Aryl Hydrocarbon Receptor (AHR)

The Aryl Hydrocarbon Receptor (AHR) is a receptor protein found within cells. It plays a critical role in immune responses and tissue healing. AHR regulates the immune system's response to environmental pollutants, bacteria, and metabolites. Insufficient AHR activation can cause an immune system imbalance, leading to diseases. Restoring AHR activity has shown promise in aiding wound healing and treating autoimmune diseases, particularly systemic lupus erythematosus (lupus). AHR's role in tissue healing involves activating molecules that promote regeneration, and it is also influenced by external factors such as pollutants.

Partial Reprogramming

Partial reprogramming achieved by the transient expression of the transcription factors (TFs) Oct4, Sox2, Klf4 and C-Myc (abbreviated OSKM) can erase aging and damage features in cells, leading to increased healthspan, lifespan and tissue regeneration. Recent reports suggest that the mechanisms of partial reprogramming may share some similarities with natural dedifferentiation and regeneration. Both processes appear to involve the transient repression of somatic identity through the sequestration of somatic identity TFs to noncanonical sites, which are opened by the high expression of pioneer TFs, leading to transient dedifferentiation into a fetal-like state.

Cdkn2a Positive Cells

Cdkn2a positive cells are a type of senescent cell that have been identified as a potential target for rejuvenation therapies in the context of aging and age-related diseases. Recent studies have demonstrated that targeted partial reprogramming of Cdkn2a positive cells can restore function and improve markers of health in mouse models of aging. This approach involves the delivery of specific reprogramming factors, such as Oct4, Sox2, and Klf4 (OSK), to Cdkn2a positive cells via adeno-associated virus (AAV).

Mechanisms of Rejuvenation

The rejuvenation of Cdkn2a positive cells is thought to occur through the modulation of inflammation-associated genes and the restoration of tissue integrity. This process has been shown to improve lifespan, reduce inflammation, and enhance wound healing in mouse models.

Therapeutic Potential

The targeted reprogramming of Cdkn2a positive cells has significant therapeutic potential for the treatment of age-associated disorders. As a safer alternative to systemic senolytic therapies, this approach may offer a promising strategy for combating age-related deterioration at the cellular, tissue, and organismal levels.

Conclusion

Cdkn2a positive cells are an important target for rejuvenation therapies in the context of aging and age-related diseases. The targeted partial reprogramming of these cells has shown promising results in preclinical models, highlighting its potential as a novel therapeutic approach for improving healthspan and treating age-associated disorders.