Aging seems to be an irresistible natural law, and at the same time, how to “fight aging and achieve immortality” has become an eternal research topic. Nowadays, thanks to the rapid development of biotechnology, research on anti-aging has become increasingly popular.
In 2006, the team of Shinya Yamanaka of Kyoto University in Japan first reported related research on induced pluripotent stem cells (iPSC). They found that by introducing four transcription factors, Oct4, Sox2, c-Myc, and Klf4, the terminally differentiated Somatic cell can be “reprogrammed” into pluripotent stem cells, which are similar to embryonic stem cells in morphology, differentiation ability, epigenetic modification status, and many other aspects. Based on his research on “cell reprogramming technology”, he won the 2012 Nobel Prize in Physiology or Medicine. Four transcription factors (Oct4, Sox2, c-Myc, Klf4) are also known as “Yamanaka factors”.
Since then, cell reprogramming technology has become popular, especially in the field of anti-aging. Based on cell reprogramming, it can restore cell vitality and become an important technological means in current anti-aging research.
Recently, researchers from the Regenerative Medicine Center of Dongguk University in South Korea found that activating the Oct4 gene, one of the Yamanaka factors, can induce cell regeneration in premature aging model mice, so that premature aging mice can recover their vitality and extend their life span. Currently, this study has been published in Aging Cell.
(J Kim J, et al. 2023)
Hutchinson-Gliford progeria syndrome (HGPS) is a rare genetic disease caused by a gene mutation. Patients begin to show signs of aging early in life. The aging process is 5-10 times faster than normal. At the same time, the accelerated decline of organs causes physiological decline. Most of the children die of cardiovascular disease or stroke. The average life span is about 13 years.
Previous studies have shown that premature senility is caused by the mutation of the gene encoding Lamin A (Lamin A is a protein that wraps and protects the nucleus from damage), and this mutation will lead to a shorter and invalid version of Lamin A, namely premature senility protein.
In this study, researchers first explored changes in Epigenetics based on cell tests. They activated the Oct4 gene in mouse fibroblasts and found that activation changed the epigenetics of these fibroblasts, leading to changes in the expression of genes responsible for differentiation and dedifferentiation.
Next, researchers will continue to explore the effect of Oct4 on premature aging fibroblasts. They changed healthy fibroblasts to produce mutant premature senescence type Lamin A, and then activated the Oct4 gene in these cells. They found that these premature senescence cells can regenerate and also inhibit mutant Lamin A in fibroblasts.
At the mechanism level, the researchers said that the activation of Oct4 reduced DNA breaks (DNA breaks gradually accumulated with age) and also reduced the number of premature aging precursor cells. In addition, activating the Oct4 gene in premature aging fibroblasts can restore the activity mode of stress response and aging-related genes.
In summary, these cell experiments indicate that the activation of Oct4 can effectively alleviate the age-related phenotype of fibroblasts in premature aging mice.
Based on the positive results of cell experiments, they continued to test Oct4 in model animals. By activating the Oct4 gene of premature aging mice, they found that compared with the control group, the weight of premature aging mice in the test group was reduced, the appearance was improved, and the median life span and Maximum life span were also significantly increased.
Generally, the death cause of premature aging mice is mostly cardiovascular disease related to aging, and the main driving factor is the death of vascular smooth muscle cells. In this experiment, the researchers also observed this phenomenon in the premature aging mouse model, which led to aortic sclerosis and cardiac function damage in mice. However, this phenomenon was not found in the Oct4 gene-activated premature aging mice, and no aortic thickening was observed.
In addition, the researchers evaluated gene expression in other organs and found that in premature aging mice activated by Oct4, the activity of aging-related genes was significantly reduced, and some tissues, including the skin and kidneys, showed signs of recovery.
Based on the findings obtained in premature aging mice, it prompted them to continue exploring the effects of Oct4 activation on normal mice. By evaluating the expression of aging-related genes in multiple organs of two-year-old mice, they found that the activation of Oct4 in these mice led to a significant reduction in the activity of aging-related genes, fewer harmful epigenetics changes, and fewer age-related cardiovascular abnormalities.
Based on the findings of this study, researchers said that activating the Oct4 gene is expected to develop a regenerative therapy to treat premature aging caused by mutation of Lamin A.
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Reference
J Kim J, Hwang Y, Kim S, Chang Y, Kim Y, Kwon Y, Kim J. Transcriptional activation of endogenous Oct4 via the CRISPR/dCas9 activator ameliorates Hutchinson-Gilford progeria syndrome in mice. Aging Cell. 2023 Jun;22(6):e13825. doi: 10.1111/acel.13825. Epub 2023 Mar 25. PMID: 36964992; PMCID: PMC10265166.