Ten years after Shinya Yamanaka of Kyoto University’s discovery of a mix of proteins that remodel adult cells into flexible stem cells earned him a share of the Nobel Prize, two groups have argued that the proteins can reverse aging in entire creatures, potentially even humans in the future. One biotech lab managed to somewhat increase the lifespan of elderly mice by using gene therapy to introduce certain “Yamanaka variables.” Another group used a similar approach to turn back the effects of aging in genetically modified mice.
The first study
The Yamanaka factors in both cases appear to have reverted some of the epigenomes of the animals to a more youthful state. The epigenome is a set of chemical changes in DNA and proteins that govern gene activity. Scientists who were not engaged in the study, however, say talk of turning back the hands of time is premature. Epigenetic changes occur with age, but these experiments use reprogramming factors to undo them.
Multiple research teams have revealed that genetically altered mice that start expressing Yamanaka factors in adulthood are able to reverse some of the effects of aging. The San Diego firm Rejuvenate Bio injected adeno-associated viruses (AAVs) with genes for three of the components, collectively known as OSK, into aged mice to test a strategy that could lead to a more practical treatment for people.
The business disclosed these findings in a preprint on bioRxiv last month, noting that the median survival time for these mice increased from 9 to 18 weeks. They also reverted to several of the DNA methylation patterns found in younger animals. Despite the fact that some research indicates Yamanaka factors may promote cancer, Rejuvenate’s chief scientific officer and co-founder, Noah Davidsohn, claims the company has seen no observable detrimental effects in mice treated with the gene therapy.
The second study
The second study came from a group led by geneticist David Sinclair of Harvard Medical School. Sinclair has supported various controversial antiaging therapies during the past two decades. Sinclair’s group wanted to put his idea that accumulated damage to our DNA and RNA causes aging to the test. According to him, these identifiers are degraded by the cell’s DNA repair systems, which work continuously throughout an individual’s lifespan to repair DNA cuts and other damage.
In order to put this idea to the test in mammals, the scientists genetically altered a strain of mice to produce an enzyme that, when combined with a certain medication, causes the mice to sustain DNA breaks at 20 different locations in the genome, which are then efficiently repaired. Gene expression and DNA methylation patterns in cells were dramatically altered afterward, corroborated by Sinclair’s idea. The mice developed an epigenetic profile characteristic of older animals, and they became sicker as a result. After only a few weeks, they began to bald and lose their colour, and after a few months, they displayed several symptoms of weakness and accelerated tissue aging.
As Sinclair’s team previously demonstrated that AAVs containing OSK genes might cure loss of vision in aging animals, the researchers injected some of these apparently aged mice with the vectors to test the reversibility of the epigenetic degradation. Results from studies on the mice’s muscles, kidneys, and retinas indicate that the cocktail was successful in reversing some of the epigenetic modifications brought on by the DNA breaks. Sinclair says the results lend credence to the concept of epigenome-targeting therapy for aging in humans and suggest a mechanism to manipulate the aging process in animals.
Wolf Reik, head of the Altos Cambridge Institute of Science (established last year by rejuvenation-focused startup Altos Labs), complimented the depth and thoroughness of the Harvard team’s study but argued that the researchers’ indirect method of creating epigenetic alterations with significant DNA breaks that could have other impacts makes it challenging to prove that these changes are what cause aging. Furthermore, according to Albert Einstein College of Medicine geneticist Jan Vijg, it is not known how accurately mice with induced DNA breaks represent naturally aged animals.
Both articles found only modest benefits from OSK treatment, with one finding a modest increase in life expectancy and the other finding a partial reversal of artificially created symptoms, prompting him and others to emphasize that aging is a complicated process with several contributing elements.
However, the goal of both organizations is to have their research implemented in clinical settings eventually. Rejuvenate is currently investigating the treatment’s action mechanisms and making adjustments to its administration and chemical make-up.
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