Novel Strategies to Escape Aging and Death
The quest for immortality has long been a human endeavor, with aging as the primary obstacle that inevitably leads to death. Efforts to counteract aging have spanned different eras and civilizations, with a variety of strategies and beliefs. It's only in the recent past that science has made tangible progress, not in a quest to defeat aging and death, but as part of curiosity-driven scientific inquiry. The 1990s were particularly pivotal for aging research, with breakthrough experiments that significantly delayed aging and extended the lifespan of nematodes, a type of worm often used in laboratory work, through genetic methods. These developments ushered in a new era in the study of aging, focusing on the role of molecular biology in understanding and potentially manipulating the aging process. Encouraged, some pinned their hopes on molecular interventions as a means to one day achieve an indefinite lifespan in humans. Many others remain highly skeptical, and given the pace of progress, their skepticism is warranted. But is there another way?
The Drugs Don’t Work
The prevailing approach in academic research, and more recently in the longevity biotech space, to delay, mitigate, or reverse aging has focused predominantly on drug interventions. These range from small molecules to more advanced biologics, including gene therapies. However, this strategy faces several notable limitations that may make the ultimate goal of significantly extending lifespan within the next few decades unattainable:
Scale and complexity of biological systems: The nanoscale nature of biological systems severely limits our ability to measure or manipulate them, and their enormous complexity makes them extremely difficult to decipher or model. Aging is especially difficult to understand due to its multifaceted nature.
Extent of intervention efficacy: It remains uncertain to what extent any drug intervention can reverse aging. Current interventions primarily enhance innate homeostasis or self-repair mechanisms. However, it's unclear whether these mechanisms can address all forms of age-related damage, particularly tissue-level changes and extracellular matrix defects.
Time constraints: Biological processes operate on inherent time constants that are long and immutable. Given the iterative nature of discovering and testing new interventions, the entire process could be protracted, hindering rapid progress.
Limitations of laboratory models: Often, laboratory models like worms or mice do not fully replicate the complexity of human physiology, leading to disappointing results when these interventions are tested in clinical settings.
Clinical trial challenges: Conducting human trials for these interventions is compounded by economic and regulatory hurdles, making clinical trials lengthy and costly.
Some noteworthy attempts were made to work around these limitations. SENS (Strategies for Engineered Negligible Senescence), an approach developed by Aubrey de Grey, sidesteps the need to fully unravel the complexity of our biology, instead targeting 7 damage forms using a bioengineering approach. Others have tried to accelerate the path to obtaining interventional in-human data, either through alternative regulatory frameworks for fast-tracking clinical trials, or by using pets as an onramp to human trials. But these address only some of the limitations, and do so only partially.
Given these limitations, it's reasonable to explore alternative strategies for achieving significant life extension. Drawing parallels with how we maintain machines such as cars and computers, one logical approach is to replace body parts as they fail, rather than attempting intricate repairs. While our bodies have the capacity for self-repair, the complexity of repairing biological systems may outweigh the challenges of reproducing and replacing them. So the pertinent question is: Can we realistically replicate body parts? Let's look at several possibilities and assess their feasibility.
Cell Therapy
In contrast to traditional pharmaceuticals that aim to repair or rejuvenate aged cells, an alternative approach is to replace these cells with new, functional ones. Stem cells are particularly valuable in this context due to their self-renewal and capacity for differentiation into the diverse array of specialized cells required for tissue function.
One method to acquire stem cells has involved sourcing embryonic stem cells from birth tissues such as umbilical cord blood or placenta. This approach faces immunocompatibility issues due to genetic mismatches between the fetus and the recipient, as well as supply issues, limiting its application. A significant breakthrough was the discovery of induced pluripotent stem cells (iPSCs) in the early 2000s. Shinya Yamanaka showed that using four transcription factors, adult cells of any given type can be reprogrammed into pluripotent stem cells akin to those in early embryonic stages, which can theoretically be redifferentiated into all possible cell types. This enables the generation of a diverse cell bank from an individual's own tissue, offering a wide range of applications for autologous cell replacement. Importantly, a growing body of work seems to suggest that cells that underwent reprogramming are rejuvenated for multiple hallmarks of aging, irrespective of the age of the donor.
Despite its promise, current technology limits the diversity and scalability of iPSCs products for clinical use. An emerging solution is embryoids - three-dimensional structures mimicking early embryonic stages, derived from stem cells rather than from fertilized eggs. If successfully incubated for several months, embryoids could generate diverse cell lineages in scale.
Caption: mouse (top) and human (bottom) embryoids.
Presently, cell therapy's primary uses include bone marrow transplantation and CAR T cell treatments for blood cancers, and dopaminergic neuron transplantation for Parkinson's disease. Applications in aging will need scalable solutions and better control over cell differentiation and engraftment. Interestingly, stem cell clinics around the world already offer therapies for a variety of conditions, including aging. While anecdotal evidence suggests potential benefits, rigorous validation is still pending.
Aging also affects the extracellular matrix (ECM), the scaffold of proteins and other molecules that surrounds cells and maintains the tissue’s physical structure, while also facilitating important cellular functions. Some ECM proteins, which do not turnover throughout life, may place limits on human longevity. These proteins accumulate cross-links, a type of chemical bond that significantly alters their properties and functions, and that cannot be broken down by any cellular enzyme. This exemplifies age-related damage that may not be reversed by cell therapy alone. Other examples are large-scale structural changes like spinal curvature.
Organ Replacement
Given these considerations, a potential complementary strategy could be the replacement of entire tissues or organs. But what can be the source of such organs?
3D Bioprinting
3D bioprinting uses "bioinks" - a mixture of living cells, growth factors, and biocompatible materials - to build physiological structures, layer by layer, capable of maturing into functional organs. Several such technologies are under development, including Inkjet-based bioprinting, which relies on fine droplets, laser-Assisted bioprinting, which uses laser pulses to precisely position cell-laden materials, and extrusion-based bioprinting, which mirrors a traditional 3D printer with a nozzle.
Organ vascularization is essential to creating fully functional, transplantable organs. This is achieved by embedding specialized cells in the bioinks to line the inner vessel and using materials that guide vessel growth. Interestingly, intricate capillaries and other structures can naturally form after printing, a testament to evolved self-organize capabilities of cells.
There have been significant advances in the bioprinting of simple single tissues. For example, skin grafts for burn victims and joint repair using bioprinted cartilage are current areas of success, as well as nose and ear grafts. The development of complex organs such as the heart, liver or kidney is still in early stages, with mini-organs or organoids marking progress. In essence, the scope of 3D bioprinting can extend beyond visceral organs to the creation of non-visceral structures such as the spine and components of the musculoskeletal system, the successful transplantation of which will require custom surgical techniques and extensive post-transplant rehabilitation.
Caption: London UK - August, 16 2019: Ear and nose made from a patient’s own cells using a 3D Bioprinter by The Institute of Regenerative Medicine at Wake Forest Institute.
Multiple academic labs are researching 3D bioprinting, and according to BBC research, the private market was valued at $2.1 billion in 2021, small compared to the longevity biotech sector, but projected to grow rapidly. While drug development for aging is deeply rooted in molecular biology, pharmacology, and the regulatory landscape of clinical trials, bioprinting leans more toward engineering, materials science, biomechanics, and 3D modeling. From my perspective, these latter domains are more conducive to human innovativion, and less encumbered by the inherent slow pace of biological processes and regulatory constraints.
Xenotransplantation
One might ask - why bother to fabricate organs when they can grow naturally from a single cell? The challenge is that organs need the context of the body, including cross-talk between organs, to develop properly. So to grow an organ for transplantation, you would have to grow a whole body.
One possibility is to grow animals, such as pigs, that have some degree of physiological compatibility with humans to use their organs for transplants. This process, called xenotransplantation, involves the transplantation of organs or tissues from one species to another.
The human immune system typically rejects animal organs unless the recipient's immune system is severely suppressed. However, recent research indicates that most xenotransplant rejections are due to a few molecules. This discovery suggests that genetically modifying these molecules in donor animals could achieve immunocompatibility.
Another potential incompatibility stems from biochemical differences. While organs like the heart are mostly mechanical, others like the liver and intestine perform complex biochemical functions, and the differences between animals and humans in these functions are substantial. This might set a hard limit on the usability of xenotransplantation for certain organs.
Blastocyst complementation
Blastocyst complementation is a technique aimed at growing human organs inside animals for transplantation. The process involves injecting human pluripotent stem cells into an animal blastocyst—a very early stage embryo—of a species like pigs or sheep. As the embryo develops, these human cells can integrate and differentiate into specific organs within the host animal, potentially allowing for the growth of organs that are immunologically and functionally compatible with human recipients.
One of the significant advantages of blastocyst complementation is its ability to create organs that are tailored to individual patients, reducing the risk of immune rejection and the need for lifelong immunosuppressive therapy.
Caption: generation of human organs using organogenesis-disabled pigs as a platform. From Growing human organs in pigs—A dream or reality?, Hiroshi Nagashima & Hitomi Matsunari, Theriogenology 2016.
Cloning
This need for organ compatibility segues into the concept of cloning for organ harvesting. This concept was explored in the Hollywood film "The Island" (2005), directed by Michael Bay. The movie presents a future where clones are created as living, breathing organ banks, and explores the ethical complexities and of using clones for the benefit of their genetic originals. It's been years since I've seen it, but I believe the moral is that just because you gave someone life doesn't allow you to take it away.
To address these ethical concerns, it's been proposed that genetic engineering could create clones without brains. In particular, knocking out (i.e. removing) the LIM homeobox 1 (Lim-1) gene has been observed to lead to the development of acephalous, “headless”, mice in the laboratory, suggesting its potential application in creating organ-donating clones which, lacking a head, would be non-sentient.
Caption: a. wild-type (left) vs. Lim-1 knockout (right) mouse embryos. b. Lim-1 knockout (left) vs wild-type (right) mouse pups. From Requirement for LIml in head-organizer function, William Shawlot & Richard R. Behringer, Nature 1995.
Some brain signals might be essential for appropriate body growth, which is why retaining some non-conscious brain parts is important. For this reason, genetic modifications other than LIM KO are being explored to selectively inhibit the development of the cortex. Since the cortex is associated with consciousness, and severe injury to that region makes a person eligible for euthanasia, its absence in the clone may reduce ethical concerns.
Hydranencephaly is a rare central nervous system disorder where the brain’s cerebral hemispheres, including the cortex, are absent and replaced by sacs filled with cerebrospinal fluid. Infants with hydranencephaly have been known to survive up to 32 years in rare cases. This suggests that a functioning brainstem may be sufficient to support body growth, albeit imperfectly.
Caption: T1-weighted MRI showing the sagittal (A) and axial (B) sections of a 32-year-old woman with hydranencephaly. The cerebral hemispheres are absent, with only remnants of cortical tissue. A small brainstem is visible in both the sagittal and axial sections. From Preservation of brainstem neurophysiological function in hydranencephaly, S.A. Counter, Journal of the Neurological Sciences, 2007.
The cloning process would start with gestation via a surrogate, followed by life support systems to promote further growth. Advances in ex utero technology may eventually allow the entire process to take place in a vat. Currently, however, this remains a significant limitation of the technology, in addition to the very low efficiency of cloning. Practically, the slow growth of the human body results in prolonged research timelines and extended waiting periods for organ maturation for transplantation. However, most organs will become viable for transplant much sooner than reaching full development. Additionally, there may be ways to accelerate the developmental process, especially if full brain development is not required. After all, some animals, such as horses, grow much larger much faster.
In considering the prospect of creating clones for organ donation, it's important to recognize that public perception is expected to be strongly negative. This is obvious because even the perception of old-school with-head cloning is negative. The concept of a human-like body growing in a vat, even if understood to be brainless and unconscious and thus rationally justified as an organ donor, is guaranteed to cause discomfort and raise objections in the general public.
The pushback on cloning contrasts with the enthusiastic adoption of the vision of 3D bioprinting as a potential solution to organ donor shortage. This disparity in attitudes towards two technologies with identical end products underscores human irrationality towards technological advancements. A full bioprinted body will elicit a sense of awe, while the exact same body grown in a vat will elicit revulsion. It's unfortunate that perceptual biases and a lack of open-mindedness could impede the progress of this technology, a development that has the potential to save countless lives if realized successfully.
Despite technological and ethical challenges, at least two stealth-mode commercial companies are already pursuing these ideas.
Cloning has the potential to create a personalized bank for internal organ harvesting. Surgical medicine has already achieved the transplantation of all visceral organs. Given that all organs of an aged body need replacement, it might be simpler to transplant the visceral complex as a single unit instead of transplanting organs individually. But what about transplanting the entire body as a single unit?
Head Transplant
In the 1950s, Soviet surgeon Vladimir Demikhov did groundbreaking work in transplant surgery, including grafting the head of a dog onto the side of another dog. This macabre procedure, which naturally stirred quite an uproar, was surprisingly successful, with both the animals responsive and surviving in this state for up to 29 days. Christiaan Barnard, known for performing the first human heart transplant, attempted a similar procedure in 1962 after hearing of Demikhov's work. Barnard's experiment, which resulted in the survival of the animal for several days, further ignited debates and drew the ire of animal rights activists. It led to unique demonstrations, including medical students creating a two-headed dog effigy for a parade.
Caption: from At the Cutting Edge of the Impossible, A Tribute to Vladimir P. Demikhov, Igor E. Konstantinov, 2009
In the 1970s, neurosurgeon Robert J. White advanced the field of transplant surgery by performing head transplants on monkeys, grafting the head on the neck rather than on the side like Demikhov’s dogs. Despite successfully maintaining brain function, the procedures did not achieve spinal cord reconnection, resulting in paralysis and short survival times for the subjects. White's work demonstrated the technical feasibility of such transplants but also highlighted the significant challenges in fully restoring bodily functions.
Fast forward to 2015, Xiaoping Ren was performing mouse head transplants in China. Out of 1,000 procedures, the longest survival post-surgery was 7 hours, during which the mouse managed to open its eyes and exhibit limited movement. This was 9 years ago, and recent updates on this line of research are scarce.
Sergio Canavero, an Italian neurosurgeon, gained worldwide attention for his proposal to perform the first human head transplant. The patient, Valery Spiridonov, suffers from Werdnig-Hoffmann disease, a muscle-wasting disorder that severely limits life expectancy and quality of life. The plan, which was highly controversial and debated in the medical community, involved several complex and unprecedented technical steps: selecting and preparing a brain-dead donor and Spiridonov, performing simultaneous surgeries on both, and fusing Spiridonov's head to the donor's spinal cord using a special biocompatible glue, polyethylene glycol. The procedure would also require reconnection of blood vessels and muscles to maintain cerebral blood flow.
It was estimated that it would take 80 hours to complete the surgery, followed by extensive postoperative care, including a 3-month long medically induced coma and rehabilitation for Spiridonov to potentially adapt to the new body.
Despite the detailed planning, the procedure was ultimately not carried out. Reports suggest that Spiridonov had a change of heart and has pulled out of the experimental operation, following newfound love and the birth of his son. Canavero maintains that there is still a waiting list for the surgery, but no date has been scheduled as of yet.
Brain Transplant and the Significance of the Brain
The brain is considered the core of our identity. While the loss of a limb may not change our sense of self, a brain injury can fundamentally alter who we are. This underscores the unique role of the brain in defining our individuality and consciousness. Therefore, sustaining the brain and its functionality is the only truly crucial aspect of life extension.
The life-sustaining blood supply to the brain is primarily controlled by just four major arteries: the internal carotid arteries, the main conduits for oxygenated blood to the brain, and the vertebral arteries, which join to form the basilar artery, providing blood to the base of the brain. A perfect clone with an undeveloped brain, or a full bioprinted body, could theoretically enable a pure brain transplant. Forgoing the ultra-complex re-establishment of neural reconnection to the spinal cord, a brain transplant may present a simplified surgical procedure compared to a head transplant.
In the context of advanced aging, while restoring full functionality of the body would be ideal, my view is that it suffices that the body can support the brain to make the procedure worthwhile. However, some cranial nerves will have to be reconnected because sensory input is critical for the long-term retention of cognitive abilities, mental sanity, and general well-being.
To my knowledge, there have been no efforts in this direction even in lab animals.
The Cyborg
The narrative moves from biological replacements to a concept deeply rooted in science fiction but increasingly plausible in reality: the cyborg. Prosthetic limbs and artificial organs already in use today demonstrate the feasibility of this idea. These mechanical enhancements, immune to the natural aging process, could potentially give us abilities beyond our natural capabilities. Interestingly, creating these mechanical components may be simpler than replicating biological tissues.
The primary objective of the cyborg will be to serve as a life-support system for the brain. Essential functions of delivering nutrients and oxygen, removing waste, and ensuring a stable environment, which are naturally managed by the circulatory system, would have to be replicated artificially. This would involve synthesizing a nutrient-rich plasma supplemented with red blood cells to facilitate oxygen delivery and carbon dioxide removal, and wiring it to the brain via the four arteries. In this controlled setting, sterility could compensate for the absence of blood-borne immune cells.
This brain life support system, while lacking the full range of bodily functions, may be more feasible to develop than a bioprinted or cloned body. While this route may initially limit sensory imput and movement, it could in the future facilitate connecting the brain to advanced robotics that would bridge the gap between neural impulses and mechanical actions. Imagine something like the Teenage Mutant Ninja Turtles antagonist Krang or the Doom franchise boss Spider Mastermind - a brain encased in a robotic exoskeleton.
Caption: TMNT’s Krang (left) and Doom’s Spider Mastermind (right). Lol why do they have a face directly on the brain?
Although these pop culture depictions are surreal, they capture the essence of a practical alternative to biological manufacturing. This approach requires us to focus on what the brain needs to survive and function, redefining the boundaries of human life and longevity.
Progressive Brain Replacement
What about brain aging? I've danced around this point. We know that young-to-old blood exchange in mice causes the young brain to age and the old brain to rejuvenate. This suggests some coupling between the aging of the body and that of the brain, however, the brain most definitely also ages independently of the body. If we replace everything but the brain, then the optimization of the blood supply, together with the reduced risks associated with the absence of a body, could potentially extend the healthy lifespan of the brain by several decades before dementia sets in. But it won’t completely rejuvenate it.
As already stated, the brain is where our thoughts, personality, and memories reside, the things that make us who we are, the “self”. Because the brain IS us, we cannot simply replace it like any other organ as it ages. To address this problem, Jean Hébert has proposed a novel approach to progressively replace aged brain tissue with the goal of preserving the individual's distinct mental attributes and memories.
A critical aspect of this method is the insight gained from the behavior of slow-growing benign tumors in the brain. Hébert points out that such tumors can expand without necessarily disrupting cognitive function or memory. An incredible demonstration of this principle is the case from 2007 of a 44-year-old man who discovered during a physical examination that only 10% of his brain tissue was present, with the rest of his skull filled with cerebrospinal fluid (hydrocephalus). The fluid’s gradual expansion must have allowed the brain to adapt, and despite this condition, the man had an IQ of 75 and led a normal life.
Accordingly, brain replacement would proceed by slowly deactivating confined brain regions, allowing the associated function and information to relocate into adjacent regions. Thereafter, the old deactivated tissue can be removed, and a fresh graft introduced in a slow and controlled manner. The grafts will consist of neurons generated from the patient’s own cells using iPSC techniques, ensuring immune compatibility.
Caption: screenshots from Jean’s latest interview.
The replacement process would begin in less complex areas of the brain and gradually move to more complex regions. This careful, staged approach is designed to monitor the effects of new tissue integration on cognitive function and identity, thus supporting the continuity of self.
Replacement will have to maintain the complex wiring of the brain, including subtypes of neurons that span considerable distances in the brain. Encouragingly, several mouse studies showed that transplanting young precursor cells into adult mice leads to new neurons that incorporate into existing circuitry, acquiring the appropriate shape and connections, and even responding to light in a way that is similar to host neurons.
You may read more about this topic in Jean’s book “Replacing Aging”.
Cyborg Brain
A cyborg body is a relatively familiar idea. What about a cyborg brain? While initiatives such as Neuralink have focused on transmitting signals to and from the brain and stimulating specific brain regions, which may be critical for the Krang approach, I have in mind a different concept: the integration of artificial components that mimic real brain tissue and actively engage in cognitive processes such as perception, memory, and thought formation. I believe this would involve creating artificial neurons that can both interface with their biological counterparts and replicate their dynamics. This could create a symbiotic cognitive system where thoughts and processes are a collaborative outcome of both biological and artificial neural networks.
To be clear, this is a brain-machine interface, NOT a brain-computer interface. The artificial components in question are not designed to function as a computer, but rather to replicate the characteristics of neurons essential for information processing, without the biochemical overhead. An extension of the brain's neural tissue. The goal is to emulate brain functions without fully unraveling the brain's complex mechanisms, analogous to the way digital neural networks learn so effectively by implementing a certain architecture. Ideally, biological neurons would be unable to discern biological from artificial counterparts that are seamlessly integrated. While this concept is indeed speculative and likely presents more challenges than integrating fresh lab-grown neurons, it offers a potentially more durable and modular solution compared to using aging-prone biological tissue.
According to the preliminary research I've done, achieving this level of integration on a significant scale is still uncharted territory in bioengineering. The most relevant advance I have been able to find involves the development of "conductance-based organic electrochemical neurons" (c-OECNs) by researchers at Linköping University. These artificial neurons mimic 15 out of 20 characteristics of biological nerve cells and control electronic current using ions through n-type conducting polymers. Notably, these c-OECNs were successfully integrated into the vagus nerve in mice, demonstrating biocompatibility.
In another study, researchers successfully modeled the nonlinear responses of neurons to electrical stimuli and designed silicon chips that accurately mimic biological ion channels. Ion channels control the flow of ions (such as sodium, potassium, and calcium) into and out of the neuron, which generates electrical signals. Because the silicon neurons use the same mechanism to generate these signals, they may be able to effectively interface with real neurons. The researchers also demonstrated that these silicon neurons can replicate the full dynamics of rat hippocampal and respiratory neurons under various stimuli.
I envision a future in which durable, modular artificial components are incorporated into the brain and gradually become dominant, replacing biological components. This can be called the artificialization or de-biolization of the brain. Theoretically, this process could be done adiabatically, i.e., at an imperceptibly slow pace so that no information is lost.
A holistic approach to brain artificialization would involve connecting the brain to machines that provide the necessary nourishment for its biological components and power for its artificial parts during the bionic/cyborg transition phase. Over time, the biological brain and body could be gradually replaced, leading to a stage where the fully artificial brain is integrated with a robotic system. This system would facilitate input, output, and mobility, effectively completing the transformation. The artificialization of the brain will not only protect us from the scourge of aging, but will also extend our minds into unprecedented realms, providing a means to evolve with, and potentially safeguard against, the rise of AI.
Digital Clones
The concept of a cyborg naturally evolves into the idea of a digital human. We recognize the brain as the repository of our thoughts and memories, and thus the cornerstone of our identity. This leads to the idea that preserving our identity requires preserving the brain. The possibility of replacing the organic brain with functionally equivalent artificial components has been explored, but this raises a question: Is physical equivalence essential to preserving the mind, or can it be abstracted and preserved separately?
The "mind upload," a staple of science fiction and transhumanist thought, suggests that our identity is rooted not in biology or any physical substrate, but in the function of the mind, much like a program running on the hardware of the brain. This notion posits that transferring this "program" to a non-biological medium, such as a computer chip, could circumvent aging and biological limitations while preserving one's identity and even offering enhancements through software updates.
More specifically, mapping the brain connectome - the intricate network of connections between all the neurons in the brain - has been proposed as a means to digitally reconstruct the human mind. However, this approach is overly simplistic, as a static snapshot of the connections does not capture the brain's dynamic processes, which depend on various cellular and tissue parameters not represented in the connectome. To accurately reconstruct the brain, one would need to measure the cellular states with extremely high precision and develop a dynamic model of the physical system, taking into account the complex biochemical and electrophysiological interactions within the brain.
While intriguing, I find the feasibility of this idea lessened than the other approaches. The challenge of accurately mapping and replicating the state of the brain is daunting. Our current methods of measuring the brain are relatively basic, which casts doubt on the near-future realization of such a technology. Moreover, the process would likely be destructive, possibly involving invasive techniques such as slicing the brain, and this assumes that brain states are classical (rather than quantum) and can be measured without irreversibly altering them.
Identity, Consciousness, Fidelity, and Concluding Thoughts
This exploration of “self” preservation raises profound philosophical questions. It echoes the "Ship of Theseus" thought experiment, which asks whether a ship that has had all of its components replaced retains its identity. Given that our bodies are in a state of constant atomic and cellular renewal, this question can be posed independently of this discussion. But it becomes even more pertinent when considering replacement strategies. What is this identity we are trying to preserve?
Intuitively, it is our unique mental abilities and memories, rather than our physical attributes such as appearance. But this answer pushes the discussion into even murkier philosophical waters. Each of our surrogate versions could theoretically reproduce our behavioral output with such accuracy that no test could distinguish the surrogate from the original. But there is a non-communicable first-person internal experience, our conscious experience, that is not necessarily reproduced along with this output. Much philosophical literature has been written on this subject. What is the relationship between consciousness and the physical brain?
While I cannot give a definitive answer, it may have to do with the physical substrate and the operating principles of the implementing hardware. Herein lies the distinction between physical and digital approaches. The physical approaches, both biological and synthetic, emulate the original brain by preserving its basic structure and operating principles. The digital approach, on the other hand, reproduces the output using very different hardware and software principles. If these factors are key to our consciousness, then just as a simulation of a hurricane is not a hurricane, a famous dictum in philosophy of mind, a digital clone is only a simulation of the original person, not the original itself.
All replacement strategies deal with the issue of fidelity - ensuring that the replacement is a true representation of the original self. Exhaustive confirmation of this is impractical. However, in the case of continuous replacement, any deviations may fall within the natural range of change we experience through learning and adaptation.
Ultimately, these questions remain mostly impenetrable, forcing me to resort to common sense. From this standpoint, I believe that a digital clone that survives posthumously may provide some solace, but it does not constitute a true continuation of one's life. The digital approach can also create a situation where you have two or more copies of yourself, adding layers of ambiguity. In contrast, I see the gradual replacement of body parts with organic or synthetic components as a viable path to life extension. It will, in my estimation, outpace drug-based methods. Reflecting on the limitations I discussed earlier in this post:
Scale and complexity of biological systems: There's no need for an intricate understanding of molecular biology or the aging process.
Extent of intervention efficacy: This becomes a non-issue, as a new body effectively means no aging concerns.
Time constraints: While cloning still faces temporal limitations, bioprinting is much less hindered by these constraints, and synthetic solutions are not bound by them at all.
Limitations of laboratory models: Initial organ testing will be done in animals, and the fabrication and surgical procedures should carry well into humans compared to drug effects.
Clinical trial challenges: Early trials will likely involve terminal patients, significantly improving the risk/reward ratio.
Naturally, the replacement approaches will encounter their own unique challenges. In any case, given the speculative nature of these technologies, a diversified approach seems prudent in our quest for immortality.