researchers succeeded in rejuvenating dermal cells by 30 years

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Our desire for rejuvenation is almost omnipresent in our societies. If the “young” physical aspect is one of the objectives, another is the possibility of stopping the progressive decline of cellular mechanisms, vectors of diseases, whether chronic, neurodegenerative, etc. Moreover, the world population is ageing. According to the United Nations, one in six people in the world will be over 65 (16%) by 2050, compared to one in eleven in 2019 (9%). Recently, researchers have developed a new method to reverse the aging of human cells by 30 years, a revolution for regenerative medicine.

Aging is a continuous and gradual process of natural weathering that begins early in adulthood. During early middle age, many bodily functions begin to gradually decline. From a biological perspective, aging is therefore the product of the accumulation of a wide range of molecular and cellular damage over time. These lead to a progressive deterioration of physical and mental capacities, an increase in the risk of disease and, ultimately, death. These changes are neither linear nor regular and are not closely associated with the number of years. However, even if it is inevitable, aging can be influenced.

This is why regenerative medicine offers great hopes. The latter aims to repair, replace or regenerate faulty genes, cells or organs in order to restore normal functioning. It therefore has the potential to reverse age-related changes. The treatments consist in grafting to the patient, in the damaged zone, repairing cells. Once nestled in (or near) the target organ, these do the work themselves, rebuilding healthy tissue. These repair cells are stem cells. In simple terms, they are unspecialized — undifferentiated — cells capable of infinite self-renewal and of giving rise, depending on the environment in which they are found, to the various constituent cells of the tissue.

The technique to obtain these cells is a process of converting somatic cells into induced pluripotent stem cells (iPSC). It consists of taking practically any cell from an adult and genetically reprogramming it to make it pluripotent, that is, capable of infinitely multiplying and differentiating into all the types of cells that make up an adult organism — like an embryonic stem cell.

Unfortunately, these iPSC cells, following the numerous steps necessary for their reprogramming, lose some of their specific functions, acquired with age. They often resemble fetal cells rather than mature adult cells. Recently, a team of researchers from the Babraham Institute in Cambridge has developed a method to reprogram cells in such a way as to make them biologically younger while being able to regain their specialized cellular function. The study was published in the journal eLife.

Go back in time to the “right time”

With the aim of preserving the specificities of the cells while making them rejuvenate, the researchers are relying on the work of Shinya Yamanaka who, in 2007, was the first scientist to demonstrate the ability to transform normal cells into stem cells. This process takes about 50 days using four key molecules called the “Yamanaka Factors”. This technical prowess earned him the Nobel Prize in Physiology and Medicine in 2012. Moreover, recent work has shown that the epigenome — all the modifications of a cell altering the expression of genes without modifying the underlying DNA sequence — is already rejuvenated by the first stage of reprogramming (phase ripening). This suggests that complete iPSC reprogramming is not required to reverse somatic cell aging.

Accordingly, the researchers used dermal fibroblasts from middle-aged donors to find out when to stop the reprogramming process. They first exposed them to Yamanaka factors, and found that the cells temporarily lost and then regained their fibroblast identity after just 13 days. This could be due to epigenetic memory at the level of activators and/or the persistent expression of certain fibroblast genes. This new method is called “transient reprogramming of the maturation phase”.

Aging, question of chronological or biological age?

As Dr. Diljeet Gill, a postdoc in the lab of Wolf Reik at the Institute (who conducted the work as a PhD student), explained in a statement: Our understanding of aging at the molecular level has advanced over the past decade, giving rise to techniques that allow researchers to measure age-related biological changes in human cells. We were able to apply this to our experiment to determine the extent of reprogramming of our new method. “.

Dr. Diljeet Gill during the experiments. © Babraham Institute

Indeed, to check if the regeneration process had succeeded, they examined on the one hand what is called the epigenetic clock; on the other hand the transcriptome. The latter corresponds to all the messenger RNA molecules of a cell, replicas of the genes which are in the active state in a cell. For its part, the epigenetic clock is a mathematical model that predicts age by measuring DNA methylation levels at different sites in the genome.

You should know that DNA methylation is a process by which methyl groups are added to the DNA molecule, which can alter the function of a gene without changing the underlying DNA sequence. This DNA methylation is essential for healthy cell growth and development and is affected by lifestyle and environmental factors. Epigenetic clocks can therefore be used to estimate the biological age of a tissue, cell type or organ, by comparing the “DNA methylation age” (or biological age) with chronological age, in different tissues. Using these two measures, the reprogrammed cells matched the profile of cells that were 30 years younger than the reference data sets.

Implications for regenerative medicine

Subsequently, the analysis showed that the cells had found characteristic markers of skin cells, in particular by observing the production of collagen in the reprogrammed cells. Fibroblasts produce collagen. This molecule is present in bones, skin tendons and ligaments, and helps structure tissues and heal wounds. The researchers noted a greater production of collagen by the rejuvenated fibroblasts than by the control cells (which had not undergone the reprogramming process).

anti aging fibroblast 30 years
On the left, fibroblasts from a 20-22 year old person. In the middle, aged fibroblasts that have not undergone reprogramming. On the right, reprogrammed cells. Collagen is shown in red. © Gill et al., 2022

Moreover, livefibroblasts move into areas that need to be repaired. The researchers then tested this ability in partially rejuvenated cells. For this purpose, they incised a layer of cells, like a cut in the skin. They found that their treated fibroblasts moved through space faster than older cells. The researchers point out that this is a promising sign as to the future possibility of creating cells capable of better healing wounds.

Finally, the analysis of the transcriptome, mentioned above, highlighted signs of rejuvenation at the level of two specific genes involved in age-related diseases and symptoms: the APBA2 gene, associated with Alzheimer’s disease, and the MAF gene, playing a role in the development of cataracts. Professor Wolf Reik, who is leading the research, says: “ This work has very interesting implications. Eventually, we may be able to identify genes that rejuvenate without reprogramming, and specifically target those that reduce the effects of aging “.

Indeed, even if the mechanism behind transient reprogramming is not yet fully understood, scientists believe that key areas of the genome, involved in the formation of cellular identity, could escape the reprogramming process. Gill concludes: Our results represent a major step forward in our understanding of cellular reprogramming. We have proven that cells can be rejuvenated without losing their function and that rejuvenation seeks to restore certain functions of old cells. The fact that we also observed a reversal of aging indicators in disease-associated genes is particularly promising for the future of this work. “.

Source: eLife

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