Researchers at Sinclair Lab have managed to successfully reprogram the genes of mice multiple times. Rejuvenating eyes, muscles and brains of these creatures while working towards resetting all body systems.
Their work proves it is possible to reverse aging without unleashing unchecked cell growth – an essential step toward rejuvenation.
How it works
For years, the predominant theory of aging has been that changes to DNA lead to it no longer functioning correctly, leading to cells losing their identities and eventually tissues and organs degrading. But a recent study suggests that not just mutations but also breakdowns in how genes are regulated may play a part. Reversing gene activity disruption may offer one way of combatting aging.
Researchers used damaged DNA mouse cells for this study and temporarily switched off an OSKM gene that regulates how often chromosomes unwind and rewind – this caused their cells to age quickly; when turned back on again however, the researchers were surprised to see that it actually reversed this trend – clearing away senescent cells as part of normal body functioning and rejuvenating tissues and organs for physical rejuvenation in mice.
Epigenetic changes – which govern how DNA is regulated – have now been shown to contribute independently to aging rather than just changes to genetic code itself, according to research published this month in Cell.
The team tested six chemical combinations that could reverse cellular aging in human and mouse skin cells using advanced, high-throughput cell-based assays capable of distinguishing young from old cells as well as senescent (cells that have stopped dividing) ones.
Scientists discovered that using five to seven compounds, including nicotinamide mononucleotide (NMN), which has been shown in preclinical trials to raise levels of NAD, they could restore DNA methylation patterns to those seen in younger mice. These patterns determine which genes are expressed and help regulate their activity, while scientists also conducted tests on whether the cocktail could restore telomere length, which decreases with each cell division; results were positive. However, clinical trials with humans will take several years before beginning, being assessed and being approved by the FDA if successful. Scientists not associated with this work have cautioned that suggestions of reversing aging in mice and monkeys to an near-perfect state is premature.
Results
Researchers conducted this study by inducing epigenetic changes by cutting up parts of DNA. This is different than mutations caused by damaged genes; rather it replicates what happens over time due to stress and other environmental factors. They then treated mice with drugs designed to reverse those epigenetic changes and rejuvenate them without altering the genetic code directly – resulting in much younger-looking mice and biomarkers of aging being restored back to normal levels.
Telomere shortening is one of the primary causes of how people age. Every time cells divide, their ends shorten gradually until they no longer function and trigger self-destruct mechanisms known as apoptosis or senescence that results in self-destruction resulting in wrinkles, hair loss and diminished cognitive abilities.
Scientists have developed various techniques for slowing or even stopping telomere shortening by manipulating cellular processes that regulate chromosome maintenance and repair. In one such study, researchers took advantage of a genetic mutation in mice which makes it easier to alter epigenetics – which refers to how genes turn on or off without altering genetic sequence – more effectively; they used this model mouse as evidence that epigenetic changes rather than genetic mutations cause aging.
Harvard researchers tested three of Yamanaka factors on cells from aged mice’s eyes. The team discovered that individually administered cocktails of chemicals delivered over less than a week restored vision and revived telomeres; as a result, these mice regained eyesight while also returning to more youthful cell states.
Researchers are currently devising ways of applying the same cocktail of chemical interventions to every cell in order to achieve whole-body rejuvenation. While any anti-ageing therapies derived from this research may take decades before being put through clinical trials in humans, its results indicate that affordable therapies for all-body rejuvenation may soon come into existence.
Conclusions
Researchers have finally proven, after 13 years of work, that degradation in how DNA is organized and regulated drives aging. This field is known as epigenetics; reverse this degradation to reverse it in mice. According to Cell magazine’s Jan. 12 findings, mice displaying signs of premature aging due to changes in their epigenetic code alone.
The team successfully made epigenetic changes in mice by administering a drug that caused temporary, fast-healing cuts at 20 sites on their DNA, mimicking the low-grade, ongoing breaks mammalian chromosomes experience every day from activities like breathing, exposure to sunlight and cosmic rays, contact with certain chemicals, etc. Over time these breaks cause the ends of chromosomes (also called telomeres) to shorten gradually over time; by reverseing this process they found they could extend telomere length significantly while slowing many hallmarks of aging symptoms significantly.
Once they had reversed signs of aging in mice, researchers wondered whether they could replicate it with human cells. So they developed chemical cocktails containing five to seven agents — such as medications already prescribed for various conditions, like valproic acid, tranylcypromine and pramipexole — which rejuvenated senescent (older, degenerating) cells without altering their identities – to rejuvenate senescent (older and degenerating) cells without erasing their identity and found that all six “epigenetic rejuvenation cocktails” reduced both biological and chronological aging as well as human senescent cells isolated from various chronic conditions like rheumatoid arthritis.
Rejuvenate Bio of San Diego has also reported similar success using different combinations of Yamanaka factors. Their mice lived an additional 18 weeks on average compared to 9 weeks in control animals, their cell senescence diminished significantly and patterns of DNA methylation (a reflection of how often cells divide) were closer to that seen among younger mice.
Though these new findings could bring us one step closer to an anti-aging remedy that restores youthful vitality, longevity experts remain cautious of jumping too quickly on board with these claims. Luigi Fontana, author of The Manual of Healthy Longevity & Wellbeing at University of Sydney’s Healthy Longevity & Wellness Program tells Fortune that it is too soon to say whether these chemicals can successfully reverse aging in humans.
Future directions
Harvard researchers recently reversed aging in mice, and are now hoping to apply their discoveries to human cells, thus treating various diseases, such as heart disease and dementia. But this will be no easy task: scientists must first create a chemical that mimics epigenetic changes without sparking unregulated cell growth; while also finding ways of increasing levels of NAD+ (nicotinamide adenine dinucleotide), which tends to accumulate more readily among younger cells.
Scientists had long held that changes to a cell’s DNA sequence were the main contributor to its aging. A new study offers evidence for another possibility: epigenetics. Epigenetics refers to how environmental conditions influence gene activity – including epigenetic drugs that target these signals could actually slow or reverse aging processes. The research is published in Cell and is already showing promising results: drug therapies targeting these signals could reverse or even stop their impact on cells’ aging processes.
Harvard researchers performed extensive screening of thousands of molecules to find ones that, combined, reversed cellular senescence and rejuvenated both human and mouse skin cells. By employing advanced assays that differentiate young from old cells, the researchers were able to identify six chemical concoctions which visibly reversed aging in both mice and humans.
All six chemicals targeted epigenetic processes involved in cellular senescence, and all six compounds successfully decreased biological and chronological aging below those seen in non-senescent cells. Transcriptomic analysis indicated that all six cocktails caused similar epigenetic reprogramming processes, suggesting they target similar pathways.
Thomas Rando, a molecular biologist from the Broad Institute who wasn’t involved with this study, lauded its sophistication and thoroughness but pointed out that its team used dramatic DNA breaks to trigger epigenetic changes which might also cause other effects than just aging – making it hard to prove these specific modifications are truly responsible for aging.
Still, this work provides the basis for future studies that examine whether these same chemical compounds can reduce cell aging in human cells and lead to drugs that slow or reverse various diseases. Furthermore, it suggests a genetic alternative to gene therapy that could allow for lower costs and quicker timelines for its implementation.
