Scientists have discovered that certain combinations of molecular compounds can “reset” aging mice. The combination affects gene activity via epigenetics – which allows lifestyle and environmental influences to change how genes operate without actually changing their DNA sequence.
A team led by Izpisua Belmonte of the Salk Institute in La Jolla, California used four Yamanaka factors to rejuvenate fibroblasts and enhance mouse health. Their approach revived fibroblasts while improving overall wellbeing.
Yamanaka factors
Ten years ago, Kyoto University biologist Shinichi Nishizawa revolutionized biological research when he used a cocktail of four proteins to turn mature cells into stem cells called induced Pluripotent Stem Cells (iPSCs). These iPSCs can potentially form any cell in your body and thus revolutionized biomedical research. This groundbreaking discovery represents a major advance that could transform how we treat age-related diseases, leading to anti-ageing products and an exciting new line of drugs. Scientists are now using similar strategies to reverse aging in mice; ultimately this strategy could one day work its magic on humans as well. Researchers used Yamanaka factors to inject old mouse cells with an injection that resets them back to younger developmental states, producing striking results: reduced metabolic stress levels and an extended life span in animals.
Scientists first identified the Yamanaka factors in 2005, and since have isolated four essential genes: Oct3/4, Sox2, Klf4 and c-Myc. These genes control embryonic stem cell development as well as somatic cell transformation into iPSCs; when all four were overexpressed together they could transform mouse skin cells into iPSCs.
Reprogramming cells can be highly powerful, yet can result in the destruction of their identity, making them unsuitable for therapeutic uses. To circumvent this issue, scientists introduced a third gene into each cell that would suppress c-Myc and allow activation of other genes without losing cell identity. This allowed them to successfully activate other genes without altering or losing identity of cells.
Recent research by a team saw their team inject three genes into older mice and observe rejuvenated cells; as a result, these mice enjoyed better health and lived longer than unreprogrammed counterparts; but it remains uncertain whether this technique will work on human cells as well.
Next steps involve testing whether the genes can be used to reprogram cells from other parts of the body, leading to new therapies to combat aging and disease. A larger investigation would likely be necessary, yet such an advance could provide us with new approaches to fighting age and disease.
RNA molecule
Researchers have recently made the groundbreaking discovery that a specific mixture of molecular compounds can retrain cells to reverse effects of aging by undoing damage caused to RNA molecules. RNA serves as the biological macromolecule storing genetic information in living organisms as well as performing certain catalytic functions like ribozyme function; scientists believe RNA was once their main form of genetic storage and even performed some catalytic functions currently carried out by DNA-based enzymes.
In particular, they found that increasing levels of pre-mRNA can alter thousands of genes to exhibit activity similar to younger mice and reduce fat buildup and liver damage associated with aging. Furthermore, similar adjustments might also help alleviate other health problems related to ageing.
Young microbiome
Researchers may have discovered the Fountain of Youth after searching in vain: it could lie within our gut microbes! These microscopic organisms are responsible for our digestion as well as producing molecules which influence physiology and psychology, with recent research finding that transplanting young microbes into older mice could reverse age-related symptoms such as liver damage and cancer; the findings were published in Science Advances journal.
Researchers obtained eight young mice’ fecal samples and used FMT to repopulate their original microbiomes into aged C57BL/6J mice as part of an inflammageing experiment, with results showing significant attenuation of features associated with inflammageing such as increased pathogen recognition receptor (PRR) activity and serum levels of inflammatory mediators; they also saw evidence suggesting one specific group of bacteria species may be responsible for these results.
To isolate the taxa responsible, they used hierarchical clustering to classify bacterial families into four groups according to their abundance. Members of phylum Firmicutes such as Lachnospiraceae and Ruminococcaceae were strongly associated with restored phenotypes; furthermore they upregulated genes in muscles and skin tissue which resulted in improved grip strength and water retention. By comparison, those belonging to the phylum Bacteroidetes such as Muribaculaceae and Bacteroidetes were associated with poorer effects, including reduced grip strength and brain size.
Not only did the young microbiome reduce amyloid plaque formation and neurofibrillary tangle formation, it also suppressed expression of MDM2 gene associated with liver cancer development – suggesting that restoring microbiome may be an effective strategy against hepatocellular carcinoma and other forms of liver cancer.
Researchers are exploring the effects of young microbiomes on other aging-related conditions, including atherosclerosis and cardiovascular disease. If successful, their studies may lead to new therapies designed to prolong life with better health while lessening aging-related disorders.
Fecal transplants
Researchers used fecal transplants to exchange microbes between young and old mice. The transplants caused significant changes in recipient gut microbiota, altering how these microbes produced health-related metabolites as well as altering which genes/proteins they expressed – an effect which may also have significant ramifications for humans – suggesting that such transplants could potentially reverse age-related declines in our bodies.
The team performed two kinds of fecal transplants. One group received transplants from the jejunum (first section of small intestine), while another group received them from cecum which connects large and small intestines. Researchers observed that even just a single transplant can create regional mismatches that persisted for months post transplant.
As part of your procedure, you’ll be sedated before having an enema that should take only three to five minutes. A fecal transplant enema comes in a bag connected to a tube with a clamp; once in, they’ll apply lubricant inside your anus before inserting it and release its clamp before raising its bag to allow donor microbes into your colon.
After conducting their transplants, scientists closely observed their recipients’ blood and tissues. They discovered that transferring aged microbes to young mice increased inflammation within their central nervous system (CNS), retinal inflammation, cytokine signaling pathways, increased intestinal barrier permeability as well as loss of key functional proteins within the intestinal epithelium.
But this effect was not seen when researchers conducted heterochronic fecal transplants between young and older mice, whereby transplanted microbes from younger animals favored signature species such as Prevotella sp. MGM2 and L. intestinalis while aged ones favored species specific to their own age such as Muribaculaceae bacterium DSM103720 and Lachnospiraceae bacterium 10-1; suggesting age plays more of an impactful role when conducting heterochronic fecal transplants than type of microbes being transferred.