Biologist Alex Plesa argues that the body ages where tissue cannot be replaced: a path to replacement is in sight for every organ except the brain

Biologist Alex Plesa argues that the body ages where tissue cannot be replaced: a path to replacement is in sight for every organ except the brain

On October 30, Plesa published an essay, “Why Biology Wasn't Made to Last”. He asks why the body ages even though most of its cells are younger than the person.

The intestinal lining is replaced within days, while structures that are never replaced remain old: proteins at the center of the lens and neurons in the cerebral cortex are as old as the person.

According to Plesa, the body either repairs damage or replaces the affected part. Repair requires an intact copy of the damaged region nearby, and its cost rises with the number of types of damage: each type of DNA damage has its own repair enzyme. Replacement requires only detecting a departure from normal. The same mechanism can handle new types of damage, and its cost scales with the amount that must be rebuilt. Replacement is therefore the usual approach, while repair is reserved primarily for the genome, the template for everything else. There is no substitute for the genome, and a damaged DNA strand is repaired using the other strand as a template.

In Plesa's model, replacement requires three conditions. First, a part must be expendable without compromising the body's function, as the intestinal lining is. The lens has no such expendable part: its cells destroy their own contents to become transparent and lose their ability to renew themselves. Second, the instructions for the new part must outlast the old one. An immune cell recognizes a pathogen through a receptor whose gene is encoded in its DNA and passed to its descendants. This is why, according to Plesa, transplanted bone marrow transfers the donor's immune memory.

Third, the interests of the new cells must align with those of the body. Yet selection occurs among cells, favoring those that reproduce faster: in people studied who were older than 75, just 12–18 clones, groups of cells descended from a single cell, produce 30–60% of new blood cells. A tumor is the extreme case: its cells divide solely for their own benefit.

The brain fails to meet the second condition: memories are encoded in the pattern of connections between neurons, and a replacement cell would not inherit that pattern. By the author's rough estimate, the genome holds about 800 megabytes, while the cortical wiring diagram holds about 100 terabytes. Development supplies the remaining information over two decades under specific circumstances. Starting that process again would produce a different brain.

A paper by Uri Alon's group at the Weizmann Institute challenges Plesa's model. In its model of damage production and removal, the best predictor of a species' lifespan is the rate of damage production, which differs by roughly ten million times between yeast and humans. Plesa responds that the model does not account for tissue replacement and that this wide variation reflects what evolution has changed. The model does not describe what an intervention could change.

Plesa's proposed solution is to move the replacement process outside the functioning body. Tissue grown outside the body provides an expendable part, while sequencing its cells' genomes allows cells with dangerous abnormalities to be screened out. Hearts, livers, kidneys, and corneas are already replaced: their function does not depend on information accumulated over a lifetime. Bone marrow transplantation provides the closest example: in ten donor–recipient pairs, recipients had lower clonal diversity than donors 9–31 years after transplantation. Clonal diversity declines with age, and the researchers estimate that this difference corresponds to 10–15 years of additional aging. They attribute it to clonal selection during cell collection and delivery, and to the expansion of mutant clones after engraftment. According to Plesa, screening should detect the latter.

Three tasks remain for the brain: reading its information from outside, rebuilding it while preserving the person, and replacing it without shutting it down, since a brain that has been shut down is dead. Plesa proposes that the brain itself should transfer its information to the grown tissue. This would circumvent all three tasks; he leaves the details for a future essay.