A big challenge facing tissue and organ replacement as a strategy to beat aging relates to the brain. The brain, especially the neocortex - the part that underlies our highest cognitive functions and self-identity - cannot obviously be replaced as a whole organ. The neocortex can be replaced by progressively replacing tissue areas over time without significant disruption in function or self-identity. In addition, immature neocortical cells transplanted in mature neocortices develop normal synaptic connections and can respond normally to sensory input or elicit motor output.
Aging at its core is the accumulation of macromolecular damage. For example, damage to the extracellular matrix or to DNA cause the other hallmarks of aging (reviewed by Fedintsev and Moskalev, 2020; Schumacher et al., 2021). Elastin, an essential component of blood vessel walls, provides an illustrative example. Elastin progressively accumulates damage over our lifetime leading to dysfunctional blood vessels and loss of tissue function throughout the body. The damage to elastin is complex (glycation, carbamylation, breakage, racemization, and others). However, elastin is only one of many proteins that accumulate damage. And complex damage occurs not just to proteins, but also to lipids, carbohydrates, and DNA. If we do not address this damage, we will fail to significantly extend the human lifespan. These stochastic forms of damage are unlikely reversible pharmacologically, enzymatically, or genetically without disrupting the delicate balance of life-sustaining biochemistry (i.e. without overwhelming side effects). This is a major blind spot in the longevity field. On the other hand, tissue replacement would eliminate all forms of damage at once, and may therefore be worth exploring. Every part of the body (except the brain) has been surgically replaced in humans using donor tissues and organs, demonstrating implementability. In a growing number of cases, lab-grown cells and organs or increasingly sophisticated prosthetics are used as replacement parts. Regenerative medicine is thus on track to being able to replace all cells and tissues of the body. A big challenge facing replacement as a strategy to beat aging relates to the brain. The brain, especially the neocortex - the part that underlies our highest cognitive functions and self-identity - cannot obviously be replaced as a whole organ. Yet, the neocortex can be replaced by progressively replacing tissue areas over time without significant disruption in function or self-identity (reviewed by Hébert and Vijg, 2018; and see for example Duffau, 2014, who documents the relocation over time of language without a disruption in speech in older adults in which the original language center was slowly destroyed due to disease). In addition, immature neocortical cells transplanted in mature neocortices develop normal synaptic connections and can respond normally to sensory input or elicit motor output (Falkner et al., 2016; Michelsen et al., 2015; Espuny-Camacho et al., 2013; and our data at doi.org/10.1101/2021.02.27.433204 3). These studies support the feasibility of age reversal for the neocortex via progressive tissue replacement.
Tissue replacement (cells, tissues, organs, etc.) is not a new idea - it’s one of the possible approaches to defeat aging. If replacements are ever going to be useful, we need to figure out how to apply them to the brain. Replacements per se, in terms of implementation, are not that problematic. Every part of the body was surgically replaced over the last few decades to treat disease and injury. The problem is with the replacements themselves, so there is a need for lab grown organs and improved prosthetics. Progress is painfully slow, and investments are rather limited. Eventually, we will be able to replace all parts of the body, except the brain. The brain is the most important part - you don’t want to live in a young body with a senile brain. It cannot be replaced as a whole organ, however, but could be replaceable progressively via brain cell replacements without losing our identity. The human brain is mainly neocortex. That’s where our thought patterns and self-identity are stored. The neocortex is extremely plastic by nature, functions can change their substrate over time. In cases where older patients (50 or 60 years old) had benign tumors removed from their brain, and the tumor was where the language centre was, we have observed that the transfer of function must’ve happened progressively, because they didn’t lose the ability to speak. Therefore, it should be possible to do this progressively with an intervention that provides young naive tissue over time, as well. The other reason why tissue replacements make sense is the evidence from studies that were putting in immature precursor cells for the neocortex and showing that these immature precursors differentiate into neurons that make the appropriate connections to distant parts of the brain in model animals. Hypothesis on General Process for Brain Cell Replacement: - Aging brain loses a lot of volume, which creates space. - We implant new grafted functional tissue in that space. - We could silence the old tissue and the area of neocortex we want to get rid of, that is nearby the new grafted one. That should be possible pharmacologically. - Then we could remove that old tissue once it’s silenced and not used anymore and the functions have moved to new locations, in particular, this naive implanted substrate. - This progressively regenerates the neocortex in that area.
Progressive neocortical tissue replacement will require the reassembly in situ of multiple precursor cell types in the correct ratios, relative differentiation stages, and cytoarchitecture to allow the new immature tissue to differentiate normally. To date, we have grafted human neuronal precursors with human vessel-forming vascular precursors, resulting in efficient neuronal and vascular integration with the host (the adult mouse neocortex is used as a test platform for building human tissue). An essential next step is to add astrocytic precursors to the grafts. Astrocytes are essential for proper maturation and function of neurons and for the blood-brain-barrier (BBB). Outcome measures of neuronal function and BBB integrity will include comparing grafts with and without astrocytes.