Following up based on John’s points about turnover, we can add in a “template decay” aspect to this model. The body has many templates: DNA, of course, but also stem cells, and tissue architectures, possibly among others. Templates offer a highly but not perfectly durable repository of information or, more intuitively in some cases, structural guidance for turnover and regeneration processes.
When damage factors impact the downstream products of various templates (mRNA and proteins, differentiated cells, organs), turnover initiated by the upstream template can mitigate or eliminate the downstream impact. For example, protein damage can be repaired by degredation in proteasomes, differentiated cell dysfunction can be repaired by apoptosis, stem cell proliferation and differentiation into a replacement for the dysfunctional cell. Wounds can be regenerated as long as sufficient local tissue architecture remains intact to guide tissue reconstruction.
But templates cannot themselves be repaired unless there is a higher-order upstream template from which to initiate this repair. A key question is redundancy. DNA has no redundancy within the cell, but stem cells could potentially offer that redundancy at the level of the cell. If one stem cell dies or becomes senescent, can another stem cell copy itself and replace it? Yet we know stem cells age and lose proliferative and differentiation capacity. And this redundancy would only provide a lasting solution if there was a selecting force to regulate compatibility with host architecture instead of turning into cancer. So whatever redundancy they offer, it’s not enough for long-term stem cell health.
For an individual’s DNA sequence at least, durable storage is not a bottleneck. We are challenged to provide durable external repositories for other forms of information, such as tissue architecture and epigenetic information. We also lack adequate capacity to use any such stored information to perform “engineered turnover.”
We might categorize medicine in two categories under this paradigm:
Delay of deterioration, which would encompass much of the entire current medical paradigm. Chemo delays deterioration due to cancer. Vaccines and antibiotics prevent deterioration due to infection. Seatbelts prevent acute deterioration due to injury from car crashes. Low-dose rapamycin may be a general preventative of deterioration, as is exercise and good diet.
Template restoration, which has a few examples in current medicine, such as organ, tissue, and fecal transplants. Gene therapy is a second example. Some surgeries that reposition tissues to facilitate a new equilibrium of well-formed growth is a third example. If it becomes possible to de-age stem cells, or to replace DNA that has mutated with age with the youthful template, these interventions would also be categorizwed as template restoration.
Template replacement. An example is an artificial heart, which is based on a fundamentally different template than a biological heart, and is subject to entirely different deterioration dynamics and restoration possibilities.
The ultimate aim is to apply organized energy from outside the patient’s system, primarily in the form of biomedical interventions, to create a more stringent selection force within the patient’s body for a molecular, cellular, and tissue architecture compatible with long-term health and survival of the patient. In theory, it ought to be possible to make this selection force so stringent that there is no hard limit to the patient’s lifespan.
By this point, “there’s no such thing as a cure for cancer” is a cliche. But I don’t think this is necessarily true. If we can increase the stringency of selection for normal, healthy cells and against the formation of cancer, then we can effectively eliminate it. Our current medicine does not have the ability to target asymptomatic accumulated cellular disorder, the generator of cancer, for repair or replacement. When we can do this, we will have effectively cured cancer, along with a host of other diseases.
De-aging tissue can be conceived of as:
Delivering an intervention to host cells in situ to effect repair, such as a gene therapy that identifies and replaces mutated DNA in host cells with the original sequence.
Extracting healthy cells from the host, proliferating them in vitro, and transplanting them back into the host, either as cells or in the form of engineered tissues.
Replacing tissue with synthetic or cybernetic constructs that accomplish the same function, such as hip replacements, the destination artificial heart, and (someday soon) the bioartificial kidney.
None of this will be easy. Implanted stem cells and gene therapy can both trigger cancer at this stage in our technological development. Our bioproduction capacities are limited—many protocols are limited by our ability to culture a sufficient quantity of cells. But these are all tractable problems with short feedback loops.
As John points out, the key problem is that too many of our resources are not being applied to the right bottlenecks, and there isn’t quite enough of a cohesive blueprint or plan for how all these interventions will come together and result in longevity escape velocity. But at the same time, I tend to be pretty impressed with the research strategy of the lab directors I’ve spoken with.
Following up based on John’s points about turnover, we can add in a “template decay” aspect to this model. The body has many templates: DNA, of course, but also stem cells, and tissue architectures, possibly among others. Templates offer a highly but not perfectly durable repository of information or, more intuitively in some cases, structural guidance for turnover and regeneration processes.
When damage factors impact the downstream products of various templates (mRNA and proteins, differentiated cells, organs), turnover initiated by the upstream template can mitigate or eliminate the downstream impact. For example, protein damage can be repaired by degredation in proteasomes, differentiated cell dysfunction can be repaired by apoptosis, stem cell proliferation and differentiation into a replacement for the dysfunctional cell. Wounds can be regenerated as long as sufficient local tissue architecture remains intact to guide tissue reconstruction.
But templates cannot themselves be repaired unless there is a higher-order upstream template from which to initiate this repair. A key question is redundancy. DNA has no redundancy within the cell, but stem cells could potentially offer that redundancy at the level of the cell. If one stem cell dies or becomes senescent, can another stem cell copy itself and replace it? Yet we know stem cells age and lose proliferative and differentiation capacity. And this redundancy would only provide a lasting solution if there was a selecting force to regulate compatibility with host architecture instead of turning into cancer. So whatever redundancy they offer, it’s not enough for long-term stem cell health.
For an individual’s DNA sequence at least, durable storage is not a bottleneck. We are challenged to provide durable external repositories for other forms of information, such as tissue architecture and epigenetic information. We also lack adequate capacity to use any such stored information to perform “engineered turnover.”
We might categorize medicine in two categories under this paradigm:
Delay of deterioration, which would encompass much of the entire current medical paradigm. Chemo delays deterioration due to cancer. Vaccines and antibiotics prevent deterioration due to infection. Seatbelts prevent acute deterioration due to injury from car crashes. Low-dose rapamycin may be a general preventative of deterioration, as is exercise and good diet.
Template restoration, which has a few examples in current medicine, such as organ, tissue, and fecal transplants. Gene therapy is a second example. Some surgeries that reposition tissues to facilitate a new equilibrium of well-formed growth is a third example. If it becomes possible to de-age stem cells, or to replace DNA that has mutated with age with the youthful template, these interventions would also be categorizwed as template restoration.
Template replacement. An example is an artificial heart, which is based on a fundamentally different template than a biological heart, and is subject to entirely different deterioration dynamics and restoration possibilities.
The ultimate aim is to apply organized energy from outside the patient’s system, primarily in the form of biomedical interventions, to create a more stringent selection force within the patient’s body for a molecular, cellular, and tissue architecture compatible with long-term health and survival of the patient. In theory, it ought to be possible to make this selection force so stringent that there is no hard limit to the patient’s lifespan.
By this point, “there’s no such thing as a cure for cancer” is a cliche. But I don’t think this is necessarily true. If we can increase the stringency of selection for normal, healthy cells and against the formation of cancer, then we can effectively eliminate it. Our current medicine does not have the ability to target asymptomatic accumulated cellular disorder, the generator of cancer, for repair or replacement. When we can do this, we will have effectively cured cancer, along with a host of other diseases.
De-aging tissue can be conceived of as:
Delivering an intervention to host cells in situ to effect repair, such as a gene therapy that identifies and replaces mutated DNA in host cells with the original sequence.
Extracting healthy cells from the host, proliferating them in vitro, and transplanting them back into the host, either as cells or in the form of engineered tissues.
Replacing tissue with synthetic or cybernetic constructs that accomplish the same function, such as hip replacements, the destination artificial heart, and (someday soon) the bioartificial kidney.
None of this will be easy. Implanted stem cells and gene therapy can both trigger cancer at this stage in our technological development. Our bioproduction capacities are limited—many protocols are limited by our ability to culture a sufficient quantity of cells. But these are all tractable problems with short feedback loops.
As John points out, the key problem is that too many of our resources are not being applied to the right bottlenecks, and there isn’t quite enough of a cohesive blueprint or plan for how all these interventions will come together and result in longevity escape velocity. But at the same time, I tend to be pretty impressed with the research strategy of the lab directors I’ve spoken with.