older.
www.statnews.com
Here's the relevant chunk from the actual journal publication:
- Activation of invariant natural killer T cells eliminated senescent cells in vivo
- Removal of senescent preadipocytes improves glucose control in obese mice
- Removal of senescent cells decreased lung fibrosis and improved survival
- Human iNKT cells were preferentially cytotoxic to senescent lung fibroblasts
Basically, the natural immune mechanism by which our Natural Killer cells remove senescent cells has been elucidated. If the mechanism can be adjusted in humans, we don't have to worry about targeting the right cells, the immune system has that covered. Invariant NK cells cruise the bloodstream, and they get activated by a lipid substance called ɑ-galactosylceramide, if it is attached to CD-1d. CD-1d is a protein expressed by senescent cells. This is a specific targeting system. Give an injection of ɑ-gal-cer, and the NK cells just home in and take out the senescent cells. And only those.
Ok, so this is just looking at ONE anti-ageing approach, out of many. The volume of research is staggering. Even specialized scientists in the field itself cannot keep up. But we can be certain of this: if the research proves to work in humans, medical textbooks are going to become museum artifacts, and we are going to live long enough to actually read some of the research papers.
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