Scientists have successfully reversed aging in mice by altering changes to how DNA operates. This development is particularly significant as most experts agree that mutations of DNA play an essential role in aging processes.
Scientists used mixtures of four Yamanaka factors to restore cells back to a biologically younger state and rejuvenate mice by improving their ability to heal and regenerate tissue.
Epigenetics
The genetic code determines which genes are active or inactive in any cell, but various other mechanisms also affect which parts of DNA are bundled up or unspooled at any one time. Epigenetics enables cells to alter gene expression without altering the sequence itself – Conrad Waddington first used this term back in 1940s to describe molecular pathways that modulated genotype into phenotype. Today, scientific community generally refers to epigenetic changes as changes that do not involve changing DNA sequence, but instead affect how genes are regulated instead.
As scientists studied aging, they began to believe that something other than genetic mutations was the source of tissue and organ breakdown. Their list expanded to include other factors which worked with or instead of DNA changes and which affected how DNA segments are packed and unpacked – such as chromatin. Chromatin is an intricate set of physical structures which tightly coil DNA until genes are expressed – then changes to allow those genes into cells where they can be copied and translated into proteins.
Sinclair and his colleagues decided to investigate whether aging could be caused by malfunctions in the epigenetic system. To do this, they increased the rate at which breaks occurred in mice’s DNA without disturbing the coding regions of any genes, before giving long-term treatment with Yamanaka factors which alter epigenetic landscape and restore youthful states in chromatin structure.
Their findings, published online Jan. 12 in Cell, demonstrate how ICE therapy reversed signs of aging in mice. Furthermore, this reprogramming effect persisted longer when mice received Yamanaka factors for seven or 10 months as opposed to just a month.
Sinclair and his colleagues discovered that mammalian cells retain a backup copy of earlier epigenetic information that can be accessed to restore youthful gene expression patterns and chromatin structures. Next up for their research? Exploring how chemicals, when administered at specific dosage levels, reset chromatin states and rejuvenate tissues in real time.
MicroRNA
MicroRNAs are small RNA molecules that regulate gene expression. Their action has been seen to play an essential role in normal physiological processes like development and cell homeostasis; as well as disease states ranging from cancer to cardiovascular disease. Their expression has been extensively researched at both cell, tissue and organism levels and their expression is subject to internal and external forces that determine its expression levels.
Researchers published in Nature found a way to reverse aging in mice using microRNA injection. Mice who received injections lived longer, experienced less hair loss and were generally healthier – this proves their importance for normal physiology as well as being potential therapeutic targets.
To identify miRNAs that are regulated by age, the team used next-generation sequencing (NGS) on PBMCs from 3-, 8- and 12-month-old mice. They selected differentially expressed (DERs) miRNAs with at least a 2-fold change between time points; six miRNAs were identified in this way; their expression was confirmed using real-time qPCR, while western blotting analysis confirmed these expressions – all six miRNAs showed downregulation with age in older mice.
Overexpression of miR-34a has been linked with neuronal dysfunction, decreased learning and memory in Alzheimer mouse models and diet restrictions (calorie restriction increases its expression while simultaneously decreasing levels of mRNA encoding for synaptic proteins) (Agostini et al, 2011). MiR-34a expression is controlled by the p53 family member p73 which may act as an inhibitor against age related pathways.
MiRNAs were encased in lipid and administered via intravenous injection to the mice livers. Once administered, these miRNAs restored expression levels of targeted proteins as well as associated ageing genes in their livers.
Results of this study demonstrate that synthetic microRNA can significantly extend the lives of mice. Though its impact in humans remains uncertain, mice injected with microRNA lived longer and displayed fewer signs of aging than control mice injected without microRNA reverse therapy injection. Researchers believe this technology may also prove useful for treating human diseases related to aging.
Fecal Transplants
Fecal transplant, also known as “poop transplant”, is a medical procedure which transfers healthy stool samples to someone suffering from diseased colon. It is currently used as an effective means to treat Clostridium difficile (C. diff) infections.
An intact digestive tract contains millions of beneficial or harmless bacteria. Unfortunately, some medications such as antibiotics can kill many of these beneficial strains and allow bad ones such as C. diff to take control – leading to diarrhea and severe cramping symptoms.
Scientists have recently discovered that reincorporating friendly microbes back into an individual’s gut microbiome can restore balance to it and even alter their metabolism and behavior. Mice who were given transplanted fecal samples from young animals outlived control mice despite age differences; cholesterol levels also fell significantly more. Scientists saw changes in liver metabolism as well as changes in gene activity related to immune functions.
Fecal transplants may be administered via various means, including an enema or oral capsule. When receiving an enema, typically you’ll wear a hospital gown and lie on a table with your knees bent towards your chest; your healthcare provider will apply an anus lubricant before inserting a tube containing your transplant about five inches into the colon and release its clamp so its contents can flow in by gravity.
Studies published by the New England Journal of Medicine demonstrated that over 80% of people treated for C. diff with fecal transplants were completely cured within one month, leading researchers to explore ways they can replicate those results with human volunteers participating in other experiments.
FMT in this study that included both young and aged mice led to significant compositional shifts in recipient gut microbiota, including increased signature species such as Prevotella sp. MGM2, Leptostrema muridarum and Lachnospiraceae bacterium 10-1 as well as decreased levels of Enterorhabdus caecimuris, Muribaculaceae bacterium DSM103720, Akkermansia muciniphila (Figs 6A& B). However these shifts were less prominent among aged recipients (Figs 6A& B).
Stem Cells
Scientists are actively looking into ways to extend the lives of stem cells, which have the ability to produce specialized cells that form tissues and organs. While stem cells have limited starting material and reduced renewal capacity compared with mature cells, they offer promise as a renewable source for cell-based therapies.
Researchers have long understood that stem cells are susceptible to mutations that prevent cells from functioning normally and lead to disease. Over time, accumulation of mutations may cause cells in an individual tissue or entire body to lose their original identity and lead to age-related conditions.
Many studies have demonstrated that reducing mutation rates can significantly delay or reverse cellular aging; one team led by University of California Los Angeles researcher David Jones discovered that some adult stem cells accumulate too many lipids that impeded their ability to divide and generate new specialized cells, impairing division and generation of new specialized cells. They created an enzyme-targeting therapy to remove them, leading to a decrease in mutation rates of over 50% among stem cells studied by this team.
Scientists are discovering innovative techniques for delaying cell aging. One such technique, known as Induced Pluripotent Stem Cell Conversion (iPSC), has already shown promising results in treating certain diseases, and is being explored for use in transplant medicine.
One Cedars-Sinai study published in Advanced Science produced “youthful” immune cells by infusing human iPS cells with rejuvenating proteins known as Yamanaka factors. When introduced into mice with Alzheimer’s disease, these young immune cells protected their brains against neurodegeneration while improving memory tests.
Researchers from Stanford University School of Medicine used iPS-based study to reverse aging of skeletal muscle stem cells in old mice and restore their strength. Their team employed rejuvenating proteins to transform adult skeletal muscle cells into iPS-like stem cells that could then give rise to any tissue type within their bodies – this treatment provided recovery of strength as well as less inflammation than untreated mice.
