Scientists have long held that mutations to DNA were one of the leading factors contributing to aging, but new research indicates that changes in how genes are activated could also play a part.
Sinclair’s laboratory genetically engineered mice with shortened telomeres to see whether or not cells would rejuvenate when exposed for short duration to Yamanaka factors. Once they determined this would happen, they used harmless viruses to deliver these factors directly to retinal ganglion cells located behind each eyeball and to see which retinal ganglion cells responded best.
Epigenetics
Epigenetics is the study of chemical modifications to DNA that do not alter its sequence, but instead regulate how genes are turned on or off. Such modifications include changes to chromatin structure, DNA methylation and expression of non-coding RNA that control gene expression during development, tissue maintenance and responding to environmental cues throughout an organism’s lifetime (Kane and Sinclair 2019).
Epigenetics has recently become a buzzword across all fields of medicine, as its applications help explain the relationship between an individual’s genetic background, their environment, and aging. Furthermore, epigenetics can identify biomarkers for therapeutic intervention as well as provide new treatments.
Studies are increasingly showing that mammals maintain an epigenetic memory bank that stores in chromatin (protein-DNA structures that encase DNA nuclei). This epigenetic information influences whether genes are expressed or not and can even be reversed over time.
Researchers used to think that epigenetic information would be permanently erased during the formation of sperm and egg cells and not passed along to subsequent generations, however recent studies have disproved this belief. Damage to chromosomes can have similar aging-like effects; certain cell injuries result in loss of epigenetic tags which regulate gene expression; these changes appear to accelerate aging as well as lead to age-related diseases.
Scientists recently utilized a genetically engineered mouse called an ICE mouse in this latest research project to test their abilities to manipulate its epigenetics and reverse aging effects. These mice are known for having special resistance against the effects of aging due to an enzyme mutation which prevents it from demethylating DNA, leading to its return back into its original state.
Researchers using ICE mice demonstrated they could significantly extend the average lifespan of these animals by reprogramming their chromatin to an earlier state using Oct4, Sox2, and Klf4 genes expressed into retinal ganglion cells of their eyes – this restored youthful markings, transcriptomes, axon regeneration in these eyes of these mice, while also preventing age-related changes that lead to visual loss due to glaucoma.
Stem cells
Stem cells are regenerative cells found throughout the body that replenish organ and tissue cells to aid healing wounds and combat illness. Furthermore, stem cells can transform into more specialized forms, such as blood and bone cells that better fulfill their duties.
Scientists have recently made groundbreaking discoveries regarding stem cells’ abilities to reverse and slow aging in mice. As a result, this has spurred further investigation of human stem cell therapies; with some believing human stem cells could be reprogrammed so as to mimic younger versions more closely and reverse or extend life span in this way.
Reprogramming involves unwinding a stem cell’s “clock.” Researchers have discovered that cells from older people and animals exhibit distinct chemical patterns along their DNA from those from younger people and animals; these differences are known as epigenetic markers. Researchers also discovered that adding four reprogramming proteins known as Yamanaka factors can reset these epigenetic markers back to their original positions and transform adult cells back into stem cells.
Once returned to its stem cell state, it can proliferate and differentiate into various cell types – similar to how infants develop during infancy. Scientists have also discovered that stem cells’ capacity for differentiation does not depend on genetic code – they can differentiate into skin, muscle and brain cells among others.
Another study revealed that stem cell regeneration decreases with age, suggesting one cause of aging. Furthermore, its susceptibility to genotoxic stressors might decrease over time as well.
Scientists have also observed that as mice age, the number of hematopoietic stem cells decrease in their bone marrow. This discovery is significant since lack of these hematologic stem cells is often linked with diseases like aplastic anemia and complete bone marrow failure; allogeneic bone marrow transplantation relies heavily on this method due to rapid engraftment with allogeneic donors.
Reprogramming
Reprogramming is an effective method to reset the epigenetic clock and rejuvenate cells. Reprogramming can be completed in two different ways – complete and partial. Complete reprogramming involves turning differentiated cells into pluripotent stem cells; partial reprogramming achieves epigenetic rejuvenation without this transformation (Basu and Tiwari 2023a). Researchers have demonstrated how reprogramming can prevent age-related diseases by altering gene expression or changing cell functions of specific types such as neurons or vascular smooth muscle cells
Recent research from the Salk Institute has demonstrated how reprogramming can reverse the effects of aging in mice. They treated genetically predisposed to rapid aging with Yamanaka factors to erase genetic markers associated with rapid aging; this process, known as epigenetic rejuvenation, may revolutionize anti-ageing research.
Researchers have successfully reprogrammed somatic cells to pluripotency in vitro, but doing so in vivo remains challenging. Reprogramming requires expression of certain genes required for pluripotency – but their expression has been linked with tumor development and teratoma formation in animals. To address this challenge, scientists developed piggyBac (PB), a non-viral vector system which allows expression of pluripotency genes without risking integration into host genomes.
The PB system employs a small molecule to activate the reprogramming process by inducing double-strand breaks in the genome – similar to how viruses cause cell reprogramming. As well as initiating this process, PB has also proven effective against teratomas and other cancers in mice.
Salk Institute scientists conducted their study by injecting mice with genetic mutations that cause them to age faster than normal with the PB-Yamanaka factor combination, then over the next five weeks continuously expressing Yamanaka factors for five weeks continuously, these mice displayed less signs of aging and lived longer than untreated counterparts.
Notably, however, these findings are preliminary and require further validation. Furthermore, it remains unknown if Yamanaka factors can actually reverse cellular aging in humans – this would represent a tremendous advancement towards increasing healthspan while decreasing risks related to age-related illnesses.
Injections
Injections are a popular means of giving substances to mice. They can be used to administer medications, compounds and test products effectively while minimizing the risk of injection site infections; this is especially beneficial if repeated administration of the same compound occurs. It is essential that each injection be given using a separate needle; this will both limit spread of infection as well as provide less discomfort to your animal.
An innovative technique of injecting substances directly into mice could reverse the signs of ageing. It involves using a special virus to target specific brain cells, then deliver rejuvenating Yamanaka factors directly to these cells via an injection. According to scientists, this may increase lifespan up to 50%; they’re still researching its exact mechanisms though.
Researchers have previously demonstrated that transfering plasma from younger animals to elderly mice can reverse some of the typical signs of aging. In this current study, long-lived CBA/Ca mice were repeatedly injected with serum from young or aging mice and observed for changes in health parameters and longevity – this process was carried out blindly to ensure results weren’t caused by other variables.
Treatment was administered to aging mice using intravenous or intraperitoneal injections of heparinized saline; similarly, control mice received similar treatments via similar routes. The experiment was managed by one operator blind to any treatment group being administered; injections were given every two weeks over 16 consecutive months with 30-gauge needles used prior to each injection to minimize injury risk.
After treatment with hESC-Exos-injected mice, they lived longer lives than their controls and showed less signs of aging, such as reduced expression of g-H2AX as an indicator of DNA damage and higher levels of H3K9me3 which promotes genomic stability. Furthermore, these mice displayed stronger immune systems capable of combating viruses more efficiently.
Similar results were achieved when injecting this same antibody directly into the skin of older mice, rejuvenating their immune systems significantly and suggesting that similar treatments could enhance human health as we age by reinvigorating blood stem cells and increasing their ability to fight infections.
