Reversing aging may seem like an impossible goal, but studies on animals indicate it could actually be done.
The team has already initiated rejuvenation in human skin cells and extended lifespan of mice with an age-related disease that causes premature aging. They hope their work will eventually lead to whole-body cell rejuvenation.
Stem Cells
Stem cells are master cells found within our own bodies that have the capacity to regenerate damaged or diseased tissues by multiplying and differentiating into specific cell types that make up each organ and tissue type in our bodies, such as bone, blood, muscle, fat or nerves. Stem cells have become the focus of intense research as researchers use stem cell research as an avenue to better understanding diseases like diabetes or heart disease and treating it effectively with new therapeutic cells derived from stem cells.
In 2006, scientists made a groundbreaking discovery when they demonstrated that adult cells could be genetically reprogrammed back into stem cells via genetic modification. These newly created stem cells, known as Induced Pluripotent Stem Cells or “iPSCs”, could then grow into any tissue of the body and potentially reverse or cure diseases through injection of these iPSCs into patients’ bodies.
Lifelong stem cell populations exist throughout our tissues and organs, acting as master cells to regenerate replacements for other cells that have limited lifespans, such as brain or skin cells. Unfortunately, their ability to regenerate declines with age and exposure to environmental stressors such as oxidative damage or chronic inflammation.
Scientists are working hard to increase the potency of existing stem cells so they can be used for transplant and regenerative medicine applications. One way is cultivating mesenchymal stem cells found in bone marrow and other tissue, which have the ability to produce numerous cell types like adipogenic, osteogenic, myogenic and endothelial.
Reactivation of dormant or quiescent stem cells is another way to boost their potency, with specific growth factors being added directly onto them to encourage them to produce new cells and begin creating more.
Researchers are exploring other avenues of reversing aging as well, such as using naked mole-rat genetic code to create cells with longer lifespans, or by increasing protein production that declines over time and can lead to senescence in old cells.
Reprogrammed T Cells
Ever since Ponce de Leon sought the legendary Fountain of Youth, humans have dreamt of discovering ways to extend life. While no such spring exists yet, scientists are making strides toward understanding the biological mechanisms governing longevity. Reprogramming stable differentiated cells into other cell types provides for replacement or regeneration of impaired tissues and organs while potentially increasing our natural lifespans.
Scientists have developed CAR-T cells from peripheral blood mononuclear cells in order to create immunotherapies designed specifically to fight cancer. CAR-Ts have demonstrated success treating some forms of leukemia and lymphoma, as well as targeting tumors in the brain, breast, and prostate. Reprogramming involves two steps: Generation of T cells from PBMCs followed by genetic modification with surface receptors capable of targeting specific tumors before infusing these T cells back into patients via intravenous injection.
Another approach to combatting the aging process may involve targeting cellular senescence. Cellular senescence occurs naturally when cells accumulate damage and exceed certain stress thresholds, leading to no longer dividing and producing issues such as inflammation and cell dysfunction. Members of JAAM and JAAF are researching methods of preventing or reversing its onset.
One promising approach to rejuvenation of senescent cells is expressing Yamanaka factors in these cells, which can effectively erase their senescence while also resetting chromatin structures and gene expression patterns. Studies using both mouse and human cells have demonstrated that this form of reprogramming dramatically improves tissue function as well as protecting against age-related diseases such as macular degeneration and kidney failure.
Sinclair lab scientists recently conducted an ingenious experiment, showing how chemical cocktails can reverse the senescent state in mature human T cells without leading to unchecked cell division or tumorigenesis. A combination of OSKM, KSAA, SBAS, MAP3K4, PIK3CA and TGFBR1 significantly reduced estimated chronological age of senescent cells after only four days – comparable with an annual-long treatment focused on restoring epigenetic information as documented in an 2019 study.
AP2A1 Protein
What if there was a way to turn back time at a cellular level? Research into AP2A1 protein could provide this answer and could offer hope of rejuvenation in years to come.
The AP2A1 protein is an adaptor protein complex that assists cells as they transition into their growth phase and protects against damaged protein accumulation. Found in every cell, its presence was discovered at Osaka University where researchers developed genetic tools to reduce production of this protein in both fibroblasts (specialized cells that maintain tissue structure) and epithelial cells (which cover inside and exterior surfaces of tissues).
Researchers discovered rejuvenation when they decreased AP2A1 expression in senescent fibroblasts by suppressing expression. When this happened, cells shrank back down to their original size, began growing, and stopped dividing; moreover, rejuvenated cells also stopped producing damaged proteins which characterize senescence as well as genetic markers of it. When artificially increasing expression in young cells however, the cells began expanding, growing thicker stress fibers, and producing damaged proteins characteristic of aging; artificially increasing it resulted in large expansion as well as thicker stress fibers as well as beginning production of damaged proteins associated with aging; when artificially increased expression resulted in large cells expanding over time and beginning producing damaged proteins characteristic of aging (including genetic markers associated with it).
These findings led the scientists to the conclusion that AP2A1 is essential for the progression of senescence, with their speculation being that it mediates how cells attach to their environment by regulating integrin b1. Integrin b1 usually moves linearly along stress fibers in normal cells; however, in senescent fibroblasts there is an unexpected increase in its transport speed, necessitating translocation by AP2A1 which promotes its translocation as well as focal adhesion formation thus helping these senescent cells stay attached.
Now, researchers are striving to develop drugs that target AP2A1 and stimulate cell rejuvenation, with hopes of being useful in treating diseases that involve accumulations of senescent cells such as neurodegenerative disorders or cardiovascular diseases.
Cellular Rejuvenation
Cellular rejuvenation is the belief that we can reverse aging by making our cells healthier. Healthy cells help your body function more efficiently while simultaneously decreasing signs of aging such as wrinkles or low energy. While cellular rejuvenation treatments like stem cell therapies exist, some approaches include more basic interventions like healthy eating and exercising at home.
Scientists have already made strides toward partially reversing cellular aging in mice by using proteins to induce pluripotency, leading them to shed their old identities and return to more youthful state. While complete reprogramming may cause tumors or unexpected side effects, partial reprogramming offers similar advantages without risk of tumor formation or unintended side effects. Now researchers are trying to discover ways these proteins could be utilized for human rejuvenation purposes.
Researchers are exploring various approaches to reset the epigenetic landscape and restore youthful gene expression patterns, but this can be a complex endeavor requiring many chemicals and may make its effects hard to predict on one cell at a time.
Scientists are turning to single-cell RNA-seq in order to gain a deeper understanding of how these chemicals work, by analyzing individual cell genomes for changes that could cause rejuvenation. This method could potentially allow us to find rejuvenation factors specific to certain cell types.
Scientists conducted an experiment in which they reduced levels of AP2A1 in senescent cells to accelerate senescence-related genetic markers expression and stop division. When researchers reduced AP2A1, these cells reverted back to more youthful states and stopped growing larger.
Results from this research demonstrate that six chemical cocktails can, within seven days, reset an epigenetic landscape and restore youthful expression without altering cell identity or altering gene code coding for cells. Their discovery offers hope for the future of cellular rejuvenation therapies that could potentially extend lifespan by slowing or even reversing aging processes.
