#019: Replacing Aging.
Jean Hébert's bold anti-aging program. 3D Bioprinting. Mesoblast double failure.
📡 In this edition of Longevity Marketcap Telemetry
Last Week in Longevity
A Review of “Replacing Aging” by Jean Hébert
Longevity Companies Working on Replacing Aging and Regeneration
Book Notes: Replacing Aging by Hébert
Disclaimer: None of this information should be taken as financial advice. It is for education purposes only.
SENS Research Fundraising: Several prominent donors (Jim Mellon and Michael Antonov included) are matching donations x3 (!) till the end of the year. SENS does incredible basic research work and outreach in longevity / anti-aging. Please consider donating -- your donation will be 3x leveraged! The returns on basic research cannot be overstated.
-Nathan Cheng @realNathanCheng
LongevityMarketcap.com // LongevityList.com // BiohackStack.com
📝 Last Week in Longevity
Mesoblast Revascor Phase 3 Failure and remestemcel-l COVID ARDS Phase 3 Failure. The Australian stem cell company’s stock cratered over 44% on the news of both trial failures. Revascor is an allogeneic mesenchymal-derived stem cell therapy developed to reduce inflammation and promote regeneration for patients with cardiac failure. Remestemcel-L (essentially the same product) was being trialled in Covid-19 patients with acute respiratory distress syndrome.
Robert Nelson’s Biohacking Stack. What does a Biotech VC take for longevity? Robert Nelson, founder of ARCH Venture Partners (backed Unity Biotechnology, Juno Therapeutics, Denali Therapeutics, Beam Therapeutics, Illumina, Grail, Fate Therapeutics, etc) spilled the beans on his updated drugs and supplements stack he takes for longevity on Twitter. His stack includes:
Metformin (extended release) 500 mg 3x / day
Lipitor 10 mg
Elysium Basis (Nicotinamide Riboside + pterostilbene)
Nutrigold Triple Fish Oil 2x
CoQ10 400 mg
Thorn 2 a Day multivitamin
NMN (nicotinamide mononucleotide)
Vitamin D 4000 IU + Zinc (for Covid)
Consults with doctor for renal and liver panel
📅 Longevity Futures
DNA Tie Club / Biotech / Life Sciences Clubhouse Meeting 1:00 PM EST Saturday. Every Saturday Joshua Elkington (VC @ Axial) hosts a biology / biotech chat on Clubhouse. A wide range of participants from industry and academia show up regularly to discuss everything biology and biotech. Super interesting stuff. Clubhouse is invite only (and iOS only) for now. I have two extra Clubhouse invites to give away. First readers to email me with proof of a new donation to SENS Research Foundation before end of year can claim an invite. **Invites have been claimed!
January 26- 28, 2021: 3rd Annual Longevity Therapeutics Conference. Will include speakers from Unity Biotechnology (Ned David), SENS Research Foundation (Aubrey de Grey), Insilico Medicine (Alex Zhavoronkov), Alkahest, Stealth BioTherapeutics, Lineage Cell Therapeutics, Rubedo Life Sciences, Rejuversen, Laura Deming and others. Online. Cost: $1099 - $1899.
Interested in learning more about investing in longevity biotechnology? Make sure to subscribe to receive the weekly Longevity Marketcap Newsletter.
Replacing Aging: Book Review
Replacing Aging is a provocative new book written by Jean Hébert, a Professor of Genetics and Neuroscience at Albert Einstein College of Medicine.
The main thesis of Hébert’s book is that the current focus on pharmaceutical approaches to cure aging will have limited success and the best way to defeat aging completely is by whole replacement of the components of the body, including the brain (albeit progressively).
Although replacement strategies are presently being developed by some longevity companies, the vast majority of anti-aging efforts are indeed drug-based. Hébert’s book is a rallying call to increase efforts for replacement-based anti-aging strategies. He also provides a roadmap of how such a program would work based on advances in tissue engineering and neuroscience.
After reading Replacing Aging, I felt that more people should be aware of this book and Hébert’s strategy for complete reversal of aging. This review article will outline Hébert’s main ideas in Replacing Aging -- annotated with my musings and notes.
Replacing Aging: Key Takeaways
Aging is the accumulation of a myriad of complex macromolecular damage.
Current drug-based targeting of “Hallmarks of Aging” are unlikely to completely reverse or halt the complex macromolecular damage of aging. (Drugs might be able to slow or partially treat aging.)
Replacing the components of the body to cure aging is our best strategy to cure aging. We can already replace most types of organs and tissues through transplants. Donor organs and tissues can be engineered in the lab with 3D bioprinting, induced-pluripotent stem cells, embryonic stem cells, or through genetically engineered headless/brainless fetuses (yikes!). Also prosthetics/bionics.
Replacement of the brain is possible by progressive replacement of brain cells. The neocortex is plastic and adapts to slow changes to its structure. Experiments demonstrate that young neurons transplanted in the brain can integrate and survive for decades.
Longevity Semantics: What does it mean to fight aging?
Weak or Strong Longevity? Systemic age reversal or local age reversal? Median life span or maximal life span?
Before we get started it would be useful to first examine the different definitions of “fighting aging”. When someone says they are “working on aging” they could mean anything from trying to improve health in old age to abolishing death through transhumanist technology.
I like to categorize anti-aging strategies with three different levels of scope or goals:
Weak Longevity / Healthspan Extension: Ameliorate symptoms of aging. Increase number of healthy years, but no increase in maximal life span. Possibly increase median life span and compress morbidity.
Moderate Longevity: Slowing aging or partial reversing/stopping of aging. Possibly increasing maximal life span beyond the current records (125 years). Increase median life span, but life span has a limit. Still able to succumb to aging.
Strong Longevity: Complete cure for aging. Extending maximal life span indefinitely or at least to the extrinsic mortality limit. Limiting factor will be from accidents, disasters, homicide, etc.
To be clear, extending life span is NOT the same as curing aging. Curing aging requires the complete halting, reversal, or massive dilution of macromolecular damage.
Replacing Aging: Crazy or Practical?
Tissue engineering. Lab grown organs. Head transplants. Headless Fetuses. Brain cell replacement.
Most people will probably find some of the ideas in Hébert’s book radical -- even to those already familiar with longevity. However a first principles examination of Hébert’s arguments lead me to believe that the conclusions in Replacing Aging are mostly correct, depending on the framing of the problem that one intends to be solving (more on this later, see “Longevity Semantics”). If we want to cure aging completely (“Strong Longevity”) then a replacement strategy is likely to be the easiest and most likely to succeed.
Hébert argues current drug-based approaches that target “Hallmarks of Aging” haven’t shown much success in complete halting or reversing macromolecular damage and are unlikely to succeed in general. The Replacing Aging program on the other hand is a fundamentally robust approach to curing whole body aging and unlocking indefinite lifespan.
Replacement of parts is logical-- it’s what we do to extend the lives of cars and nuclear reactors. But what about the brain? Hébert’s great insight is that the brain can also be rejuvenated through slow progressive replacement of brain cells, as demonstrated in preliminary experiments.
That being said, pursuing modest extensions of life through pharmaceutical therapies is not a waste of resources. Current pharma approaches do have the potential to extend healthspan and median life span (slowing aging) even if they cannot completely stop the accumulation of macromolecular damage / aging. The rewards for investing in temporary treatments for aging can be immense in light of longevity escape velocity and the exponential improvement rate in technology and artificial intelligence. However, I do agree we should be investing more in long term robust longevity approaches like replacement.
One major note: I don’t think most longevity drug companies claim to be trying to fully cure aging -- at least not in the short term. For instance, Jim Mellon and the folks at Juvenescence only have the “modest” goal of increasing (healthy) median life spans to 120 or so, which would be an impressive feat in its own right. That’s ~40 extra years compared to current life expectancy. Think of how much robust longevity technology we (and our AI overlords) could develop in that time -- replacement strategies included.
Longevity Companies Working on Replacing Aging
The bulk of the longevity industry is developing drug-based therapies. But there are some companies actively pursuing replacement or regeneration strategies that could be used to partially reverse aging. In general, tissue engineering and regenerative medicine is a sector investors should pay attention to.
LyGenesis: This Juvenescence-backed startup is attempting to regenerate livers by injecting allogeneic hepatocytes into lymph nodes. After promising results in pigs the company is now recruiting patients for a Phase 2 trial to treat liver failure.
eGenesis: This George Church-affiliated startup is developing xenotransplantation of organs from genetically engineering pigs.
Organovo (NASDAQ:ONVO): 3D bioprinting of organs. Backed by the Methuselah Fund. Also a holding in Cathie Wood’s ARKG. Company performance has been disastrous in the last few years but has seen some extreme investor interest in the last week.
Frequency Therapeutics (NASDAQ:FREQ): A Bob Langer company using small molecule drugs to stimulate progenitor stem cells in the inner ear to divide and differentiate into “hair cells” to reverse age-related hearing loss. Perhaps this cannot be done indefinitely if the progenitor stem cells do not divide indefinitely.
AgeX Therapeutics (NYSE:AGE): Mike West’s early stage stem cell and regenerative medicine company. AgeX develops allogeneic embryonic-derived stem cells to regenerate damaged tissues. They also have an induced-tissue regeneration pipeline attempting to epigenetically reprogram cells to a youthful and proliferative state.
Lineage Cell Therapeutics (NYSE:LCTX): Formerly BioTime, this stem cell biotech is developing allogeneic retina pigment epithelial (RPE) cells to treat age-related macular degeneration.
Samumed: A secretive $12 billion dollar private company that develops drugs that stimulate the Wnt pathway to activate stem cells in the body to regenerate tissues. They are currently in Phase 2 trials for osteoarthritis.
Revivicor: A subsidiary of United Therapeutics. Xenotransplantation with genetically engineered pigs, similar to eGenesis.
Cellink (STO:CLNK-B) is a Swedish 3D bioprinting stock that isn’t Organovo. It has a market cap of $1.4 B USD. Their bioinks and bioprinters are used by research institutions and industry all over the world. The stock is up 188% YTD and up 10x since it IPO’d in 2016.
Other bioprinting companies here. Certainly an industry to watch.
Book Notes: Replacing Aging by Jean Hébert
Jean Hébert’s Replacing Aging is divided into five parts:
The Nature of Aging: Introduces basic science behind aging and the definition that aging is the accumulation of macromolecular damage.
Drugs Won’t Work to Reverse Aging: Hébert argues that current pharmaceutical approaches will not be able to reverse aging or cure it as a whole.
Replacements to Reverse Aging: Hébert outlines the general strategy of replacing components of the body to cure aging completely.
Replacement, Even for the Brain: Hébert addresses the main objection to the replacement strategy, the brain, with results from advances in neuroscience that suggest a slow progressive replacement of brain cells is a viable strategy.
So What Are We Waiting For?: Societal impediments to the replacement strategy for aging and how to overcome them.
Italics are my own thoughts, scatterbrain as they may be.
Part 1: The Nature of Aging
Aging is a complex multitude of progressive damage to our macromolecules.
Every machine succumbs to wear and tear over time. Like Aubrey de Grey, Hébert likens the body to a machine that degrades over time intrinsically with operation. This analogy is apt. Some components of cells are so much like molecular machines that they even resemble man-made machines of similar form and function.
Aging is complex and results from progressive macromolecular damage. Humans are made up of water and macromolecular substances (proteins, lipids, nucleic acids, carbohydrates). These macromolecular substances accumulate damage over time due to a multitude of natural metabolic processes in the body. The macromolecule defines the smallest unit of aging damage -- a sort of Planck unit. We don’t have to worry about changes to the individual atoms or electrons that make up our bodies, but changes to macromolecules can cause noticeable loss of their function, which propagates up the stack to phenotypic aging. Unfortunately there is a lot of diversity in macromolecules and also the ways that they can be damaged. It’s complex.
Types of macromolecular damage: Oxidation, glycation, racemization, deamidation, depurination, depyrimidination, cross-linking, breakage of polymer chains, etc. These are categories of macromolecular damage. We have many different macromolecules and many different ways they can be damaged.
Some damage is irreversible (in the context of drugs). This includes DNA damage, loss of chromosomes, and insoluble products (lipofuscins). DNA mutations cannot be reversed with “dumb” drugs without knowing the original state. Perhaps this can be mitigated with whole genome sequencing, gene editing, or RNA therapies. Lipofuscins are intracellular residues of lysosomal digestion. They are made of oxidized proteins, lipids, and also contain sugars and metals.
Some organisms do not show signs of aging (bristlecone pine, tortoises, lobsters, quahogs, etc). Maybe we can design drugs or therapies to mimic their anti-aging mechanisms? No, unfortunately, these organisms escape aging by unconstrained growth and therefore dilution of damage or selection against damaged cells. Hébert makes this argument while conspicuously leaving out naked mole rats -- they show no increased rates of mortality with age and have stable adult size. I could not find reports that naked mole rats have increased cell turnover. They may in fact have reduced protein turnover (Swovick et al. 2020). However, it is not immediately clear how we would translate the naked mole rat’s negligible senescence to humans.
Humans have innate (but limited) repair mechanisms. Can’t we extend these abilities to reverse aging damage instead of replacement? Unfortunately, our repair mechanisms are not complete. And one malfunctioned repair mechanism is enough to succumb to aging. It is true that we can regenerate some tissues (skin, digestive, etc) but most tissue cannot be self-repaired innately. We would need to engineer the ability for most tissues. In order to completely reverse or halt aging, repair systems would need to work more or less perfectly. Hébert uses the example of Werner’s Syndrome, an accelerated aging disease caused by a genetic mutation in DNA repair machinery to demonstrate the sensitivity.
Part 2: Drugs Won’t Work to Reverse Aging
Targeting individual hallmarks of aging cannot completely reverse or halt aging on their own.
Humans have been trying “magic bullets” to extend life since antiquity. I suppose the thinking is that drugs and gene therapies can cure some diseases and if aging is a disease then we should be able to cure it with existing modalities as well. Unfortunately aging is complex and multifactorial. We would likely need a multitude of drugs to even begin thinking of halting or reversing aging and that’s why I believe Herbert is correct to prefer replacement for this purpose.
Aging biologists have been cataloguing the most fundamental cellular level changes that occur in the with age. These “Hallmarks of Aging” (telomere attrition, senescent cells, deregulated nutrient sensing, stem cell exhaustion, loss of proteostasis, DNA mutations, mitochondrial dysfunction, extracellular and intracellular aggregates, and extracellular matrix stiffening) are used as targets for anti-aging therapies. The Hallmarks of Aging are called “Hallmarks” and not “Causes” for a reason: We don’t know for sure that they are causes or merely effects of the aging process. The only way to know for sure is to reverse them and see if it reverses aging.
Targeting individual Hallmarks of Aging have not proven effective at extending maximum life span. The main exception is nutrient sensing or caloric restriction mimetics, which extends maximal life span in mice and simpler organisms. Restriction of caloric intake extends maximum life span by 30 - 50% in mice (and also similar results in lemurs). It is believed that caloric restriction causes organisms to enter a state of improved repair and cellular turnover, an evolved response to weather famines. As such, caloric restriction has little effect on extending life spans of long-lived organisms. Calorie restriction experiments in rhesus monkeys did not convincingly demonstrate life span extension, though it did increase healthspan.
Telomere attrition is one of the most well known Hallmarks of Aging. Hébert believes there is little to no evidence that lengthening telomeres in mice increases maximum life span or a cure for aging. Some cells in our body, like neurons, don’t replicate or shorten their telomeres much at all but age anyway. So lengthening their telomeres wouldn’t reverse aging. Telomeres are the caps on the ends of our chromosomes that shorten with every cell replication. At some critical telomere length the cell commits suicide or becomes senescent. This is believed to be an evolved mechanism to limit cancer growth. The rate of shortening of telomeres is a predictor of life span across species (Whittemore et al. 2019). But this doesn’t prove telomere shortening causes aging. More suggestive results by the Blasco lab demonstrated that chimeric mice created with embryonic stem cells that had hyper-long telomeres showed an 8% increase in maximum life span (Muñoz-Lorente et al. 2019). A telomerase gene therapy that extends telomeres in mice have demonstrated an increase of 9% in maximum life span (Bernardes de Jesus et al. 2012). Hébert also raises the concern of increased incidence of cancer associated with some examples of telomerase therapy.
Mitochondrial dysfunction is a poorly defined target. Both increasing and decreasing mitochondrial function can shorten life span. Mitochondria are the powerhouse of the cell but they also have other signalling / apoptosis functions. Deterioration of mitochondrial function is one of the hallmarks of aging. Herbert believes manipulating mitochondria is a bad strategy to reverse aging given how complex and uncertain we are about what we want to change. From a fundamental perspective mitochondria are like another organism living inside the cell (see endosymbiosis theory) so it makes sense that their repair would be complicated. Nonetheless, a number of longevity biotech companies are targeting mitochondrial dysfunction including Stealth BioTherapeutics, Mitotech, CohBar, and GenSight Therapeutics. I think the programme of allotopic expression of mitochondrial genes in the nucleus seems likely to be straightforward and beneficial but it is unclear how to repair other aspects of the mitochondria.
There is no evidence that senescent cell clearance extends maximal life span in naturally aged mice. Senescent cells are damaged cells that lose the ability to divide. They emit factors (SASP) that cause inflammation and other deleterious effects. The most cited senolytic therapy experiment (Baker et al 2016) used mice with an engineered cellular suicide transgene that was triggered by p16INK4a expression (a biomarker of senescence) and a chemical-inducer. While phenotypes of aging in the mice were reversed and median survival was increased, there was no significant increase in maximum lifespan for male or female mice. I couldn’t find any instances where senolytics extended maximal life span in naturally aged mice. It looks like we cannot expect senolytics to extend maximum life span on their own.
Longevity genes: Life span is partially genetic. Different species have variable life span. Long life is common in centenarian family histories. Hébert believes these “longevity genes'' mostly help to reduce risk of death due to disease and do not help reduce the accumulation of macromolecular damage. Even if we could determine which genes are responsible for longevity we would need to do systemic genetic engineering for therapeutic applications. But even that would not be a long term solution to cure aging. Genetic mutations in insulin signalling / nutrient sensing pathways (age-1, DAF-2, DAF-16, etc) extends the maximum life span of the model organism C. elegans (nematode) up to 10-fold (Ayyadevara et al. 2008). Mutations in genes that modulate insulin signalling and growth hormone in mice can extend the lifespan of mice by up to 70% (Ames dwarf mouse). Hébert believes it might be possible to extend lives beyond 115 by interfering in these or other metabolic pathways. But it won’t cure aging. Damage still progressively accumulates in these modified model organisms.
Reversing epigenetic alterations have not demonstrated the slowing or reversal of macromolecular damage. Epigenetic alterations are heritable changes of the genome that do not involve a change in DNA sequence. These changes include DNA methylation and histone acetylation, which both modulate gene expression. DNA methylation patterns change with age and can be used to construct predictors of biological age and mortality. But it isn’t clear whether the changes in epigenetics are the cause or effect of aging. Perhaps the closest refutation of Hébert’s dismissal of epigenetic reversal of aging is David Sinclair’s recent work of restoration of vision in old mice using Yamanaka epigenetic reprogramming factors (Lu et al. 2020). The experiment demonstrated that DNA demethylation was required for rejuvenation, which implies that DNA methylation could be considered a type of macromolecular damage. However, epigenetic reprogramming alone is likely not enough to overcome all types of macromolecular damage. It seems like it just resets transcriptional activity to a youthful state.
Solving stem cell exhaustion will not reverse aging or accumulation of macromolecular damage. Stem cells are undifferentiated cells that have that function to renew lost cells in the body. The regenerative capacity of adult stem cells decreases with age. Even if we could rejuvenate our stem cells it would not solve aging for cells that do not turnover (neurons).
My thoughts: Hébert analyzes most of the Hallmarks of Aging individually and says they cannot reverse aging. But what about Hallmarks of Aging in combination? The whole purpose of the Hallmarks and SENS categories is to enumerate the multifactorial probable causes of aging in order to fix them.
I think the best way to frame the pro-replacement argument is not so much that targeting all the Hallmarks of Aging will definitely fail, but that replacement is a simpler strategy with less risk.
Here’s an analogy: You need to drive 1000 km to another city but your car is old and broken. Which solution will have the greatest chance of success?: a) Give your car to a mechanic and hope he can identify and fix all the issues or b) Replace your car with a new one.
Aging is complex. We have an incomplete scientific picture of what will be required to completely halt or reverse aging using drugs. In contrast, replacing aging only requires engineering; it works in principle and can be iteratively improved. Organ growing techniques developed in mouse models will probably translate well to humans whereas the same cannot necessarily be said of drugs.
In choosing between replacement vs drugs, I am reminded of what Elon Musk said when he was deciding whether to continue his graduate school research to develop ultracapacitors for electric vehicles: “You want success to be one of the possible outcomes.” Success is not a clear outcome for drug-based curing of aging. (Drugs might be able to treat aging though)
Part 3: Replacements to Reverse Aging
3D bioprinting, stem cells, head transplants, headless fetus-like-things, and more..
Aging biologists think we need to understand aging completely in order to overcome it. Historically, this has not been the case for other diseases. A surgeon does not need to understand the cause of cancer to remove a tumour. Aspirin / willow bark has been taken for pain relief for over 2400 years but its mechanism of action was only discovered in 1979.
The human body is a complex machine. We are capable of maintaining complex machines like cars indefinitely through replacement of parts. Humans are much more complex, which makes the case for replacement even stronger. Reverse engineering a complex system is harder than engineering a replacement.
We know all the components that make up the body. This is mostly true for anatomy at the macroscopic level. Most new discoveries in anatomy are in classification of interstitial structures.
Building replacements for components of the body is easier than you think because we can leverage the fact that the body already knows how to build itself. Humans have been growing other humans since the beginning of the species. A fertilized embryo can be placed in virtually any working uterus and it self-assembles into a human with youthful body parts.
Embryonic stem cells can grow into any type of cell given the right environment. With enough of the right cells you can build an entire organ.
Replacement is already routine. Virtually every type of organ and tissue has been successfully transplanted into recipient patients -- except for the brain. The first kidney transplant was in 1954. By 2008, 70,000 kidney transplants were done globally. Replacement / organ transplants aren’t used to treat aging today because of donor organ scarcity. But in theory it should work.
Lab grown organs are the key to increasing donor organ supply. Some organs and tissues have already been grown in the lab and successfully transplanted into patients (windpipe, skin, bladder, bone marrow). The field of tissue engineering has been making steady advances. New technologies such as 3D bioprinting have potential to revolutionize regenerative medicine. Usage of patient-derived induced pluripotent stem cells (iPS cells) should reduce the chances of immunogenic rejection of lab grown organs. Traditional 3D printing can be used to create scaffolds to grow stem cells into full organs. The biggest challenge in lab grown organs today is vascularization. It may take decades before we are able to successfully grow a functioning kidney in the lab. (See Anthony Atala’s work in tissue engineering)
Prosthetics, synthetic implants, artificial organs. Artificial limbs and joints are already routinely used in patients. SynCardia’s Total Artificial Heart is FDA approved and has been implanted more than 1,800 times with patients survival times up to 4.5 years. Artificial cochlea can restore some hearing function for the deaf.
Whole body replacement and head transplants. Zombies. Hébert gets radical and suggests that we could do head transplants to rejuvenate the body. Early experimental head transplants in monkeys showed some success (eye response, chewing, EEG signals).
To solve the lack of whole body donors, one could leverage birth defects that result in the lack of development parts of the brain or head (anencephaly, atelencephaly, aprosencephaly, acephaly). There are cases where women voluntarily carry fetuses with these birth defects to term so that their organs can be used to save the lives of other newborns. Intentional creation of these birth defects are already possible in mice: Mice pups can be born without heads by inactivating the Lim1 gene (Shawlot et al. 1995).
Another possibility is using embryonic stem cells-- they tend to self assemble into headless fetuses on petri dishes (Beccari et al. 2018). Artificial uterine environments can be developed to incubate these “zombies” (see Biobags).
As ghastly as this approach seems it is a solution that I have also converged on from a different perspective: Drug testing. Growing armies of brainless human zombies would be an unbeatable test platform for pharmaceutical therapies in addition to their potential for organ and whole body transplants. This is probably the only idea that could tempt me to form a new company. If you are passionate about this please contact me.
Brain machine interfaces may solve the spinal cord problem. A head transplant requires the severing of the spinal cord. This results in paralysis below the head. A brain machine interface could restore function of the movement of limbs and other parts of the body.
Some other possibilities include in-situ regeneration of organs or tissues. LyGenesis is attempting to inject hepatocytes into lymph nodes to regenerate livers, with the possibility of extending the technique to other organs. Frequency Therapeutics and Samumed use small molecule drugs to stimulate stem cells to divide and differentiate for regenerative therapies. However, it isn’t clear if these methods will be able to sufficiently dilute or reverse macromolecular aging. Xenotransplantation from gene-edited pigs is also being pursued (eGenesis).
Part 4: Replacement, Even for the Brain
Slow progressive replacement of neurons is the key to rejuvenating the brain.
The brain is plastic, even in old age. We don’t need to worry about replacing the brain in an exact replica configuration to preserve self-identity. Neuronal connections themselves change naturally.
The neocortex, the center of thought and cognition, is a thin sheet of brain cells. It is very plastic. A cognitive function associated with one area of the neocortex can migrate gradually to a different part of the neocortex under certain conditions. Some slowly growing brain tumours in the language center of the neocortex force other parts of the neocortex to take on language function. When the tumour is removed, patients can still speak normally. The brain can adapt to changes in structure.
Young brain cells can integrate themselves into the adult neocortex in mice. Transplantation of young fetal neuronal tissue into adults has been tried to treat Parkinson’s disease in humans. Some patients had success with dopaminergic nerve cells surviving 24 years after the transplant. Other results were mixed, possibly because of donor variability.
Replacement of neurons need to mimic fetal development. The neocortex is made of 6 layers. The fetal neocortex develops layer by layer. Replacement strategies of brain cells may need to mimic this development to allow the cells to integrate in a natural manner. This has never been tried yet.
Basic replacement strategy: Replace old neurons by silencing, removing, and transplanting young cells. Interrupting the signalling to a certain part of the neocortex will cause that function to migrate to a different part of the neocortex. The cells in the old functionless part of the neocortex can then be removed and replaced with young neurons. Neuroscience techniques such as optogenetics and chemogenetics allow for silencing or activation of specific neurons.
Replacement of the brain will require all major cell types (neurons, glial, vascular). Microglial clean up debris and remodel damaged blood vessels, astrocytes regulate blood vessel dilation, oligodendrocytes produce myelin, etc. Young brain cells derived from fetal tissue are multi-type and can survive when transplanted. But cells produced by induced pluripotent stem cells are single type and have low survival. Another solution is to use microglial, which self-spread evenly in the brain, and reprogram them into other cell types. This reprogramming has been demonstrated in mice in vitro and in vivo.
Extracellular matrix in the brain will also need to be replaced. Cells secrete proteins that form the extracellular matrix scaffold. These proteins can accumulate molecular damage and may require removal through enzymatic or cellular techniques.
Can we replace 20 billion neurons of the neocortex in a reasonable amount of time? Yes. Using the rate at which new neurons can grow and integrate themselves in the dentate gyrus of mice, it can be estimated that it would take 10 years to replace 20 billion neurons in the neocortex.
I think the big question here is whether cognitive functions can be progressively transferred to artificial neurons communicating with the neocortex, migrating away from wetware completely. If this is possible then brain machine interfaces would be the most important thing to be working on right now.
Part 5: So What Are We Waiting For?
Why aren’t we working on replacing aging?
Not much funding for replacement therapies for aging. The NIA and AFAR do not fund replacement approaches for aging. I’m sure there is a reasonable amount of funding going towards tissue engineering for organ transplants, which could be translated for combating aging. But the fact that these anti-aging agencies don’t promote replacement strategies is an issue.
Not enough companies working on replacement therapies and tissue engineering. Tissue engineering is still in its infancy. Not enough investors are willing to invest on decade time horizons. Organovo went public in 2012 and hype drove the stock price more than 8-fold before it crashed 99%. It is unclear when bioprinting technology will be able to print complex organs.
We need a grassroots campaign that assembles scientists, bioengineers, and physicians to advocate for replacement strategies. Historical movements to cure major diseases like AIDS and cancer required leaders and groups to advocate for them.
My speculation is that whole body replacement is too extreme for most people to consider a possibility, even if it makes sense. The general public isn’t even aware of the longevity movement, let alone replacement. On the other hand, taking a pill to treat aging requires less of a jump of the imagination.
Steelmanning Replacing Aging
Here are what I would consider to be strongest arguments against replacement over current pharmaceutical approaches for aging.
We don’t need to halt or reverse aging indefinitely with drugs. Accidents will be the limiting factor to longevity. We only need to slow aging to the point that maximum life span is roughly equal to expected life span based on extrinsic factors (accidents, etc). Even if we could cure aging we would eventually succumb to other accidents and other background risks. Hébert argues against targeting individual “Hallmarks of Aging” because they (probably) cannot completely halt or reverse accumulated macromolecular damage. But if targeting Hallmarks (individually or in combination) could get us to ~500 years life span there would be little added benefit to going with replacement strategies instead. Of course the extrinsic risk can always decrease in the future (driverless cars, etc) so 500 years is a moving target.
Cells made from our own induced-pluripotent stem cells can still induce an immunogenic response. The cells may be genetically identical but epigenetic changes can still cause immune system rejection. Immunogenic risk should be lower than allogeneic transplants, though. Probably can be overcome with immunosuppressants or antigen engineering.
It might be impossible to prove preservation of self-identity when progressively replacing brain cells. This argument probably applies equally well to brain surgery patients. Perhaps even to sleep? I cannot think of a test that would definitively prove a patient’s self-identity still has temporal continuity. This is more of a philosophical objection and might have no answer.
I don’t believe these counter arguments are strong. From a first principles view complete age reversal through replacement still has a clearer path to success than developing a cornucopia of different drugs.
Let’s see what price momentum indicators are saying about specific longevity and biotech stocks.
ARK Genomics Revolution ETF (ARKG)
ARK Invest’s Genomics Revolution ETF is getting a lot of attention after founder Cathie Wood said she expected the genomics fund to outperform her other holdings in the next 5 years. I agree.
But in the short term it looks like we are exhausting upside momentum. TD 9 Sequential Sell indicator has been triggered on the monthly scale and will be triggered next week for the weekly. The TD 9 monthly was a good indicator for the local top the previous two times it appeared -- take that as you will. Anecdotally, the ETF is also seeing increased interest on /r/wallstreetbets and from some of my friends who previously had no interest in biotech.
ARKG is already down ~14% from its recent highs. I have a position in ARKG and many of their holdings and will look to buy the dip in the coming days/weeks.
This 3D bioprinting stock is the only longevity stock in the holdings of ARKG. The stock price has been a disaster in the recent past, crashing 99% from its highs in 2013. However, last week the stock nearly tripled from its lows, though it has retraced much of that gain as of today.
The market cap is $90 million USD and just recently broke through its highs from May 2019, possibly due to founder Keith Murphy returning as CEO and restarting the company’s therapeutic direction.
908 Devices (NASDAQ:MASS)
908 Devices is the maker of a bench top mass spectrometry device used by many companies in the life sciences and pharmaceutical industry. It IPO’d only a week ago (and immediately doubled in price on the open) so not much can be said in the way of technical analysis.
However, on an hourly scale the chart looks interesting (TD Sequential 9 Buy). The stock was down 16% today, which could be a decent buying opportunity. Overall not a strong signal. I presently have a small position.
A lot of the IPO and SPAC stocks that were so frothy this year are dropping this week. Something to be cautious of if the trend continues.
This was an extremely interesting article, which brought up some new ideas I had never even thought of. "This is probably the only idea that could tempt me to form a new company. If you are passionate about this please contact me." I would like to hear further thoughts from you on this.
Great one, Nathan! Keep it up.