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Epigenetic Reprogramming Shows Promise in Reversing Ageing, Finds New Study

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Researchers have identified epigenetic reprogramming as a significant factor in reversing ageing and increasing longevity. The study, published in the Ageing Research Reviews, delves into the mechanisms of ageing at the cellular level and explores how epigenetic modifications can potentially rejuvenate cells and extend lifespan.

A progressive decline in cellular function and an increased susceptibility to diseases are characteristics of ageing. One of the primary mechanisms behind this process involves changes in the epigenetic landscape, including DNA methylation, histone modification, and non-coding RNA expression. These alterations lead to genomic instability, disrupted gene expression, and the eventual senescence of cells.

Epigenetics refers to modifications in gene expression that do not involve changes to the underlying DNA sequence. These changes are reversible and are subject to a variety of influences, including the environment and way of life. In recent years, scientists have focused on how manipulating these epigenetic marks could potentially reverse ageing.

The concept of reprogramming cells to a more youthful state is not new. In regenerative medicine, complete reprogramming, which changes somatic cells into induced pluripotent stem cells (iPSCs), has shown promise. But it comes with risks like the growth of tumours and the loss of cellular identity. Alternatively, partial reprogramming aims to reset the ageing clock without erasing the cells’ identities, thus minimising the risk of cancer.

Partial reprogramming uses a set of transcription factors, including the Yamanaka factors (Oct4, Sox2, Klf4, and cMyc), to rejuvenate cells. By temporarily expressing these factors, researchers can reverse age-related changes in cells, improving their function and regenerative potential without inducing pluripotency. This method has been successful in various tissues, including neurons, muscle cells, and retinal cells in animal models.

The study highlights several promising strategies for inducing epigenetic rejuvenation. One approach involves the use of small molecules that can modify epigenetic marks. DNA methyltransferase inhibitors and histone deacetylase inhibitors have shown potential in preclinical studies, rejuvenating aged cells and tissues, improving cellular metabolism, and activating stress response pathways. These small molecules offer a non-invasive, cost-effective alternative to genetic reprogramming .

One study used an adeno-associated virus (AAV) to express three of the Yamanaka factors: Octt4, Sox2, and Klf4. This allowed researchers to restore vision to an old mouse model of glaucoma. This intervention rejuvenated neurons in the retinal ganglion cells, restoring youthful vision without oncogenic effects.

Despite the promising results, several challenges remain. The stability of the rejuvenated state, potential risks of neoplastic development, and the translation of these findings to humans are significant hurdles. Current reprogramming techniques often rely on viral vectors, which can introduce safety concerns such as insertional mutagenesis and off-target effects. Moreover, the long-term effects of these interventions are still not fully understood.

To address these challenges, further research is necessary to refine these techniques and ensure their safety and efficacy. Larger animal models and eventually human trials will be crucial in determining the potential of epigenetic reprogramming for clinical applications.

The development of epigenetic clocks, which measure biological age based on DNA methylation patterns, has been a significant advancement in ageing research. These clocks allow researchers to accurately assess the effectiveness of longevity interventions and predict the biological age of tissues and individuals. Horvath’s clock and GrimAge are among the most widely used and reliable epigenetic clocks, providing valuable tools for evaluating the impact of reprogramming strategies on ageing.

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