Rejuvenating our cells through reprogramming

By connecting the circulatory systems from a young to an old organism (parabiosis), it has been demonstrated that the blood from a young animal possesses rejuvenating properties.

The clearance of senescent cells in mice delays the onset of age-related diseases and can extend lifespan. In this context, medications (referred to as senolytics) that selectively induce the removal of senescent cells have become a key research area in cellular aging.

Dietary manipulation is also one of the most studied anti-aging interventions. Various diets (caloric restriction, intermittent fasting, ketogenic diet, etc.) influence specific biochemical pathways related to energy intake, resulting in increased lifespan and reduced metabolic risk factors. Certain medications, such as rapamycin, mimic the effects of caloric restriction and induce autophagy (the process of eliminating and recycling damaged cellular components), whose decline in which is associated with several age-related diseases.

In 1957, Conrad Waddington postulated that once a cell is fully differentiated, meaning it has specialized in performing a particular function, it cannot revert to a pluripotent embryonic state capable of regenerating any tissue in the body.

However, the first evidence that cellular differentiation is not irreversible came shortly after with nuclear transfer experiments. In these experiments, the nucleus of a mature differentiated cell is transferred into an enucleated, unfertilized egg, which then divides to form an embryo genetically identical to the donor cell. Early cloning attempts using nuclear transfer were conducted with frogs, and the process gained public attention when it was used to clone the first mammal, "Dolly" the sheep.

In 2006, the groundbreaking work of Takahashi and Yamanaka demonstrated that the identity of differentiated cells could be erased, and their functions reassigned. They showed that the overexpression of four transcription factors (proteins that regulate the expression of specific genes), now known as "Yamanaka factors," could convert differentiated cells into pluripotent cells with most characteristics of embryonic stem cells. These cells are referred to as induced pluripotent stem cells.

In vitro use of these cells revealed that cellular identity is set not by the loss or alteration of cellular DNA but rather by epigenetic changes—modifications to the information stored in non-genomic molecular structures capable of altering gene activity.

The process of generating iPSCs has been optimized over the years, particularly through modifying the components of Yamanaka factors and introducing them into the cell as a cocktail of messenger RNAs corresponding to these transcription factors, thereby reducing the risk of cancer development. One of the major challenges was that reverting a mature differentiated cell to a pluripotent stem cell state carried a risk of cancer when these cells were used in vivo.

These cells offer the promise of targeted and personalized regenerative therapy. They can be produced and cultured from a patient’s own cells, minimizing compatibility issues for treating diseases such as neurodegenerative diseases, cardiovascular conditions, type I diabetes, as well as liver, lung, and kidney disorders. However, ethical and safety considerations must be addressed before iPSCs can be used in vivo, particularly regarding cancer risk.

After reprogramming, many signs of cellular aging improve. When a cell converts to a pluripotent state, its epigenetic age clock is reset. This holds true even for differentiated cells that no longer divide and for cells taken from centenarians.

However, when a mature differentiated cell undergoes reprogramming to acquire stem cell-like properties, this dedifferentiation process increases the risk of cancer. Furthermore, the loss of cellular identity is undesirable in the context of in vivo cellular rejuvenation.

To avoid these pitfalls, another strategy has been proposed: epigenetic rejuvenation without dedifferentiation, meaning without loss of cellular identity. The hypothesis was that if the reversal of cellular age could be decoupled from dedifferentiation, a viable rejuvenation strategy free from cancer risk might exist.

This outcome was achieved through partial reprogramming. By examining intermediate stages of dedifferentiation, where cells begin to undergo epigenetic changes but have not yet acquired pluripotent stem cell characteristics, it was demonstrated that partial reprogramming through transient and periodic induction of Yamanaka factors could improve signs of aging without causing loss of cellular identity or inducing cancer.