Loss of Cell Identity.. Science Reveals the Secret of Human Aging

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Two new research papers have been published - one in the journal Nature conducted by Vadim Gladyshev and his colleagues at Harvard University, and the other in the journal Cell by Juan Carlos Izpisua Belmonte and his team at Altos Labs, presenting a new model for the biology of aging and potential interventions to reverse its course.

Until recently, the prevailing belief was that cellular aging results from "wear and tear," similar to car rust. Now, the idea that accumulated damage is the main pathway for cellular aging is complemented by the model of "cell identity loss." However, we still do not know the relative contribution or the nature of the interconnection between these two models in the aging process.

According to a report prepared by physicist Eric Topol in his blog titled Ground Truths, the concept of cell identity loss leads to what is known as "mediated drift," which involves the formation of fibrous scars and the occurrence of inflammation, potentially enhancing the possibility of intervening in the aging process.

During embryonic stages and early developmental phases, human cells acquire a specific identity that remains stable throughout life unless this identity is lost during the aging process. Although the DNA in each cell of the human body is identical (or very similar), the epigenetic structure - which includes the side chains of methylation, histones, nucleosomes, and chromatin - takes on a three-dimensional shape that varies by cell type. These processes occur within the cell's control center, the nucleus; the epigenetic structure is the fundamental basis for the specific identity of the cell.

There is an organizational system consisting of three layers to maintain cell identity. The fast layer responds to acute stresses within minutes to hours and relies on the production of transcription factors, such as factor AP-1. The medium layer takes days or weeks to respond, going through transitional phases of cell state, such as activating the cell to enhance tissue healing and then returning to its baseline state. The greatest importance lies in the slow layer, which is responsible for stabilizing and isolating cell identity, forming a strict barrier based on chromatin structure.

Topol adds that this leads to the model of the "landscape of epigenetics," proposed by Waddington to explain how cells differentiate or lose their differentiation, a model that has stood the test of time since Conrad Waddington introduced it in 1957. The stable cell at the bottom of the valley represents a specialized and distinct cell. The deep slope surrounding a deep basin indicates the property of robustness or what is known as "pathway guidance," where this structure maintains cell identity and enhances its stability.

The differentiated cell remains "committed to its path" in this model, constrained so that it does not slip outside or change its identity. However, with aging, the valleys lose their steepness and the basins gradually become shallow, causing epigenetic constraints to fade, leading to instability in cell identity. This paves the way for what is known as "cell identity drift," or what can be considered "intermediate drift."

Over the lifespan and after reaching peak maturity, where specialized cells (in the brain, liver, heart, kidneys, and others) have fully and definitively differentiated, the valleys begin to lose their steepness and the basins gradually become shallow, a phenomenon known as "loss of pathway guidance." The problem lies in the lack of evolutionary pressure to maintain the grooves, valleys, and basins in their youthful state, as the "shadow of selection" falls within the temporal pathway post-reproductive stage.

The "Polycomb" repressive complex 2 can be considered the sculptor of this epigenetic landscape, as it is the molecular mechanism that shapes the grooves, valleys, and basins; it establishes the strict boundaries and deep epigenetic constraints that define cell identity.

The epigenetic clocks are remarkably informative tools across 348 species of mammals - including humans - to predict maximum lifespan and life history, but it was not known what these clocks actually measure. It has been found that they measure the activity of the PRC2 complex, specifically the rate of erosion of the "slow layer," and more precisely, they measure regions with low methylation associated with the PRC2 complex.

The PRC2 complex comes into play when chronic inflammation occurs that exceeds the ability of the "fast layer" to respond and hinders the function of PRC2, leading to the erosion of the Waddington landscape and promoting the loss of cell identity. Even after the chronic inflammation subsides, epigenetic changes in the chromatin may persist. This loss of epigenetic marks can provide a foundation for the growth of cancerous cells. The gradual erosion of the slow layer leads to the collapse of the Waddington structure.

According to the research paper published in the journal Cell, the mesenchymal transition refers to the transformation of cells into a fibroblast-like state, leading to the formation of fibrous scar tissue and the deposition of extracellular material resembling soft paste. This has been verified in 46 types of tissues and is an integral part of disease progression and poor outcomes, ranging from atherosclerosis to age-related macular degeneration and Alzheimer's disease.

Intervention can be made to freeze this transition, avoid the slow erosion of the layer, and maintain the structure of the Waddington landscape, keeping cells constrained to their specific identity or, more ambitiously, reversing the erosion that has already occurred.

Caloric restriction, along with a decrease in acetyl-CoA and a reduction in PRC2 methylation, enhances the maintenance of the slow layer structure, theoretically freezing the transition.

Studies have shown that calorie restriction extends lifespan in mammals, but the results in non-human primates have been conflicting, and the amount and duration of calorie restriction required for humans is impractical. However, there may theoretically be a partial effect of avoiding large amounts of calorie intake to help prevent health deterioration.

The use of Yamanaka factors for stem cells is a large-scale intervention for cell rejuvenation that has attracted the most attention and massive investments from biotechnology companies. However, it is complicated because it requires a process known as "partial" epigenetic reprogramming to avoid complete reprogramming that erases cell memory and transforms them into pluripotent stem cells, increasing the risk of cancer.

However, during partial reprogramming using short pulses, cell rejuvenation has been observed, with the restoration of the identity of aged human fibroblasts (even from 96 years old) and in animal models. The slow layer is restored, and PRC2 domains are re-established, effectively reversing the mesenchymal drift.

A research paper published in the journal Nature also addresses lithium as an intervention to maintain the identity of neural cells by intervening in the slow layer failure pathway. The effect of lithium helps prevent tau phosphorylation in experimental models. Lithium orotate has been proposed as a potential candidate for the prevention of Alzheimer's disease, and this mechanism may be effective.